A neglected problem of developing countries: Noncystic ﬁ brosis bronchiectasis

: BACKGROUND: Bronchiectasis has been de ﬁ ned as the abnormal and permanent dilation of the bronchi. It is still an important problem in many developing countries. AIM: The aim of this study was to identify the chacteristics and underlying etiology of children followed with the diagnosis of noncystic ﬁ brosis bronchiectasis. MATERIALS AND METHODS: Children with bronchiectasis con ﬁ rmed with high-resolution computed tomography were enrolled into the study. The data of the patients, including symptoms of the disease, age at the onset of symptoms, ﬁ ndings of physical examination, labrotory investigations performed in order to identify the etiology of bronchiectasis, etiology of bronchiectasis if found, radiologic ﬁ ndings and treatment modalities were noted. RESULTS: Sixty-six children between 1 and 17 years were included in the study retrospectively. Forty-four of them were males (66.7%) and 22 (33.3%) were females. The most common presenting symptoms were cough (100%) and sputum expectoration (50%). An underlying etiology was identi ﬁ ed in 44 (66.7%) of the study subjects. The four most common underlying causes were found as infections (21.2%), asthma (16.7%), aspiration syndromes and/or gastroesophageal re ﬂ ux disease (9.1%) and immunode ﬁ ciency syndromes (7.6%), respectively. CONCLUSION: Identifying an underlying etiology will have a signi ﬁ cant effect on the management of noncystic ﬁ brosis bronchiectasis. De ﬁ ning the cause of bronchiectasis may also decrease its incidence, progression and complications.

B ronchiectasis is a progressive condition characterized by irreversible dilatation of the airways. This disease is considered as an orphan either because it is rare or because it is more prevalent in developing countries than in the developed world. Bronchiectasis unrelated to cystic fibrosis was termed an "orphan disease". [1,2] The prevalence of bronchiectasis is not well characterized. Altough improved sanitation and nutrition, introduction of childhood immunization, particularly against pertussis and measles, and the early and frequent use of antibiotics resulted in a decline in the prevalence of bronchiectasis, [3] the disease is still a problem in developing countries like our country, Turkey. [4][5][6] As bronchiectasis is now rare in many developed countries, this has lead to limited research and treatment development on this condition. Over the past years, there have been relatively few studies that have assessed the clinical features of bronchiectasis in childhood.
The aim of this study was to determine the characteristics of children with noncystic fi brosis bronchiectasis and to evaluate the etiologic factors that cause the disease.

Materials and Methods
Children followed with the diagnosis of bronchiectasis at the Dokuz Eylul University Hospital Pediatric Allergy Department in Izmir, Turkey, between 2003 and 2008 were included in the study retrospectively. The diagnosis of bronchiectasis was confi rmed radiologically by high-resolution computed tomography (HRCT) for every patient. The following information was found from the patient's file: age at the onset of symptoms, symptoms of the disease such as sputum production, cough, hemoptysis, failure to thrive, history of childhood respiratory infections, history of recurrent wheezing and family history of chronic respiratory disorders. The fi ndings of physical examination, including oscultation fi ndings and presence of clubbing and chest deformity, were also noted. Because HRCT is accepted as the gold standard for diagnosis of bronchiectasis, all patients in the study group were selected from children in whom the diagnosis was confi rmed by HRCT.
Sweat chloride tests were performed in all patients in order to exclude cystic fi brosis. In the selected patients, genetic mutation analysis for cystic fi brosis was also performed. Serum levels of immunoglobulin (Ig) A, subgroups and total G, M, E and alfa-1 antitrypsine were obtained. All patients aged more than 6 years performed pulmonary function tests with spirometry. Flexible fi beroptic broncoscopy was performed in selected cases (15 of the patients) in whom the etiology of bronchiectasis could not be found in order to exclude foreign body aspiration and to obtain bronchoalveolar lavage fl uide for culture. Foreign body aspiration was not detected in our study group.
Patients who had symptoms of swallowing problems and gastroesophageal refl ux were investigated by barium fl uoroscopy or/and gastroesophagial refl ux scintiscans.
Primary ciliary dyskinesia was diagnosed with history of recurrent sinusitis, otitis, pneumonias, presence of situs inversus totalis in two patients, and their ciliary ultrastructures were also evaulated by electron microscopy on nasal epithelial biopsies.
Patients were followed-up with medical treatments including antibiotic use in exacerbations, mucolytics, bronchodilators and chest physiotherapy. Inhaled steroids were given to patients who had bronchial hyperreactivity and positive bronchodilator reversibility. Surgery (lobectomy) was performed in only four patients who had recurrent lower respiratory tract infections and localized disease.

