IMPACT OF TOPICAL CORTICOSTEROIDS AND EARLY LIFE RISK FACTORS ON THE INCIDENCE OF PATHOLOGIC BACTERIA IN THE LOWER RESPIRATORY TRACT

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1 Aus der Klinik für Kinder- und Jugendmedizin im St. Josef-Hospital Bochum Universitätsklinik der Ruhr-Universität Bochum Direktor: Prof. Dr. med. C. Rieger IMPACT OF TOPICAL CORTICOSTEROIDS AND EARLY LIFE RISK FACTORS ON THE INCIDENCE OF PATHOLOGIC BACTERIA IN THE LOWER RESPIRATORY TRACT Inaugural-Dissertation zur Erlangung eines Doktorgrades der Medizin der Hohen Medizinischen Fakultät der Ruhr-Universität Bochum vorgelegt von Son Bui Binh Bao aus Thua Thien-Hue, Vietnam 2002

2 Dekan: Prof. Dr. med. G. Muhr Referent: Prof. Dr. med. C. Rieger Korreferent: Priv. Doz. Dr. med. B. Gallwitz Tag der mündlichen Prüfung: 07. Februar 2002

3 TABLE OF CONTENTS 1. INTRODUCTION Topical corticosteroids Pharmacokinetics of topical corticosteroids Side-effects of topical corticosteroids Topical corticosteroids and respiratory tract infections Other factors and respiratory tract infections Bronchoscopy Bronchoalveolar lavage Bronchial aspirates The value of bronchoalveolar lavage and bronchial aspirates in diagnosis of bacterial respiratory infections Aims of the study PATIENTS AND METHODS Patients Exclusion criteria Data collection Bronchoscopy technique Bronchoalveolar lavage Bronchial aspirates Bacteriological analyses Statistical analyses 17

4 3. RESULTS General characteristics of the study subjects Topical corticosteroids Indications for topical corticosteroids Types of topical corticosteroids Doses of topical corticosteroids Inhalation techniques Topical corticosteroids and detection of pathologic bacteria Topical corticosteroids and detection of pathologic bacteria Types of pathologic bacteria Systemic steroids and detection of pathologic bacteria Smoking in the family and detection of pathologic bacteria Antibiotic therapy prior to bronchoscopy and detection of pathologic bacteria Gestational age at delivery and detection of pathologic bacteria Gestational age at delivery and detection of pathologic bacteria Gestational age at delivery and topical corticosteroids Gestational age at delivery and mean duration of topical corticosteroid therapy DISCUSSION Topical corticosteroids Indications for topical corticosteroids Types of topical corticosteroids Doses of topical corticosteroids Duration of topical corticosteroid treatment.. 35

5 Inhaler devices for delivering topical corticosteroids Topical corticosteroids and detection of pathologic bacteria Topical corticosteroids and detection of pathologic bacteria Types of pathologic bacteria Systemic steroids given prior to bronchoscopy and detection of pathologic bacteria Smoking in the family and detection of pathologic bacteria Antibiotic therapy prior to bronchoscopy and detection of pathologic bacteria Premature birth and detection of pathologic bacteria CONCLUSIONS REFERENCES 47 ACKNOWLEDGEMENTS CURRICULUM VITAE

6 INTRODUCTION 1 1. INTRODUCTION: 1.1. Topical corticosteroids: Topical corticosteroids have revolutionized the treatment of asthma and have now become the mainstay of therapy for patients with chronic disease ( 1 ). Long-term use of topical corticosteroids reduces symptoms in children with asthma ( 2 ), improves quality of life in children as well as their caretakers ( 3 ), improves lung function ( 4 ), and reduces levels of inflammation markers ( 5 ), bronchial responsiveness ( 6 ), and exercise-induced asthma ( 7, 8 ). In addition, early use of topical corticosteroids may actually decrease the severity of chronic asthma ( 9 ). It has been demonstrated that, as the use of topical corticosteroids increased markedly, the admission rate to hospitals for acute asthma in older children started to decrease ( 10, 11 ), particularly for readmissions as compared to first admissions for acute asthma ( 12 ). Thus, the use of topical corticosteroids in children with asthma has a beneficial effect upon the well-being of children and their families, as well as reducing community costs for asthma by reducing admissions to hospital, the number of emergency consultations, and absence from work or school of patients, schoolchildren and parents. The clinical indications for topical corticosteroid therapy of asthma have broadened considerably over the past 20 years, and the advent of more potent drugs, more concentrated formulations, and more efficient delivery systems has greatly expanded this therapeutic potential. These changes might also increase the likelihood of side-effects, and this is a concern to parents, patients, and physicians ( 13 ). The commercially available topical corticosteroids for treatment are beclomethasone dipropionate, budesonide,

7 INTRODUCTION 2 flunisolide, fluticasone propionate, mometasone furoate, and triamcinolone acetonide ( 14 ) Pharmacokinetics of topical corticosteroids: After inhalation, a large proportion of the topical dose, 80 to 90%, is deposited in the oropharynx and swallowed. It is then available for absorption into the systemic circulation through the liver (figure 1). This fraction is markedly reduced if the glucocorticoid is administered through a large-volume spacer attached to a metered-dose inhaler or rinsing the mouth after the use of a drypowder inhaler. Between 10 and 20% of the topical drug enters the respiratory tract, where it is deposited in the airways and is available for absorption into the systemic circulation ( 1 ). Most of the studies on the distribution of topical glucocorticoids have been conducted in normal subjects. Factors such as airway inflammatory disease, airway obstruction, the age of the patient, and concomitant therapy may all alter the disposition of the topical dose. There also may be important differences in the metabolism of different glucocorticoids ( 1 ).

