MUHAMMAD H. MAEBED, M.D.*; DINA A. EZZAT, M.D.*; ABEER S. MUHAMMAD, M.D.**; OSAMA LAMEI, M.D.*** and ELHAM ABDUL MAGEED, M.Sc.*

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1 Med. J. Cairo Univ., Vol. 78, No. 2, June: 89-97, Study of Airway Remodeling in Pediatric Patients with Bronchial Asthma Using Chest High Resolution Computed Tomography (HRCT) as a Non Invasive Technique MUHAMMAD H. MAEBED, M.D.*; DINA A. EZZAT, M.D.*; ABEER S. MUHAMMAD, M.D.**; OSAMA LAMEI, M.D.*** and ELHAM ABDUL MAGEED, M.Sc.* The Departments of Pediatrics*, Chest** and Radiology***, Faculty of Medicine, Beni-Sueif University. Abstract Background: "Airway remodeling" in bronchial asthma refers to the structural changes that occur in conjunction with, or because of, chronic airway inflammation in asthma. Airway remodeling is induced by cytokines and mediators produced in chronic allergic airway inflammation. Regulation of the repair and remodeling process is not well established, but both the process of repair and its regulation are likely to be key events in explaining the persistent nature of the disease and limitations to a therapeutic response. Recent studies have shown that airway remodeling is present in children as early as 3 years old, indicating processes that begin early in the development of asthma and occur in parallel with, or may be obligatory for, the establishment of persistent inflammation. The endbronchial biopsies (EB) are currently the gold standard of airway remodeling studies. However, they have their limitations. Evidence is accumulating to suggest that HRCT scans are useful for evaluation of the proximal and distal airways in patients with asthma. Objectives: The present study aims at investigating the airway remodeling in pediatric patients with bronchial asthma using chest high resolution computed tomography as a non invasive technique. Patients and Methods: Forty one subjects above 6 years old were included in this study. They included 26 bronchial asthma patients, (11 males and 15 females). Their mean age was (8.08± 1.87) and 15 age matched healthy controls, their mean age was (8.33 ±2.02) (8 males and 7 females) Asthmatic patients were classified into 3 subgroups according to the severity of their asthma. All were subjected to: Spirometric measurements (PFTs.) including FVC, FEV!, FEF 25,50,75 & PEF, and Chest high resolution computed tomography (HRCT) scan. Results: All pulmonary function tests of the asthmatic patients were significantly lower than that of the control ( p- value <0.001). There was a statistical significant difference concerning FEV1, FEF25, FEF50 among different groups of asthma; lower values among severe asthmatics. 100% of Correspondence to: Dr. Muhammad H. Maebed, The Department of Pediatrics, Faculty of Medicine, Beni-Sueif University. severe patients, 25% of moderate asthma patients & 18.18% of mild asthma showed abnormal HRCT findings suggesting start of airway remodeling. No significant correlation was found between these findings of and either FEV 1 or FEV1/FVC. Conclusion: It is possible to assess the airway remodeling by high-resolution computed tomography (HRCT) of the thorax. This technique allows the study of the airway lumen and wall dimensions without invasive techniques. Early intervention with inhaled corticosteroids (ICS) before serious pathological changes occur, is expected to prevent the development of remodeling and improve asthma outcome. Key Words: Bronchial asthma Airway remodeling HRCT. Introduction ASTHMA is a common chronic disorder of the airways that is complex and characterized by variable and recurring symptoms, airflow obstruction, bronchial hyperresponsiveness, and an underlying inflammation [1]. Certain studies had evaluated asthma prevalence in Egypt; El-Hefny, et al. [2] found that asthma prevalence was 8.2% in children 3-15 years, while Georgy, et al. [3] found that in years-old in schools in Cairo, The overall prevalence of wheeze ever, wheeze during the last year and physiciandiagnosed asthma were 26.5% (697 out of 2,631), 14.7% (379 out of 2,570) and 9.4% (246 out of 2,609), respectively. In addition to the presence of inflammatory cells in the airway, the airway of patients with asthma exhibit varying levels of structural changes termed airway remodeling [4]. 89