Statistical analysis
The SPSS Inc., 233 S. Wacker Drive, 11 th Floor, Chicago, IL 60606-6307, 11.0 statistical package for Windows was used throughout the study. Results were shown as mean±SD.

Results
Sixty-six children who had diagnosis of bronchiectasis confi rmed with HRCT were retrospectively included in our study. Forty-four of them were males (66.7 %) and 22 (33.3 %) of them were females. Mean age of the patients was 9.20 ± 4.38 years (range 1-17 years) at presentation and they had been symptomatic for 4.30 ± 4.14 years (range 0.5-15 years). The most common presenting symptom was cough (100%) followed by sputum expectoration (50%). Hemoptysis history was detected in only three (4.5%) of our patients. Symptom history at the time of diagnosis in our study group is given in Table 1.
On physical examination, cracles were detected in 72.7% and ronchi in 15.1% of the children. Clubbing was present in 22.7% of the study group. The physical examination fi ndings of our study population are summarized in Table 2.
Forty-two (63.6%) of the children were able to do pulmonary function tests. 85.7% of them had abnormal function tests. Fourteen patients (33.3%) had obstructive lung changes, fi ve (11.9%) had restrictive lung changes and 17 (40.5%) had combined obstructive and restrictive lung changes.
An underlying etiology was identifi ed in 44 (66.7%) of our patients [ Table 3]. The four most common underlying etiologies in our patients were found as infections (21.2%), asthma (16.7%), aspiration syndromes (9.1%) and immunodefi ciency syndromes (7.6%), respectively. In five immunodeficient children with bronchiectasis, defi ciency of Ig A, defi ciency of Ig G2, defi ciency of both Ig A and Ig G2, defi ciency of Ig M and common variable immune defi ciency were detected, respectively.
In the radiologic fi ndings of the patients (CT fi ndings), 42 children (63.6%) had only one affected lobe, most commonly the left lower lobe (42.4%) [ Table 4]. Thirteen of the cases (19.7%) had two lobes involved, whereas 11 patients (16.7%) had three or more lobes involved.    The treatment modalities used by children include bronchodilators (16.7%), mucolytics (24.2%), inhaled steroids (25.2%), combination of bronchodilators and mucolytics (16.7%) and chest physiotherapy (50%). Ten of the patients (15.2%) were not using any medical treatments. Surgery (lobectomy) was performed in only four patients (6%) who had recurrent pneumonias and localized disease. One of these patients who had lobectomy performed also had a history of recurrent hemoptysis.