8 INTRODUCTION 3 Figure 1: Pharmacokinetics of topical corticosteroids Side-effects of topical corticosteroids: In recent years, there has also been a growing attention to possible side-effects of topical corticosteroids in children. There is no longer any doubt of the effectiveness of topical corticosteroids, but since topical corticosteroids are widely used in children, the issue of safety and the risk/benefit ratio assume primary importance Systemic side-effects: The more relevant systemic side-effects of topical corticosteroids concern adrenal gland function, bone metabolism, and growth pattern in children/adolescents. The occurrence and severity of these side-effects depend on a large number of variables, including the characteristics of the drug (lipophilicity, pharmacokinetics, and pharmacodynamics) and the mode of administration (dose, delivery system, coordination, etc.).

9 INTRODUCTION 4 On the hypothalamic-pituitary-adrenal axis, topical corticosteroid therapy, especially with high doses, may affect the urinary cortisol excretion and plasma cortisol ( 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 ). Besides, though certain effects of topical corticosteroids on bone metabolism such as decrease in serum osteocalcin ( 31, 32, 33 ), increased urinary hydroxyproline ( 34 ), increase in urinary phosphate ( 35 ), reduction in collagen type I or III turnover ( 36, 37 ) are detectable when high doses are used, there has been no indication that long-term treatment with topical corticosteroids is associated with reduced bone mass density or increased risk of osteoporosis or fracture in children ( 38, 39, 40, 41, 42, 43, 44, 45 ). On growth in childhood, short-term growth may be affected by high doses of topical corticosteroids ( 46, 47, 48, 49 ), but growth velocity and stature are not influenced by topical corticosteroids ( 50, 51, 52, 53, 54, 55, 56 ) and seem to depend strictly on the degree of asthma control because asthma itself may reduce the growth pattern of children, reduce their potential height or, at least, the growth velocity. Other systemic side-effects of topical corticosteroids such as posterior subcapsular cataract or open-angle glaucoma are very rare ( 57 ). Topical corticosteroids have no significant effect on glucose and lipid metabolism ( 58, 59, 60 ) and do not affect cellular immunity parameters (T and B cells and IL-2 secretion) ( 61 ) Local side-effects: Some local side-effects of topical corticosteroids such as oropharyngeal candidiasis ( 62, 63, 64, 65, 66, 67 ), dysphonia ( 68, 69, 70, 71, 72, 73 ), cough and bronchospasm ( 74, 75, 76, 77 ), contact allergy ( 78, 79, 80, 81 ), thirsty feeling ( 82, 83 ) and hoarseness ( 84, 85, 86 ) have been described in the medical literature.

10 INTRODUCTION 5 However the incidence of these systemic and local side-effects of topical corticosteroids is rare, especially when children receive topical corticosteroids at recommended doses Topical corticosteroids and respiratory tract infections: Although topical corticosteroids are now among the most carefully studied drugs in clinical use and their systemic as well as local adverse effects have been mentioned in the literature, the correlation of topical corticosteroids with bacterial infections, particularly respiratory infections is still an unanswered question and few studies have been performed on this aspect. It has been stated that increases in bacterial, viral, or fungal lung infections have not been a problem in patients treated with topical corticosteroids in North America or Europe ( 87 ). Until now there has been almost no study pointing out the relation between topical corticosteroids and respiratory infections. A few cases of complicating pulmonary tuberculosis have been reported from India ( 88 ). It is also recommended that topical corticosteroids should be avoided or used with great caution in asthmatic patients who are immunosuppressed, who have coexisting drug-resistant or atypical tuberculosis, or who have structural lung lesions that may harbor a mycetoma. In the latter case, the risk of local immunosuppression leading to proliferation of locally resident pathogens and to locally invasive or disseminated disease is a concern, especially if topical corticosteroids and oral steroid are used conjointly ( 89 ). Even if a study of Abzug et al. showed that severe varicella has complicated the use of intranasal beclomethasone dipropionate for chronic sinusitis during the incubation phase of the disease ( 90 ), the clinical course of varicella is not

11 INTRODUCTION 6 unduly severe or prolonged in asthmatic patients treated with topical corticosteroids ( 91 ). On the other hand, corticosteroids have in vitro some effects on viral-induced airway inflammatory responses in asthma. The expression of ICAM-1 (intercellular adhesion molecule-1) is increased during and following viral infection. ICAM-1 is the major human rhinovirus receptor. Binding of the virus to ICAM-1 on different cell types triggers the release of a number of cytokines and further increases in ICAM-1 expression on adjacent cells, thereby enhancing adhesion and spread of the virus. With increased expression of ICAM-1, eosinophil and neutrophil migration, adhesion and attraction are augmented; this leads to enhanced inflammation, which increases airway hyperresponsiveness ( 92 ). One of the effects of corticosteroids on gene transcription is to decrease the transcription of ICAM- 1 ( 93, 94 ) and therefore suppress the spread of the virus. However, up to now, it is not known whether there is any airway inflammatory response mechanism to respiratory bacterial infections like viral-induced airway inflammatory responses in asthma, and evidence on the influence of topical corticosteroids on respiratory bacterial infections is still lacking. There is reason to believe that topical corticosteroids do not predispose individuals to more infections. Although systemically administered steroids can alter immune function, usual doses of the topical corticosteroids for bronchial asthma have minimal to no measurable effects on the immune system ( 95, 96 ). Thus, the role of topical corticosteroids as protection or predisposing on bacterial infections/colonizations requires further study.