2 90 Study of Airway Remodeling in Pediatric Patients with Bronchial Asthma This term refers to structural changes of the surface of the airway, induced by mediators released by the activated inflammatory cells, with shedding of epitheliocyte sheets in the bronchial lumen, and complex mechanisms, only partially understood, leading to tissue repair [5]. Until recently, airway remodeling has been considered to be a secondary phenomenon, developing later in the disease process as a consequence of persistent inflammation. The presence of airway inflammation and remodeling in children with asthma indicate that the remodeling process begins early in the disease process of asthma and occurs synchronously in ongoing and repeated airway inflammation rather than as a consequence of airway inflammation [6]. Although, its clinical consequences are still controversial, current evidence suggests that airway remodeling can be responsible for persistent increases in airway responsiveness and mucus production, variable or fixed airflow limitation, and perhaps even decline in pulmonary function [7]. Studies reported evidence of airway remodeling in asthmatic children as early as three years of age [8]. So, Airway remodeling may occur early in childhood and is considered a key factor for longterm prognosis [9]. Endobronchial biopsies are currently the gold standard of airway remodeling studies Jeffery, et [10]. However, in addition to requiring an invasive procedure that is not always easily repeatable, they have their limitations. Bronchial biopsies are frequently taken from large proximal airways in asthma that might not reflect the site of disease activity and airway remodeling starts in small airways in asthma [11]. Imaging techniques such as high-resolution computed tomography (HRCT) scanning may help to assess airway wall thickness, but they do not, as yet, provide information on the various constituents of the airways, and radiation exposure limits their frequency of use De Jong, et al. [12]. Aim of work: The aim of this work is to assess the airway remodeling in pediatric patients with bronchial asthma using the chest high resolution computed tomography (HRCT) as a non invasive technique. Patients and Methods This study was conducted in the departments of Pediatrics, Chest and Radiology, Faculty of Medicine, Beni Suef University. Forty one subjects above 6 years old were included in this study. They included 26 bronchial asthma patients, (11 males and 15 females). Their mean age was (8.08 ± 1.87) and 15 age matched healthy controls, their mean age was (8.33 ±2.02) (8 males and 7 females). Patients were recruited from the pediatric outpatient clinic of Beni Suef University hospital. Patients who had any evidence of other concurrent pulmonary or systemic disease or of any upper or lower respiratory tract infection were excluded from the study. Asthma was defined according to American Thoracic Society (ATS) criteria [13]. The subjects included two groups: Group (A): Included 26 children with bronchial asthma. Group (B): Included 15 age matched healthy control. Group (A) asthmatic patients (n=26) were classified into 3 subgroups according to the severity of their asthma according to Global initiative of asthma (GINA) classification [14]. Group A-1: (Patients with mild persistent asthma, n=11) consisted of patients who had symptoms more than once a week but less than once a day, had nocturnal symptoms more often than twice a month, who were using bronchodilators with or without inhaled steroids intermittently and who had FEV 1 values 80% of predicted value. Group A-2: (Patients with moderate asthma, n=8) consisted of patients who had symptoms daily, had nocturnal symptoms more frequently than once a week, who needed bronchodilators daily, who were on moderate or high doses of inhaled steroids and whose had FEV 1 were 60 to 80%. Group A-3: (Patients with severe asthma, n=7) consisted of patients who had daily symptoms, frequent nocturnal attacks, needed daily high doses of inhaled steroids and long acting bronchodilators and who had FEV 1 values <60% [14]. All subjects were given information about the study and informed consent were taken from all participants, caregivers.

