Bronchiectasis exacerbation study on azithromycin and amoxycillin-clavulanate for respiratory exacerbations in children (BEST-2): study protocol for a randomized controlled trial.

BACKGROUND: Bronchiectasis unrelated to cystic fibrosis (CF) is being increasingly recognized in children and adults globally, both in resource-poor and in affluent countries. However, high-quality evidence to inform management is scarce. Oral amoxycillin-clavulanate is often the first antibiotic chosen for non-severe respiratory exacerbations, because of the antibiotic-susceptibility patterns detected in the respiratory pathogens commonly associated with bronchiectasis. Azithromycin has a prolonged half-life, and with its unique anti-bacterial, immunomodulatory, and anti-inflammatory properties, presents an attractive alternative. Our proposed study will test the hypothesis that oral azithromycin is non-inferior (within a 20% margin) to amoxycillin-clavulanate at achieving resolution of non-severe respiratory exacerbations by day 21 of treatment in children with non-CF bronchiectasis. METHODS: This will be a multicenter, randomized, double-blind, double-dummy, placebo-controlled, parallel group trial involving six Australian and New Zealand centers. In total, 170 eligible children will be stratified by site and bronchiectasis etiology, and randomized (allocation concealed) to receive: 1) azithromycin (5 mg/kg daily) with placebo amoxycillin-clavulanate or 2) amoxycillin-clavulanate (22.5 mg/kg twice daily) with placebo azithromycin for 21 days as treatment for non-severe respiratory exacerbations. Clinical data and a parent-proxy cough-specific quality of life (PC-QOL) score will be obtained at baseline, at the start and resolution of exacerbations, and on day 21. In most children, blood and deep-nasal swabs will also be collected at the same time points. The primary outcome is the proportion of children whose exacerbations have resolved at day 21. The main secondary outcome is the PC-QOL score. Other outcomes are: time to next exacerbation; requirement for hospitalization; duration of exacerbation, and spirometry data. Descriptive viral and bacteriological data from nasal samples and blood inflammatory markers will be reported where available. DISCUSSION: Currently, there are no published randomized controlled trials (RCT) to underpin effective, evidence-based management of acute respiratory exacerbations in children with non-CF bronchiectasis. To help address this information gap, we are conducting two RCTs. The first (bronchiectasis exacerbation study; BEST-1) evaluates the efficacy of azithromycin and amoxycillin-clavulanate compared with placebo, and the second RCT (BEST-2), described here, is designed to determine if azithromycin is non-inferior to amoxycillin-clavulanate in achieving symptom resolution by day 21 of treatment in children with acute respiratory exacerbations. TRIAL REGISTRATION: Australia and New Zealand Clinical Trials Register (ANZCTR) number http://ACTRN12612000010897. http://www.anzctr.org.au/trial_view.aspx?id=347879.

Antibiotics for bronchiectasis exacerbations in children: rationale and study protocol for a randomised placebo-controlled trial.