12 INTRODUCTION Other factors and respiratory tract infections: Although topical corticosteroids seem relatively safe and have minimal or no measurable effects on the immune system, systemic steroid treatment is associated with cellular and humoral immunosuppression, resulting in an increased risk for bacterial and viral infections, especially when patients have been treated with systemic steroids for a long time ( 97, 98 ). Many studies have emphasized the role of reducing tobacco smoking in the prevention of respiratory diseases. Children with passive tobacco smoke exposure from parental smoking have been demonstrated repeatedly to suffer significantly more often from respiratory symptoms, such as bronchial hyperresponsiveness, increased upper and lower respiratory tract infections ( 99, 100, 101, 102, 103, 104, 105, 106, 107 ), asthma ( 108 ), wheezing, and chronic bronchitis ( 109 ). Therefore, public health campaigns and prevention strategies are urgently needed to reduce the prevalence of parental smoking and its impact on children's health. Empiric antibiotic therapy remains the standard treatment for pneumonia in children. However, antibiotic pre-treatment appears to have no effect on the detection of pathologic bacteria from the lower respiratory tract at the time of diagnosis. A study of Timsit et al. ( 110 ) showed that previous antibiotics received to treat an earlier septic episode unrelated to suspected pneumonia did not affect the diagnostic yield of protected specimen brush and bronchoalveolar lavage on consecutive mechanically ventilated patients with suspected nosocomial pneumonia. Besides, according to Pereira Gomes et al., bronchoalveolar lavage might be a sensitive diagnostic method for treatment failures of clinically diagnosed pneumonias, even if performed under antibiotics ( 111 ). Moreover, colony forming unit count in bronchoalveolar

13 INTRODUCTION 8 lavage cultures was still a useful method for the diagnosis of nosocomial pneumonia associated with mechanical ventilation in patients treated with systemic antibiotics ( 112 ). Preterm birth in children is known to represent a high risk of developing bronchopulmonary dysplasia, or its milder form, chronic lung disease. These complications, in turn, might cause preterm children to get more respiratory infections. Early outcome studies on the respiratory system of preterm children with previous bronchopulmonary dysplasia showed them to be twice as likely to require rehospitalization during the first 2 years of life due to respiratory symptoms than preterm children without bronchopulmonary dysplasia ( 113 ). However, the late outcome is still controversial. While Kennedy from Australia in one study has suggested that the majority of older children and adolescents with bronchopulmonary dysplasia or chronic lung disease did not have significant respiratory symptoms ( 114 ), children with bronchopulmonary dysplasia, according to Gross et al., at school age had more airway obstruction than both preterm children without bronchopulmonary dysplasia and the term control group and bronchodilator responsiveness was observed twice as often in preterm children with previous bronchopulmonary dysplasia compared with preterm children without bronchopulmonary dysplasia or the term control group ( 115 ). Nevertheless, the role of preterm birth on respiratory infections in older children was not clearly demonstrated and needs to be further studied Bronchoscopy: Bronchoscopy is a procedure performed to visualize and manipulate the larger branches of the tracheobronchial tree ( 116 ). Indications for diagnostic bronchoscopy include recurrent or persistent pneumonia or atelectasis,

14 INTRODUCTION 9 unexplained and persistent wheezes and infiltrates, the suspected presence of a foreign body, hemoptysis, suspected congenital anomalies, mass lesions, interstitial disease, and pneumonia in the immunocompromised host, or other conditions in which bronchoscopy is the best way to obtain the information necessary for the care of the patient. Indications for therapeutic bronchoscopy include bronchial obstruction by mass lesions, foreign bodies or mucus plugs, and bronchopulmonary lavage. The individual undergoing bronchoscopy ventilates around the flexible scope, whereas with the rigid scope ventilation is accomplished through the scope. Rigid bronchoscopy is preferentially indicated for the extraction of foreign bodies and the removal of tissue masses and in patients with massive hemoptysis. In other cases, the flexible scope offers the advantage that it can be passed through endotracheal or tracheostomy tubes, can be introduced into bronchi that come off the airway at acute angles, and can be safely and effectively inserted with topical anesthesia and sedation ( 117 ) Bronchoalveolar lavage: Bronchoalveolar lavage is a method used to obtain a representative specimen of fluid and secretions from the lower respiratory tract, which is useful for the cytologic and microbiologic diagnosis of lung diseases, especially in those who are unable to expectorate sputum. Commonly, bronchoalveolar lavage is performed after the general inspection of the airways and prior to tissue sampling with a brush or biopsy forceps ( 118 ). Bronchoalveolar lavage is accomplished by gently wedging the scope into a lobar, segmental, or subsegmental bronchus. Usually the right middle lobe or the lingula is chosen because of better fluid recovery; or the respective segment in case of focal processes. After instilling (normally 3 x 1 ml/kg)

15 INTRODUCTION 10 sterile nonbacteriostatic saline via the suction channel of the flexible bronchoscope, the fluid was recovered by hand suction in a volume sufficient to ensure that some of the aspirated fluid contains material originated from the alveolar space. The fractions of bronchoalveolar lavage fluid then are used for culture, cytological studies and analysis of bronchoalveolar lavage solutes, including proteins and inflammatory mediators Bronchial aspirates: After penetration into the trachea, the bronchoscope is advanced into the right or left main bronchus, where secretions are aspirated into a sterile sputum trap. Occasionally, the secretions are collected after instilling a small amount of normal sterile saline which has been previously warmed to body temperature. Secretions are then used for cytological and microbiologic examinations The value of bronchoalveolar lavage and bronchial aspirates in diagnosis of bacterial respiratory infections: The diagnosis of bacterial pulmonary infections remains difficult. Clinical findings such as fever, physical examination, leukocytosis, or abnormal chest radiographs are often non-specific or even misleading, especially in the ventilated patient. Among the current techniques for etiologic diagnosis of pulmonary infections, bronchoalveolar lavage and bronchial aspirates are considered as the essential and reliable procedures in specific pathological situations. Bronchoalveolar lavage and bronchial aspirates can provide specimens for microbial cultures as well as cytological examination. Bronchoalveolar lavage is well established in many studies in the etiologic diagnosis of pulmonary infections, especially in immunocompromised