3 Muhammad H. Maebed, et al. 91 Clinical and demographic data including information on age, sex, duration of asthma, frequency of asthma exacerbations, admission to hospital or to an intensive care unit, and current treatment were obtained using a standardized interview form. All patients and controls were subjected to the following: 1- Full history taking and clinical examination. 2- Spirometric measurements (PFTs.). 3- Chest high resolution computed tomography (HRCT) scan. Basal spirometric measurements were done for the control group (Group A). The spirometric measurements for the asthmatic patients (Group B) were done in-between the attacks while their asthma attacks were controlled and they were free of symptoms two weeks before the the spirometric measurements and high resolution computed tomography scans were done. Pulmonary function tests: Flow-volume spirometry was performed to all patients and controls using JAEGER master screen- 105, with the subject seated using the ATS 1994 criteria for performing the manoeuvre [15]. Nose clips and disposable bacterial filters were used. At least-three technically acceptable measurements were performed with the maximum of five efforts the highest was recorded. Well trained resident and a nurse preformed the measurement. The calibration of the spirometer was checked with 3 litres. Calibration syringe once a day and when the spirometer software requested calibration. Baseline data including spirometric findings for all subjects and bronchodilator response were obtained for all asthma patients who showed obstructive readings but all show improvement of more than 12% which means that all patients were non obstructive. The lung function results were expressed a percentage for height using the data of Rosenthal, et al. [16]. Forced vital capacity (FVC) with timed measurements of the expiratory air flow as forced expiratory volume in one second was expressed as an absolute volume. The forced expiratory volume in 1 second (FEV 1) was expressed as a percent of the predicted value or as a proportion of the forced vital capacity (FVC) or FEV1/FVC. Forced Expiratory Flow (FEF) at 25,50 and 75% is the average flow (or speed) of air coming out of the lung during the different portions of the expiration. Peak Expiratory Flow (PEF) is the maximal flow (or speed) achieved during the maximally forced expiration initiated at full inspiration, measured in liters per minute [17]. High resolution computed tomography (HRCT): HRCT scans of the chest were performed with a sanner [Simen s Somatom Balance "120kv, 100mAs] at 10-intervals from the apex of the lung to the diaphragm using 1mm of collimation. All subjects underwent scanning in the supine position at full inspiration. The scanning time ranged from 1.5 to 3s. Scan images were reconstructed using a high spatial frequency (bone) algorithm and a 512 x 512 matrix. Images were photographed using window settings optimized for pediatric lungs (centre: -500H.U, width: 1500H.U.). All computed tomography scans were analyzed by a radiologist who had no knowledge about the subjects. CT scans were evaluated for evidence of the following abnormalities: Mucoid impactions, bronchial wall thickening, bronchiectasis, emphysema, centrilobular opacities, thick linear opacities and focal hyperlucency. Bronchial wall thickening was considered to be present when bronchi or bronchioles were seen in the peripheral parts of the lungs [18]. Mucoid impactions in dilated bronchi were recognized as beaded densities, gloved-finger and nodular or oval-shaped densities seen on a few consecutive scans having a segmental distribution and being greater in diameter than the adjacent pulmonary arteries. Small airway and lung parenchyma abnormalities included small centrilobular opacities, focal hyperlucency, thick linear opacities and emphysema. Nonspecific low lung attenuation areas (focal hyperlucency) were defined as areas of decreased lung density with reduction in size and number of the small pulmonary vessels corresponding to oligemia [19]. Bronchial wall thickening was reported as the most prominent abnormality in CT scans of asthmatics. It was the main feature of large airway remodeling in children. Focal hyperlucency was the main feature of small airway remodeling in children [20]. Statistical methods: Data were statistically described in terms of range, mean ± standard deviation ( ± SD), frequencies (number of cases) and relative frequencies (percentages) when appropriate. Comparison of