Discussion
Bronchiectasis was first described as ''production of fetid sputum along with bronchial dilatation''. [7] It is a pathological description of a disease process that has many possible causes. In a previous large series, the majority of the cases were due to extrinsic factors, especially childhood respiratory infections, as the cause of permanent bronchial damage. [8] In a study by Eastham et al, [9] previous respiratory tract infection was found as the most common cause of 93 noncystic fi brosis bronchiectasis cases. Immunodeficiency and bronchiolitis oblierans were the second and third most common reported causes in this study. [9] Karakoc et al, evaulated 23 children with bronchiectasis from Adana, Turkey, and they reported that infections, cystic fi brosis and immunodefi ciency syndromes were the most common causes of bronchiectasis. [4] Karadag et al, evaluated 111 children and found postinfectious etiology and immunodefi ciencies as the most common causes of noncystic fi brosis bronchiectasis. [5] The etiologic factors underlying childhood bronchiectasis were also investigated with another study from Ankara, and the authors of this study concluded that infections, asthma and primary immunodefi ciency syndromes were the three most common causes of noncystic fi brosis bronchiectasis. [6] In the recent years, with early immunization and the widespread use of antibiotics in childhood, postinfectious etiology is likely to be less relevant, especially in developed countries. Based on this information, investigations of intrinsic defects or noninfective extrinsic causes that predispose to bronchial infl ammation or infection in more developed areas can be suggested. [8] In our study, we found infections, asthma, aspiration syndromes and immunodefi ciency syndromes as the most common causes of bronchiectasis in Izmir. Izmir is the third largest city of Turkey, which has a population of approximately 3.5 million people, located in the western part of the country. Although the socioeconomic status varies widely, most of the people live under hygienic conditions and childhood immunization programmes are well organized. We believe that the more urbanized features of the city of Izmir can explain the lower propotion of infectious etiology in our study group. Bronchial asthma was found as the second common cause of noncystic fi brosis bronchiectasis in this study. This may be due to the underdiagnosis of asthma in children with only cough who had no wheeze or pulmonary oscultation fi ndings. We believe that untreated bronchial infl ammation may lead to bronchiectasis in this group of patients. Aspiration syndromes and gastroesophageal refl ux disease were found as the third common cause of bronchiectasis in the current study. In six patients (9.1%), aspiration syndromes and/or gastroesophageal refl ux disease were detected as the cause of bronchiectasis in this study. Two of these patients were mentally retarded, and it was learnt that thay were hopitalized many times because of aspiration pneumonias. The remaining four children without neurological defects were diagnosed as with gastroesophageal refl ux disease. There is evidence that gastroesophageal refl ux disease in children without neurological defects is associated with a several-fold increase in the risk of sinusitis, laryngitis, asthma, pneumonia and also bronchiectasis. [10] The majority of the clinical studies reported that bronchiectasis patients had symptoms in the preschool years. [7] In 74.2% of our study group, clinical symptoms had begun before the age of 5 years. Cough and sputum production were the major symptoms in our study, which is consistent with other reports in the literature. [3,7] Hemoptysis is a frequent symptom in adult bronchiectasis patients, but it is relatively uncommon in children. [11] Only three patients (4.5 %) in our study group suffered from hemoptysis. One of these patients who had recurrent massive hemoptysis and pneumonias had undergone surgery.
In the diagnosis of bronchiectasis, chest radiographs usually have nonspecific findings of increased lung markings. [12] HRCT has proven to be a reliable and noninvasive method for the assessment of bronchiectasis. [13,14] HRCT can accurately diagnose bronchiectasis, localize and describe areas of parenchymal and bronchiolar abnormality and also mucus plugging. [14,15] HRCT scanning is the method used in all cases in our study group in order to diagnose bronchiectasis.
Bronchiectasis is most commonly seen in the lower lobes, especially in the left lower lobe. The upper lobes are affected less frequently, except in cystic fi brosis, probably because of the faciliated mucociliary clearance by gravity. [4,6] In our study group, after the left lower lobe (42.4%), right middle lobe (25.8%), lingula (25.8%) and right lower lobes (22.7%) were the the other more affected three lobes, respectively.
In conclusion, we emphasized that identification of the underlying cause is the most important step in the treatment and prevention of bronchiectasis. Earlier diagnosis of even milder disease will also change the outcomes and decrease the morbidity and mortality of disease. Research needs urgently to be encouraged and bronchiectasis should not be an orphan any more. We were able to determine the etiology of bronchiectasis in 66.7% of our patients and infections, asthma, aspiration and immunodefi ciency syndromes were found to be the most common causes of noncystic fi brosis bronchiectasis in our study population.