16 INTRODUCTION 11 children. Furthermore, bacterial cultures of bronchoalveolar lavage fluid appeared useful in defining the presence and etiology of pneumonia in mechanically ventilated patients ( 119, 120 ). In patients suffering from pneumonia with treatment failures, bronchoalveolar lavage is a sensitive diagnostic method for treatment failures of clinically diagnosed pneumonias, even if performed under antibiotics ( 121 ) Aims of the study: The aims of this retrospective study are to: Determine the impact of topical corticosteroids on the incidence of pathologic bacteria found in the lower respiratory tract of children. Identify types of pathologic bacteria isolated in the lower respiratory tract in children with and without topical corticosteroids. Evaluate some aspects of topical corticosteroid therapy such as indications, types and doses of topical corticosteroids, duration of topical corticosteroid treatment and inhalation technique. Evaluate whether additional factors i.e. systemic steroids given prior to bronchoscopy, smoking in the family, antibiotic therapies prior to bronchoscopy and preterm birth had any influence on the incidence of pathologic bacteria in the lower respiratory tract.

17 PATIENTS AND METHODS PATIENTS AND METHODS: 2.1. Patients: This retrospective study was conducted at the Klinik für Kinder- und Jugendmedizin in St. Josef hospital, a clinic of the Ruhr University, Bochum. This is the only children s clinic in the city of Bochum and therefore responsible for immediate medical care of the population. Simultaneously, it is a referral centre for private practices, lung specialists and the surrounding clinics. The activities of this hospital include conservative and invasive diagnostics for chest and immunodeficiency diseases. Each year approximately 200 flexible and rigid bronchoscopies are performed. One hundred ninety children consecutively undergoing fiberoptic or rigid bronchoscopy with microbiological examinations (cultures) of bronchoalveolar lavage fluid or bronchial aspirates during the time from January 1999 until June 2001 were included in the study Exclusion criteria: Children under bronchoscopy without microbiological examinations of bronchoalveolar lavage fluid or bronchial aspirates and children on topical corticosteroid therapy for less than two weeks were excluded from the study Data collection: The following data were collected for each patient: Gender. Age.

18 PATIENTS AND METHODS 13 Topical corticosteroids: indications for inhalation, duration of inhalation, types and doses of topical corticosteroids and techniques of inhalation. Detection of pathologic bacteria in the lower respiratory tract. Systemic steroids given prior to bronchoscopy. Smoking in the family. Antibiotic therapy prior to bronchoscopy: continuous antibiotic use during two weeks before bronchoscopy were considered as antibiotic therapy prior to bronchoscopy. Premature birth Bronchoscopy technique: In children beyond the neonatal period, a pediatric flexible fiberoptic bronchoscope with an external diameter of mm was usually used to perform bronchoscopy. Patients more than 9 years of age usually tolerated the flexible fibreoptic bronchoscope with a diameter of mm. The flexible fiberoptic bronchoscope (Olympus ) was passed via the nasal route under sedation and local anaesthesia. An intravenous route was usually preferred for sedation, and drugs most frequently used were pethidin with midazolam and/or promethazine. Atropine was used as premedication because it minimizes vasovagally-induced bradycardia and decreases airway secretion.

19 PATIENTS AND METHODS 14 Drug Dose (mg/kg body weight) i.v Pethidin Midazolam Promethazine Atropine Table 1: Drugs most frequently used for sedation in flexible bronchoscopy With flexible bronchoscopy, the use of a local anesthetic was routine. We have used lidocaine 2% with ml/dose. Each dose was added with 9 ml air in 10 ml syringe and a maximal total dose was 4 mg/kg. First dose was given intranasally by directly spraying into the noses and onto the larynx. The second dose was applied to the region of the vocal cords, then to the trachea above the carina and the bronchi as required via the suction channel. Oxygen administration through nasal prongs has been used during flexible bronchoscopy in order to make the procedure safer and prevent desaturations, particularly in small children. Monitoring during bronchoscopy has been improved greatly by the use of ECG monitor and pulse oximetry. While flexible bronchoscopy could be performed under sedation and local anaesthesia, rigid bronchoscopy always required the use of general anaesthesia under the supervision of a anaesthesic team. Rigid bronchoscopy was used in the clinic mostly for extraction of foreign bodies Bronchoalveolar lavage: Bronchoalveolar lavage was usually carried out in the most-affected area which was identified radiologically and/or endoscopically. In diffuse lung disease, the right middle lobe was the preferred site because this area offers