4 92 Study of Airway Remodeling in Pediatric Patients with Bronchial Asthma quantitative variables between the study groups was done using Kruskal Wallis analysis of variance (ANOVA) test with Mann Whitney U test for independent samples as posthoc multiple 2-group comparisons. Correlation between various variables was done using Spearman rank, correlation equation for non normal variables. A probability value ( p- value) less than 0.05 was considered statistically significant. Results In this study 41 subjects above 6 years old were included. 26 children with bronchial asthma (Group A) and 15 age matched healthy controls (Group B). The descriptive clinical and demographic data of the patients (Group A) are shown in Table (1). Their mean age was (8.08 ± 1.87) years. They included 11 males representing (42.3%) and 15 females representing (57.92%). While the mean age of the control group (Group B) was (8.33 ±2.02) years. They included 8 males which represents (53.33%) and 7 females representing (46.66%). Table (2) and Fig. (1) shows the comparison between the patients and controls regarding the growth percentile curves of weight and height to assess the effect of bronchial asthma as a chronic illness on the growth of our patients. Table (3) shows the statistical comparison between the patients and control regarding PFTs. It reveals that all pulmonary function tests of the patients were significantly lower than that of the control (p-value <0.001). By studying the PFTs among the different subgroups of the patients, in Table (4), we found that, there was a statistical significant difference concerning FEV1, FEF25, FEF50 of the 3 groups. These parameters were significantly lower in severe asthmatic patients (p-value <0.05). Table (5) shows the high resolution computed tomography (HRCT) scan findings of our asthmatic patients (n=26) (Group A). 15 of them showed normal HRCT representing (57.69%), 6 of the patients showed bronchial wall thickening () representing (23.08%), 4 patients (15.38%) their HRCT scan showed hyperlucent areas while 1 patient (3.85%) his HRCT scan showed both and hyperlucent areas. The HRCT scan findings of the 3 groups of asthmatic patients are shown in Table (6), which revealed that, all the severe asthmatic patients, Group (3), had abnormal HRCT findings. Table (1): Descriptive demographic and clinical data of asthmatic patients (Group 1). Variable Count Percent Sex: Male Female Residence: Rural Urban Symptoms during the attack: Wheeze Cough Sputum (yes) Cyanosis (yes) Tightness Seasonal variation of symptoms: Summer Winter Perennial Precipitating factors: Viral URTI (yes) Exercise (yes) Food (yes) Passive smoking (yes) Stress (yes) Animal contact (yes) Hospitalization (yes) Treatment received During attacks: Bronchodilators only Bronchodilators, steroids In-between the attacks steroids Family history (yes) URTI: Upper respiratory tract infection. Table (2): Comparison between (Group A) patients group and (Group B) control group regarding the growth percentile curves. Weight Height Patients Controls Patients Controls 3 rd : 5th centile (9) (1) th : 10 th (4) (1) 6.67 (2) 7.69 (2) th : 25 th (4) (8) (5) (5) th : 50 th (6) (5) (4) (4) th : 75 th (1) 3.85 (1) 6.67 (4) (2) th : 90 th (1) th : 95 th 95th : 97 th <97 th

5 Muhammad H. Maebed, et al % 40 Height (Patients) Height (Controls) Table (5): HRCT findings of (Group A) patients group with bronchial asthma. Patients (Count) % Normal HRCT (15) (6) Hyperlucent areas (4) & Hyperlucent areas (1) 3.58 HRCT: High Resolution Computed Tomography. : Bronchial wall thickening. 0 <3rd 3rd : 5 th : 5 th 10th : 25th : 50th : 75th : 90 th : 10th 25th 50th 75th 90 th 95th : 95th 97th >97th Centiles Fig. (1): Comparison between (Group A) patients group and (Group B) controls regarding growth percentile curves (height). Table (3): Statistical Comparison between (Group A) patients group and (Group B) controls regarding PFTs. PFTS values Mean ± SD Patients Controls p-value Sig. FVC 92.16± ± HS FEV ± ±6.79 <0.001 HS %predicted FEV1/FVC 89.58± ±2.86 <0.001 HS FEF ± ±27.6 <0.001 HS FEF ± ±32.5 <0.001 HS FEF ± ±40.69 <0.001 HS PEF 81.76± ±22.97 <0.001 HS p-value <0.005 = Significant. *p-value <0.001 = Highly significant. *p-value >0.05 = Non Significant (NS). FVC = Forced vital capacity. FEV1 = Forced expiratory volume in first second. FEF = Forced expiratory flow. PEF = Peak expiratory flow. Table (4): Statistical Comparison between the 3 groups of asthma regarding duration of asthma and PFTs. Variable Mean ± SD Group (1) Group (2) p Group (3) value Count Duration (y) 5.91± ± ± 1.35 NS FVC 98.18± ± ±7.75 NS FEV1% ± ± ± * FEV1/FVC 91.18± ± ±3.47 NS FEF ± ± ± * FEF ± ± ± * FEF ± ± ±5.82 NS PEF 84.8± ± ± * p-value <0.005 = Significant. *p-value <0.001 = Highly significant. *p-value >0.05 = Non Significant (NS). FVC = Forced