BACKGROUND: Despite bronchiectasis being increasingly recognised as an important cause of chronic respiratory morbidity in both indigenous and non-indigenous settings globally, high quality evidence to inform management is scarce. It is assumed that antibiotics are efficacious for all bronchiectasis exacerbations, but not all practitioners agree. Inadequately treated exacerbations may risk lung function deterioration. Our study tests the hypothesis that both oral azithromycin and amoxicillin-clavulanic acid are superior to placebo at improving resolution rates of respiratory exacerbations by day 14 in children with bronchiectasis unrelated to cystic fibrosis. METHODS: We are conducting a bronchiectasis exacerbation study (BEST), which is a multicentre, randomised, double-blind, double-dummy, placebo-controlled, parallel group trial, in five centres (Brisbane, Perth, Darwin, Melbourne, Auckland). In the component of BEST presented here, 189 children fulfilling inclusion criteria are randomised (allocation-concealed) to receive amoxicillin-clavulanic acid (22.5 mg/kg twice daily) with placebo-azithromycin; azithromycin (5 mg/kg daily) with placebo-amoxicillin-clavulanic acid; or placebo-azithromycin with placebo-amoxicillin-clavulanic acid for 14 days. Clinical data and a paediatric cough-specific quality of life score are obtained at baseline, at the start and resolution of exacerbations, and at day 14. In most children, blood and deep nasal swabs are also collected at the same time points. The primary outcome is the proportion of children whose exacerbations have resolved at day 14. The main secondary outcome is the paediatric cough-specific quality of life score. Other outcomes are time to next exacerbation; requirement for hospitalisation; duration of exacerbation; and spirometry data. Descriptive viral and bacteriological data from nasal samples and blood markers will also be reported. DISCUSSION: Effective, evidence-based management of exacerbations in people with bronchiectasis is clinically important. Yet, there are few randomised controlled trials (RCTs) in the neglected area of non-cystic fibrosis bronchiectasis. Indeed, no published RCTs addressing the treatment of bronchiectasis exacerbations in children exist. Our multicentre, double-blind RCT is designed to determine if azithromycin and amoxicillin-clavulanic acid, compared with placebo, improve symptom resolution on day 14 in children with acute respiratory exacerbations. Our planned assessment of the predictors of antibiotic response, the role of antibiotic-resistant respiratory pathogens, and whether early treatment with antibiotics affects duration and time to the next exacerbation, are also all novel. TRIAL REGISTRATION: Australia and New Zealand Clinical Trials Register (ANZCTR) number ACTRN12612000011886.

A multicenter study on chronic cough in children : burden and etiologies based on a standardized management pathway.

BACKGROUND: While the burden of chronic cough in children has been documented, etiologic factors across multiple settings and age have not been described. In children with chronic cough, we aimed (1) to evaluate the burden and etiologies using a standard management pathway in various settings, and (2) to determine the influence of age and setting on disease burden and etiologies and etiology on disease burden. We hypothesized that the etiology, but not the burden, of chronic cough in children is dependent on the clinical setting and age. METHODS: From five major hospitals and three rural-remote clinics, 346 children (mean age 4.5 years) newly referred with chronic cough (> 4 weeks) were prospectively managed in accordance with an evidence-based cough algorithm. We used a priori definitions, timeframes, and validated outcome measures (parent-proxy cough-specific quality of life [PC-QOL], a generic QOL [pediatric quality of life (PedsQL)], and cough diary). RESULTS: The burden of chronic cough (PC-QOL, cough duration) significantly differed between settings (P = .014, 0.021, respectively), but was not influenced by age or etiology. PC-QOL and PedsQL did not correlate with age. The frequency of etiologies was significantly different in dissimilar settings (P = .0001); 17.6% of children had a serious underlying diagnosis (bronchiectasis, aspiration, cystic fibrosis). Except for protracted bacterial bronchitis, the frequency of other common diagnoses (asthma, bronchiectasis, resolved without specific-diagnosis) was similar across age categories. CONCLUSIONS: The high burden of cough is independent of children's age and etiology but dependent on clinical setting. Irrespective of setting and age, children with chronic cough should be carefully evaluated and child-specific evidence-based algorithms used.

Post-natal corticosteroids are associated with reduced expiratory flows in children born very preterm.