20 PATIENTS AND METHODS 15 better fluid recovery. Bronchoalveolar lavage was performed by using normal sterile saline which was previously warmed to body temperature (37 o C). 3 ml/kg of normal saline divided into three equal fractions was used for bronchoalveolar lavage. The fractions were instilled by using 3 syringes via the suction channel of the flexible bronchoscope. Each instillation was followed by sufficient air to ensure that the channel's dead space was empty. The fluid was recovered by hand suction using the same syringes. When three equal instilled fractions were used, the first aliquot collected was used for culture; the other two aliquots were pooled and submitted for cytological studies and analysis of bronchoalveolar lavage solutes, including proteins and inflammatory mediators Bronchial aspirates: After penetration into the trachea, the bronchoscope was advanced into the right or left main bronchus, where secretions were aspirated into a sterile sputum trap. Sometimes the secretions were collected after instilling a small amount of normal sterile saline which was previously warmed to body temperature. Secretions, as well as bronchoalveolar lavage fluid, were then kept at room temperature and processed for cytological and microbiological examinations as quickly as possible to avoid further contamination and loss of agents such as anaerobic bacteria. Before assessing cellular components of bronchoalveolar lavage fluid and secretions from bronchial aspirates, the fluids were filtered by using one layer of sterile gauze to remove mucous particles. In contrast, microbiological

21 PATIENTS AND METHODS 16 studies were performed on unfiltered bronchoalveolar lavage fluid as organisms could be trapped in the mucous Bacteriological analyses: The specimens from bronchoalveolar lavage fluid and from bronchial aspirates were sent immediately to the Insitut für Medizinische Mikrobiologie der Stadt Bochum for microbiological examinations, including cultures and antibiograms. Criteria for detection of pathologic bacteria: because the results of microbiological cultures from the Insitut für Medizinische Mikrobiologie der Stadt Bochum were not always in quantitative way and sometimes in semiquantitative way, we considered that a patient had a significant amount of pathologic bacteria if: Pathologic bacteria from bronchoalveolar lavage fluid or bronchial aspirates, and Quantitative bacterial cultures: /ml or - large amount (*) or - medium amount (*) (*) under the condition that the amount of physiologic flora from the same sample was less than the amount of pathologic bacteria.

22 PATIENTS AND METHODS Statistical analyses: Statistical analyses were done by using Microsoft Excel 2000 and Epi Info 6.04d, a Word Processing, Database and Statistics Program for Public Health from Centers For Disease Control & Prevention (CDC), U.S.A and World Health Organization. The incidences of significant amounts of pathologic bacteria isolated from the lower respiratory tract were compared between children with and without the following factors by using Chi-square (χ 2 ) test: Topical corticosteroids, Systemic steroids given prior to bronchoscopy, Passive exposure to tobacco smoke in the family, Antibiotic therapy prior to bronchoscopy and Premature birth. This was done to determine whether these factors had any influence on the detection of significant amounts of pathologic bacteria in the lower respiratory tract. A P value of < 0.05 was considered significant.

23 RESULTS RESULTS: 3.1. General characteristics of the study subjects: The overall study population consisted of 190 children. Out of 106 children without topical corticosteroids, 60 were boys (56.60%) and 46 were girls (43.40%). Out of 84 children on topical corticosteroids, 57 were boys (67.86%) and 27 were girls (32.14%). The average ages of children without and with topical corticosteroids were months (range, 1.73 to months) and months (range, 2.87 to months), respectively. These general characteristics were similar between two groups (Table 2). Characteristics Children on topical corticosteroids (n = 84) Children without topical corticosteroids (n = 106) Boys/girls number 57/27 60/46 Age months Mean Range Table 2: General characteristics of the study subjects 3.2. Topical corticosteroids: Indications for topical corticosteroids: The most common indications for topical corticosteroids in the study were recurrent obstructive bronchitis (51.19%), chronic cough (16.67%) and bronchial asthma (10.71%) (Table 3).

24 RESULTS 19 Indications for topical corticosteroids n = 84 % Recurrent obstructive bronchitis % Chronic cough % Bronchial asthma % Chronic cough + bronchial obstruction % Chronic neonatal lung disease % Recurrent respiratory infections % Abnormal respiratory sounds from birth % Pneumonia + bronchial obstruction % Cough + stridor % Fibrosing alveolitis % Table 3: Indications for topical corticosteroids Types of topical corticosteroids: The most frequent preparations used for children in this study were budesonide (76.2%) and fluticasone (21.4%). Beclomethasone was rarely used (2.4%) (Figure 2). Types of topical corticosteroids 2.4% 21.4% 76.2% Beclomethasone Fluticasone Budesonide Figure 2: Types of topical corticosteroids.

25 RESULTS Doses of topical corticosteroids: Types of topical corticosteroids Budesonide Inhalation devices Metered-dose inhaler with spacers (e.g. Aerochamber, Babyhaler, Rondo ) Dry powder inhalers (e.g. Diskus, Turbuhaler ) Mean daily doses (µg/d) 384 ± ± 176 Nebuliser (e.g. Pari-Boy ) 822 ± 307 Fluticasone Metered-dose inhaler with spacers (e.g. Aerochamber, Babyhaler, Rondo ) 156 ± 137 Dry powder inhaler (e.g. Diskus ) 300 ± 164 Beclomethasone Metered-dose inhaler with spacer (Rondo ) 100 Dry powder inhaler (Autohaler ) 400 Table 4: Doses of topical corticosteroids. The mean daily doses of topical corticosteroids varied from different preparations and inhalation devices as showed on table 4. The mean daily dose of budesonide administered by metered-dose inhaler with spacers was 384 ± 199 µg, while its mean daily dose administered via dry powder inhalers was 511 ± 176 µg and via nebulisers was 822 ± 307 µg. The mean daily dose

26 RESULTS 21 of fluticasone administered by metered-dose inhaler with spacers was 156 ± 137 µg and via dry powder inhaler was 300 ± 164 µg. Only 2 children in this study inhaled beclomethasone. One used a metered-dose inhaler with spacer at a daily dose of 100 µg and the other one used a dry powder inhaler at a daily dose of 400 µg. The mean duration of topical corticosteroid therapy until the time of bronchoscopy was 7.48 months, range from 0.3 months to 84 months Inhalation techniques: Children included in this study inhaled corticosteroids via different types of inhalation devices. The following table 5 shows the inhalation devices and the mean ages of children using them. Inhalation devices Mean age (months) Aerochamber ± Metered-dose inhalers Babyhaler ± Rondo ± Dry powder inhalers Diskus ± Turbuhaler ± Nebuliser Pari-Boy ± Table 5: Inhalation devices and mean ages of children.