vital capacity. FEV1 = Forced expiratory volume in first second. FEF = Forced expiratory flow. PEF = Peak expiratory flow. Table (6): HRCT findings of airway remodeling in the 3 groups of asthmatic patients. HRCT findings Normal HRCT Hyperlucent areas & hyperlucent areas Degree of asthma severity Mild Moderate Severe (count)% (count)% (count)% (9) (1) 9.09 (1) 9.09 HRCT: High Resolution Computed Tomography. : Bronchial wall thickening. (6) 75 (1) 12.5 (1) 12.5 (4) (2) (1) Four patients (75.14%) had, 2 patients (28.57%) had hyperlucent areas while 1 patient had both and hyperlucent areas representing (14.29%) and there was significant positive correlation between the HRCT abnormalities and the severity of bronchial asthma ( p-value <0.05) (r ). No significant correlation was found between the duration of asthma and HRCT findings of airway remodeling. However, all patients with 3 years asthma duration had normal HRCT findings representing 13.33%. While all the patients whose HRCT showed both and hyperlucent areas had a duration of asthma more than 6 years. There was no correlation between HRCT findings of airway remodeling and either FEV1 or FEV1/FVC. Discussion The aim of this work is to assess the airway remodeling in pediatric patients with bronchial asthma using the high resolution computed tomography (HRCT) as a non invasive technique.

6 94 Study of Airway Remodeling in Pediatric Patients with Bronchial Asthma Asthmatic patients Mild Moderate Severe 18.18% with +ve HRCT Findings 25% with +ve HRCT Findings 100% with +ve HRCT Findings 50% 50% Hyperlucent areas 50% 50% Hyperlucent areas 57.14% 28.57% Hyperlucent areas 14.29% Hyperlucent areas All our patients were poorly controlled with lack of long term control or "preventive" treatment due to absence of proper medical guidance for them. We have started this with some of them during the study and they showed improvement with marked decrease in the frequency of the acute attacks and improvement of quality of life in general, especially regarding sleep, playing and school performance. For example children with severe asthma had daily night cough which was disturbing their sleep and some of them were visiting the emergency department (ED) 5 times/week. Now, with the long term control treatment, no night cough, their asthma became stable and the need to visit the (ED) is markedly decreased; nearly once or twice in the last 8 months. Also, the study revealed that poorly controlled asthma may affect the linear growth. This draws the attention to the fact that a reduction in the growth velocity may occur in children or adolescents as a result of inadequate control of chronic diseases such as asthma. On the other hand, although low or medium doses of ICS may have the potential of decreasing growth velocity, the effects are small, nonprogressive, and may be reversible [21]. Also, this potential for adverse effects on linear growth from ICS appears to be dose dependent. In treatment of children who have mild or moderate persistent asthma, low-to medium-dose ICS therapy may be associated with a possible, but not predictable, adverse effect on linear growth [1]. While in severe persistent asthma, the use of high doses of ICS has significantly less potential adverse effect on linear growth than the use of oral systemic corticosteroids [1]. All these data lead us to the importance of early use of the proper prophylactic treatment like ICS. Brinke [22] documented that the natural course of persistent airflow limitation in asthma is poorly known, but reduced lung function at disease onset and an increased rate of decline during adult life contribute to its development. The asthmatic patients were investigated inbetween the attacks; their asthma attacks were controlled and they were free of symptoms two weeks before the spirometric measurements and high resolution computed tomography (HRCT) scans were done. However, our study showed a significantly lower pulmonary functions in those asthmatic children in comparison to the normal control group. Also, there was significant difference between the 3 groups of asthmatic patients regarding FEV1, FEF25 and FEF50 which were significantly lower in the group of severe asthmatics than mild and moderate groups. Although, PFTs were still within normal values, this may indicate the start of gradual decline in lung functions which may eventually lead to the development of irreversible airflow limitation in some patients with asthma and is related to poorer prognosis. These findings agreed with Gurra, et al. [23] who documented that in subjects who have asthma onset before 25 years of age and persistent airflow

7 Muhammad H. Maebed, et al. 95 limitation in adult life, the bulk of the FEV 1 deficit is already established before age 25 years. As we described previously, airway remodeling includes both proximal and distal airways. In our study, we found that: Some patients showed obstruction regarding pulmonary functions reflecting small airways condition; FEF25, FEF50 and FF75. This finding indicates that the small airways may be affected showing obstruction earlier than large airways. Remodeling of the small airways is believed to occur early in the disease process and worsens with disease progression. The "gold standard" for assessing small airway disease is morphometry of resected lung tissue, but the invasiveness of this approach precludes its use in clinical studies. With the advent of high-resolution computed tomography (CT), and the development of multislice CT scanning techniques, CT has become a very popular technique for the noninvasive assessment of airway disease in COPD [24]. Since, airway remodeling in the peripheral airway is critical for the pulmonary function and severity of asthma, one of the important targets of asthma therapy is the peripheral airway. It has been thought that particles of inhaled corticosteroid hardly reached to the peripheral airway. But the new types of inhaled corticosteroids, such as HFAbeclomethasone or HFA-cyclesonid, showed high deposition on peripheral airway and lung parenchyma because the particles are ultra-fine. Eosinophilic inflammation in the peripheral airway was suppressed by HFA-flunisolide in asthmatics [25]. Computed tomography (CT) scans are usually performed in children with asthma to exclude alternative diagnoses. Technical improvements of high-resolution CT (HRCT) scans allows the detection of bronchial wall thickening of the proximal airways and the assessment of small airway disease by the extent and degree of low attenuation areas [26]. Our study revealed that HRCT scanning of patients with asthma of different degrees of severity showed a thickening in airway wall in some of them compared to healthy controls and there was no correlation with FEV 1. These results correlate more or less with Ketai, et al. [27] who included in his study 28 childern with moderate to severe asthma and 18 controls and Marchac, et al. [28] who included 27 childern with difficult to treat asthma and 21 controls in his study. They found that the bronchial wall thickness () was higher in asthma children-with difficult to treat and moderate to severe asthma simultaneously - than the controls and no correlation with FEV 1. We found no correlation between HRCT findings of airway remodeling and either FEV 1, FEF25, 50 or 75. This agreed with De Blic, et al. [29] who included in his study 37 children with severe asthma and found that score of his patients was significantly higher than normal control but not correlated with FEV 1 or FEF In this study all the asthmatic patients who had HRCT findings of airway remodeling, their asthma duration where more than 3 years. This indicates that, although no direct correlation between airway remodeling and duration of asthma, in predisposed individuals, longstanding asthma has a risk of developing airway remodeling. So, early intervention with inhaled corticosteroids (ICS) before serious pathological changes occur, is expected to prevent the development of remodeling and improve asthma outcome [6]. In the current study, although the HRCT findings were related to asthma severity, we found that there was bronchial wall thickness and ill defined focal hyperlucent areas in some cases with mild asthma. A finding which suggests that some of the changes in the airway wall start in early stages, even in milder forms in asthma. These changes can be the result of individual patterns of response to frequent exacerbations, leading to a persistent chronic inflammatory process that will determine airway remodeling, even in early stages of disease and/or mild asthma [31]. While some with mild asthma showed HRCT findings of airway remodeling, others with moderate and more longstanding asthma showed no findings of airway remodeling. This indicates that patients with asthma remodel their airways at different rates. Suggesting that certain genetic factors and/or environmental factors (exacerbations, viral infections, tobacco smoke, and other unknown factors) may contribute to enhanced remodeling in a subset of patients with asthma. As long as HRCT scan abnormalities are common in patients with severe asthma and nonradiologic assessments may fail to reliably predict important bronchial wall changes; therefore, CT scan acquisition may be required in all patients with severe asthma.