27 RESULTS Topical corticosteroids and detection of pathologic bacteria: Topical corticosteroids and detection of pathologic bacteria: Topical corticosteroids and detection of pathologic bacteria % 81.13% % % 86 Significant amounts of pathologic bacteria Insignificant amounts of pathologic bacteria Topical corticosteroids No topical corticosteroids (n = 84) (n = 106) Chi-square = 0.15, p = Figure 3: Topical corticosteroids and detection of pathologic bacteria. Figure 3 shows the correlation between topical corticosteroids and the detection of pathologic bacteria. In the group of 84 children on topical corticosteroids, 14 children (16.67%) had significant amounts of pathologic bacteria from bronchoalveolar lavage fluid and bronchial aspirates, compared with 20 children (18.87%) in the group of 106 children without topical

28 RESULTS 23 corticosteroids. No significant difference was observed (Chi-square = 0.15 and p = ) Types of pathologic bacteria: The most common bacteria isolated from bronchoalveolar lavage fluid and bronchial aspirates were similar in both groups of children with and without topical corticosteroids. Haemophilus influenzae was found in 42.11% children on topical corticosteroids and in 52.00% children without topical corticosteroids; whereas these proportions for streptococcus pneumoniae were 15.79% and 28.00%, respectively % children on topical corticosteroids had moraxella catarrhalis in the bronchoalveolar lavage fluid and bronchial aspirates, compared with 12.00% in children without topical corticosteroids (Table 6). Topical corticosteroids No topical corticosteroids Haemophilus influenzae 8 (8/19 = 42.11%) 13 (13/25 = 52.00%) Streptococcus pneumoniae 3 (3/19 = 15.79%) 7 (7/25 = 28.00%) Moraxella catarrhalis 3 (3/19 = 15.79%) 3 (3/25 = 12.00%) Staphylococcus aureus 1 (1/19 = 5.26%) 1 (1/25 = 04.00%) Haemophilus parainfluenzae 1 (1/19 = 5.26%) 1 (1/25 = 04.00%) Pseudomonas aeruginosa 1 (1/19 = 5.26%) 0 (0/25 = 00.00%) E.coli 1 (1/19 = 5.26%) 0 (0/25 = 00.00%) Klebsiella oxytoca 1 (1/19 = 5.26%) 0 (0/25 = 00.00%) Table 6: Types of pathologic bacteria found in the bronchoalveolar lavage fluid and bronchial aspirates

29 RESULTS Systemic steroids and detection of pathologic bacteria: Comparison of incidence of detected pathologic bacteria in the bronchoalveolar lavage fluid and bronchial aspirates did not reveal any significant difference among both groups of children with and without systemic steroid uses prior to bronchoscopy (p = 0.476). 20% children receiving systemic steroids had significant amounts of pathologic bacteria, while 17.58% children without systemic steroid uses had significant amounts of pathologic bacteria (Figure 4). Systemic steroids and detection of pathologic bacteria % 82.42% % % 136 Significant amounts of pathologic bacteria Insignificant amounts of pathologic bacteria Systemic steroids No systemic steroids (n = 25) (n = 165) p (Fisher exact) = Figure 4: Systemic steroids and detection of pathologic bacteria

30 RESULTS Smoking in the family and detection of pathologic bacteria: Significant amounts of pathologic bacteria were found in the bronchoalveolar fluid and bronchial aspirates of 19.59% children whose parents were smoking and of 16.13% children who were not exposed passively to tobacco smoke in the family. There was no significant difference between these two groups (p = ) (Figure 5). Smoking in the family and detection of pathologic bacteria % 83.87% Significant amounts of pathologic bacteria % % 78 Insignificant amounts of pathologic bacteria Smoking in the family 15 No smoking in the family (n = 97) (n = 93) Chi-square: 0.39 p = Figure 5: Smoking in the family and detection of pathologic bacteria

31 RESULTS Antibiotic therapy prior to bronchoscopy and detection of pathologic bacteria: Antibiotic pre-treatment and detection of pathologic bacteria % 79.82% Significant amounts of pathologic bacteria % % 91 Insignificant amounts of pathologic bacteria Antibiotic pretreatment 23 No antibiotic pretreatment (n = 76) (n = 114) Chi-square = 1.01 p = Figure 6: Antibiotic pre-treatment and detection of pathologic bacteria The group of children with antibiotic therapy prior to bronchoscopy had a proportion of detected pathologic bacteria in the lower respiratory tract of 14.47%, which was not statistically different from that of the group of children without antibiotic therapy prior to bronchoscopy, 20.18% (p = ) (Figure 6).