8 96 Study of Airway Remodeling in Pediatric Patients with Bronchial Asthma Further studies are required, based particularly on the use of new multidetector-row CT scanners and including a larger group of patients, to validate the results obtained to date. This examination is highly unlikely to be used routinely for the management and follow-up of all children with asthma, because of its cost and the irradiation involved. Its use is therefore likely to be restricted to patients with severe asthma [32]. Conclusion and Recommendation: Asthma in young children is no longer considered a benign disease, since it may lead to permanent airway remodeling. HRCT is a relatively expensive but a non-invasive technique that can be used to show the bronchial wall changes in asthmatic patients. Early intervention with inhaled corticosteroid should be considered to prevent the progress of airway remodeling and prevent the reduction in growth velocity that may occur in those patients. References 1- EPR 3: Expert Panel Report 3: Guidelines for the Diagnosis and Management of Asthma-Summary Report J. Allergy Clin. Immunol. Nov. 120 (5 Suppl): S94-138, EL-HEFNY A.M.: Epidemiology of Asthma in Cairo. Med. J. Cairo Univ., 62: , GEORGY V., FAHIM H.I. and EL GAAFARY M.: Prevalence and socioeconomic associations of asthma and allergic rhinitis in northern Africa. Eur. Respir J., 28: , MAUAD T., BEL E.H. and STERK P.J.: Asthma therapy and airway remodeling. J. Allergy Clin. Immunol., 120: , ROSSI G.A.: Airway remodeling: Structure and physiology. Pediatr. Pulmonol., 26 (S): , HASHIMOTO S., MATSUMOTO K., GON Y., et al.: Update on Airway Inflammation and Remodeling in Asthma. Allergy Clin. Immunol. Int., 19 (5): , BOULET L.P. and STERK P.J.: Airway remodeling: The future. Eur. Respir., 30: , SAGLANI S., PAYNE D.N., ZHU J., WANG Z., et al.: Early detection of airway wall remodeling and eosinophilic inflammation in preschool wheezers. Am. J. Respir. Crit. Care. Med., 176: , APTER A.J. and SZEFLER S.J.: Advances in adult and pediatric asthma. J. Allergy Clin. Immunol., 117: , JEFFERY P., HOLGATE S. and WENZEL S.: Methods for the assessment of endobronchial biopsies in clinical research: Application to studies of pathogenesis and the effects of treatment. Am. J. Respir. Crit. Care. Med., 168: S1-S17, JAMES A.L., MAXWELL P. S., PEARCE-PINTO G., et al.: The relationship of reticular basement membrane thickness to airway wall remodeling in asthma. Am. J. Respir. Crit. Care. Med., 166: , DE JONG P.A., MULLER N.L., PARE P.D., et al.: Coxson HO. Computed tomographic imaging of the airways: Relationship to structure and function. Eur. Respir. J., 26: , American Thoracic Society (ATS) Criteria, Global Initiative for Asthma (GINA): Pocket guide for asthma management and prevention in children. National Institute of Health, National Heart, Lung, and Blood Institute, USA, 2006, American Thoracic Society (ATS): Standardisation of spirometry: Update. Am. J. Respir. Crit. Care. Med., 152: , ROSENTHAL M., BAIN S.H., CRAMER D., et al.: Lung function in white children aged 4 to 19 years: I-Spirometry. Thorax, 48: pp , GRIPPI M.A., METZGER L.F., SACKS A.V., et al.: Pulmonary function testing in Fishman's pulmonary diseases and disorders by Mc-Graw Hill companies, Inc., 533, LYNCH D.A., NEWELL J., HALE V., et al.: Correlation of CT findings with clinical evaluations in 261 patients with symptomatic bronchiectasis. Am. J. Roentgenol., 173: 53-58, GRENIER P., MOUREY-GEROSA I., BENALI K., et al.: Abnormalities of the airways and lung parenchyma in asthmatics: CT observations in 50 patients and interand intraobserver variability. Eur. Radiol., 6: , HARMANCI E., KEBAPCI M., METINTAS M., et al.: High-Resolution Computed Tomography Findings Are Correlated with Disease Severity in Asthma Respiration, 69 (5): , GUILBERT T.W., MORGAN W.J., ZEIGER R.S., et al.: Long-term inhaled corticosteroids in preschool children at high risk for asthma. N. Engl. J. Med., 354 (19): , BRINKE A.: Risk factors associated with irreversible airflow limitation in asthma. Curr. Opin. Allergy Clin. Immunol., 8 (1): 63-9, GUERRA S., SHERRILL D.L., KURZIUS-SPENCER M., et al.: The course of persistent airflow limitation in subjects with and without asthma) Respir. Med., 102 (10): , HASEGAWA M., NASUHARA Y., ONODERA Y., et al.: Airflow Limitation and Airway Dimensions in Chronic Obstructive Pulmonary Disease. Am. J. Respir. Crit. Care. Med., 173: , HAUBER H.P., GOTFRIED M., NEWMAN K., et al.: Effect of HFA-flunisolide on peripheral lung inflammation in asthma. J. Allergy Clin. Immunol., 112: 58-63, DE BLIC and SCHEINMANN P.: The use of imaging techniques for assessing severe childhood asthma. Allergy and Clinical Immunology, 119 (4): , 2007.

9 Muhammad H. Maebed, et al KETAI L., COUTSIAS C., WILLIAMSON S., et al.: Thin-section CT evidence of bronchial thickening in children with stable asthma: Bronchoconstriction or airway remodeling?. Acad. Radiol., 8: , MARCHAC V., EMOND S., MAMOU-MANI T., et al.: Thoracic CT in pediatric patients with difficult-to-treat asthma. AJR Am. J. Roentgenol., 179: , DE BLIC J., TILLIE-LEBLOND I., EMOND S., et al.: High-resolution computed tomography scan and airway remodeling in children with severe asthma. J. Allergy Clin. Immunol., 116: , OLIVIERI D., CHETTA A., DEL DONNO M., et al.: Effect of short-term treatment with low-dose inhaled fluticasone propionate on airway inflammation and remodeling in mild asthma: A placebo-controlled study. Am. J. Respir. Crit. Care. Med., 155: , MACHADO D., PEREIRA C., TEIXEIRA L., et al.: Thoracic high resolution computed tomography (HRCT) in asthma. Eur. Ann. Allergy Clin. Immunol., 41 (5): , ZEIDLER M.R., GOLDIN J.G., KLEERUP E.C., et al.: Small airways response to naturalistic cat allergen exposure in subjects with asthma. J. Allergy Clin. Immunol., 118: , 2006.