32 RESULTS Gestational age at delivery and detection of pathologic bacteria: Gestational age at delivery and detection of pathologic bacteria: The relationship between gestational age at delivery and detection of pathologic bacteria is shown in figure 7. The detection of pathologic bacteria in the lower respiratory tract was not significantly different between both groups of premature children (4.76%) and full-term children (19.53%) (p = 0.077). Gestational age at delivery and detection of pathologic bacteria % 80.47% % 4.76% 33 1 Premature birth Full-term birth (n = 21) (n = 169) Significant amounts of pathologic bacteria Insignificant amounts of pathologic bacteria p (Fisher exact) = Figure 7: Gestational age at delivery and detection of pathologic bacteria

33 RESULTS Gestational age at delivery and topical corticosteroids: The correlation between gestational age at delivery and topical corticosteroids is illustrated in figure 8. The incidence of topical corticosteroid use was similar between premature children and full-term children % premature children received topical corticosteroids, whereas the proportion of topical corticosteroid therapy in full-term children was 44.38%. No significant difference was observed (p = ). 60 Gestational age at delivery and topical corticosteroids 57.14% 55.62% % 44.38% Topical corticosteroids No topical corticosteroids 10 0 Premature birth Full-term birth (n = 21) (n = 169) Chi-square = 0.02 p = Figure 8: Gestational age at delivery and topical corticosteroids

34 RESULTS Gestational age at delivery and mean duration of topical corticosteroid therapy: The mean durations of topical corticosteroid therapies in premature and in full-term children were ± months and 7.16 ± months, respectively. No significant difference was observed (p = ).

35 DISCUSSION DISCUSSION: There have been many important developments in the understanding of the mechanisms by which topical corticosteroids work, and many more data on the efficacy and safety of topical corticosteroids have been published. Topical corticosteroid therapy carries less risk of complicating drug- or disease-related morbidity and mortality than that associated with other antiasthmatic drugs such as prednisone, theophylline, or ß 2 -agonist bronchodilator. Although the benefits of topical corticosteroids have been demonstrated, there are still concerns to patients, parents and physicians regarding their side-effects. There have been no data available so far that establish a link between topical corticosteroid usage and a tendency toward increased frequency or severity of infections, especially bacterial infections. This study was designed to determine whether topical corticosteroids and other factors such as systemic steroids given prior to bronchoscopy, smoking in the family, antibiotic therapy prior to bronchoscopy and premature birth had any influence on the detection of pathologic bacteria in the lower respiratory tract Topical corticosteroids: Indications for topical corticosteroids: Topical corticosteroids are indicated for the maintenance treatment of bronchial asthma as prophylactic therapy in adult and pediatric patients. They are also used for children with chronic obstructive bronchitis or chronic obstructive pulmonary disease. In asthma, the symptomatic relief of bronchospasm is no longer the only therapeutic target, but control of the inflammatory component of asthma is equally important, especially for long-

36 DISCUSSION 31 term management of the disease. At present, topical corticosteroids are the most effective drugs for reducing bronchial inflammation. In our study, the most common indications of topical corticosteroids were recurrent obstructive bronchitis (51.19%), chronic cough (16.67%) and bronchial asthma (10.71%). The relationship between recurrent wheezing and asthma is still poorly defined but rather close. Cough variant asthma is the most common cause of asthma ( 122 ). Consequently, bronchial hyperreactivity due to an asthma like disease was the indication for topical steroids in most of our patients. Other indications of topical corticosteroids in this study were chronic cough + bronchial obstruction (7.14%), chronic neonatal lung disease (3.57%), recurrent respiratory infections (3.57%), abnormal respiratory sounds from birth (2.38%), pneumonia + bronchial obstruction (2.38%), cough + stridor (1.19%), fibrosing alveolitis (1.19%). This wide range of indications shows that topical corticosteroids are rather widely used in children, not only for the maintenance treatment of asthma or for children with chronic obstructive bronchitis or chronic obstructive pulmonary disease, but also for other problems. In some studies, topical corticosteroids were also used for the therapies other than prophylactic therapy of bronchial asthma. Episodic high dose topical corticosteroids were noted to provide a partially effective strategy for the treatment of mild episodic viral wheeze of childhood ( 123 ). In bronchiectasis, regular use of topical corticosteroids may improve lung function ( 124 ). In ventilated infants with bronchopulmonary dysplasia, topical steroids administered for 1 to 4 weeks improved the rate of extubation with no apparent increase in the risk of sepsis ( 125 ). Otherwise, topical corticosteroid treatment during and after the acute phase of infant respiratory syncytial virus-

37 DISCUSSION 32 bronchiolitis may have a beneficial effect on subsequent bronchial wheezing tendency ( 126 ) Types of topical corticosteroids: Many topical corticosteroid preparations have become commercially available for treatment, such as beclomethasone dipropionate, budesonide, flunisolide, fluticasone propionate, mometasone furoate, and triamcinolone acetonide. Of the topical corticosteroids currently available, budesonide and fluticasone propionate were most commonly prescribed for children in this study with the proportions of 76.2% and 21.4%, respectively. Beclomethasone was only used in 2.4% of the patients. It is difficult to compare the efficacy of different topical corticosteroids, although a substantial number of comparative studies have been performed. Nevertheless, budesonide was used more often than fluticasone of our patients. This might be due to a better familiarity with the drug on the part of the prescribing physicians or due to its lower price Doses of topical corticosteroids: Doses vary with different preparations because differences exist in the amount of medication delivered per puff and in the relative potency of each formulation. Furthermore, doses of topical corticosteroids also depend on inhalation devices. In our study, the mean daily dose of budesonide administered by metered-dose inhaler with spacers was 384 ± 199 µg, while its mean daily dose administered via dry powder inhalers was 511 ± 176 µg and via nebulisers was 822 ± 307 µg. The mean daily dose of fluticasone administered by metered-dose inhaler with spacers was 156 ± 137 µg and via dry powder inhaler was 300 ± 164 µg. There were only 2 children who

38 DISCUSSION 33 inhaled beclomethasone, one used a metered-dose inhaler with spacer at a daily dose of 100 µg, the other one used via dry powder inhaler at a daily dose of 400 µg. Therefore we could not calculate the mean daily dose of beclomethasone. The mean daily doses of topical corticosteroids in our study coincide with the standard doses in the Drug Book for Germany Rote Liste. The following table 7 shows the comparison of the average daily doses from our study with some other studies.

39 DISCUSSION 34 Inhalation device Mean daily dose (µg) Budesonide Fluticasone Metered-dose inhaler 384 ± ± 137 This study Dry powder inhalers 511 ± ± 164 Nebuliser 822 ± 307 Metered-dose inhaler Rote Liste Dry powder inhalers Nebuliser Wigger & Stange ( 127 ) National Institutes of Health Publication, USA ( 128 ) Metered-dose inhaler Dry powder inhalers Nebuliser Low Metered-dose inhaler Dose Dry powder inhalers Medium Metered-dose inhaler Dose Dry powder inhalers High Metered-dose inhaler > 440 Dose Dry powder inhalers > 400 > 400 Pethica P.D et al. ( 129 ) No inhalation device was mentioned 436 ± 266 to 673 ± 475 Table 7: Comparison of the average daily doses of topical corticosteroids in children from different studies.

40 DISCUSSION Duration of topical corticosteroid treatment: Topical corticosteroids suppress the underlying mechanisms of bronchial asthma and cause remission of the condition, but even over long periods of treatment, do not cure the disease because the inflammatory changes of the airways are not totally reversed, even in patients with relatively mild asthma. In addition to suppressing the disease, it appears that topical corticosteroid therapy may also modify the disease outcome if prescribed early enough and long enough ( 130, 131, 132 ). When topical corticosteroid therapy is stopped, most patients will eventually experience symptoms of asthma again. The speed of this relapse is probably related to patient age, length of symptom history, severity of symptoms, signs evident at the onset of therapy, and the total duration of therapy. Infiltration of inflammatory cells into the lamina propria of the airways has been shown to persist in patients with mild-to-moderate asthma, despite regular treatment with topical corticosteroids ( 133 ), which indicated the need for regular maintenance anti-inflammatory treatment. In our study, the mean duration of topical corticosteroid treatment until the time of bronchoscopy was 7.48 months, range from 0.3 months to 84 months Inhaler devices for delivering topical corticosteroids: Numerous inhaler devices and drug combinations are now available for delivering topical corticosteroids. The appropriate use of topical corticosteroids requires the appropriate use of the delivery device, most typically a metered-dose inhaler, dry powder inhaler or nebulizer. Choosing inhaler devices for delivering topical corticosteroids to children depends on age, compliance of children.

41 DISCUSSION 36 Generally, nebulizers could be used for infants and small children ( 134 ). For patients more than 3 years of age who are able to cooperate, a mouthpiece with an extension reservoir should be used. For patients unable to negotiate a mouthpiece (usually under 3 years of age), a face mask should be used ( 135 ). In our study, the mean age of children who used nebulizers were ± months. Accordingly, nebulizers were only prescribed for small children under 3 years. It is probably not feasible to use a metered-dose inhaler in children under the age of 5. However, the use of spacer devices eliminates the requirement of coordinating deep inhalation with actuation of the device. Spacers are particularly recommended for use with topical corticosteroids to prevent the complication of oral candidiasis. The use of a face mask in addition to a spacer device may permit the use of metered-dose inhalers in small children ( 136 ). Aerochamber, Babyhaler and Rondo were spacers usually used in our study, in which Aerochamber and Babyhaler were indicated for small children under 3 years old with the mean ages of ± and ± months, respectively. Children from 5 to 10 years old with the mean age of ± months normally inhaled corticosteroids via Rondo. A dry powder inhaler is another delivery option for topical corticosteroids in children over the age of 5 because the patient must be able to generate a good inspiratory effort ( 137, 138 ). Comparing with children used metered-dose inhalers, children who used dry powder inhalers in this study were older, with the age varied from 8 to 14 years, and the mean ages of children who took Diskus and Turbuhaler were ± and ± months, respectively.

42 DISCUSSION Topical corticosteroids and detection of pathologic bacteria: Topical corticosteroids and detection of pathologic bacteria: Topical corticosteroids are the most effective long-term therapy available for patients with persistent asthma. Although the benefits of topical corticosteroids have been demonstrated, there are still many worries from parents, patients, and physicians about their side-effects. In general, topical corticosteroids are well tolerated and safe at the recommended dosages. Systemic effects have been identified, particularly at high doses, but their clinical significance remains unclear. Some local side-effects such as oropharyngeal candidiasis, dysphonia, cough and bronchospasm, contact allergy, thirsty feeling and hoarseness have been described in the medical literature. Though the manifestation of pulmonary tuberculosis in eight patients on topical beclomethasone dipropionate from India ( 139 ) and a pneumocystis carinii pneumonia associated with topical corticosteroids in an immunocompetent child with bronchial asthma ( 140 ) have been reported, there have been no more data available so far that establish a link between topical corticosteroid usage and pulmonary or systemic infections because little was done about the effects of topical corticosteroids in this respect. Agnew et al. in a prospective study on forty adult asthmatic patients have concluded that no increased incidence of lower respiratory tract infections or non-specific sore throats was found in the group of patients on topical beclomethasone ( 141 ). A review of the extensive medical literature on beclomethasone dipropionate failed to identify any association between severe viral infections and topical