AIM: Infants born very prematurely often received corticosteroids to minimise the risk of developing bronchopulmonary dysplasia (BPD) but their long term impact on lung function at school age is unclear. METHODS: A cross-sectional study of 105 children [mean gestation of 27 weeks] was undertaken. Lung function assessments were conducted at a mean age of 10 years according to standard criteria. Corticosteroid dose was obtained from the medical record. RESULTS: Spirometry in the BPD group was not significantly different to the non-BPD group, mean per-cent predicted (95% confidence interval) forced expiratory volume in 1 s (FEV1) 83% (79, 87) versus 86% (83, 90), FEF25%-75% 67% (60, 73) versus 75% (69, 81). Antenatal steroid treatment alone did not adversely affect airflow FEV1, 88% (84.92) versus 90% (82.97), and forced expiratory flow (FEF)25%-75%, 75% (69.81) versus 87% (70.104). Children who received post-natal corticosteroids had significantly lower flows than those who did not (FEV1 82% (78.85) vs. 88% (85.92), P = 0.006; FEF25%-75% 65% (59.71) vs. 78% (72.84), P = 0.003). Regression analysis revealed days on oxygen and days ventilated were statistically significant but weak predictors of airflow at 10 years of age. CONCLUSIONS: A diagnosis of BPD did not predict reduced spirometry in middle childhood. Children who received post-natal corticosteroids as preterm infants had reduced expiratory flows compared with those who did not. While post-natal corticosteroids may be a marker of severity of lung disease, the potential of post-natal corticosteroids to influence lung development requires further investigation.

Segregation of children with CF diagnosed via newborn screening and acquisition of Pseudomonas aeruginosa.

BACKGROUND: Data from the Wisconsin newborn screening (NBS) study show that neonatally diagnosed infants are at risk of early Pseudomonas aeruginosa (PsA) acquisition. We have had NBS since 1981 and in 2003, introduced PsA-free 'segregation' from older patients for children < or =5. This study investigated the effect of simple 'segregation' on acquisition of respiratory pathogens. METHODS: Sputum culture results (n=2814) and details of antibiotic use before (1999-2002) and after (2004-2007) 'segregation' were collected. RESULTS: Each year each child provided an average of 4.6 samples for culture. There was a significant decrease (p< or =0.001 Chi(2)) in the acquisition of mucoid (from 5.9% of children to 1.0%) but not non-mucoid PsA (22.3% and 22.7%, respectively) after 'segregation'. There was no significant change in other respiratory pathogens. CONCLUSIONS: Young children with CF diagnosed via NBS can be protected from the acquisition of mucoid PsA by 'segregation' and the acquisition of non-mucoid PsA is likely to be from environmental sources outside the hospital.

Cough in children: definitions and clinical evaluation.

The aetiology and management approach for cough in children differs greatly to that in adults, so the empirical approach commonly used in adults is unsuitable for children. Clinical evaluation of cough in children should include an assessment of environmental factors, particularly tobacco smoke, parental concerns and expectations. Most children with acute cough are likely to have an uncomplicated viral acute respiratory tract infection, but the possibility of a more serious problem, especially aspiration of foreign material, should always be considered. Isolated chronic cough in children is rarely asthma, and the term "cough variant asthma" should not be used. Over-the-counter and prescription medications are ineffective for the symptomatic relief of acute cough. Treatment for chronic cough should be based on aetiology. Because of the favourable natural history of cough, a "positive" response in medication trials should not be assumed to be due to the medication. Children should be reassessed within the expected timeframe of response to therapy.

Psychological and family functioning and quality of life in adolescents with cystic fibrosis.

BACKGROUND: The life expectancy of individuals with CF has increased to 33 years. Thus, issues such as quality of life and psychological well-being, previously thought to be of lesser importance than physical well-being, are now recognised as significant factors. This study examined the interrelationships between quality of life, family functioning, individual psychopathology and optimism of adolescents with CF. METHODS: Adolescents attending the CF clinic completed a number of questionnaires. Quality of Life was measured using the Cystic Fibrosis Questionnaire, family functioning by the Family Environment Scale (3rd edition), general psychopathology with the Symptom Checklist-90-Revised and optimism for the future by the Hunter Opinions and Personal Expectations Scale. Disease severity was assessed using the Shwachman score and spirometry at the time of questionnaire completion. RESULTS: The level of psychopathology (12.5% of those 13 years and over) in the group was lower than that reported for young people in Australia (15-20%). The results indicated that young people with a delayed diagnosis and those who are alienated from their families may be in need of additional psychosocial support. The group was hopeful and positive about their future and these attributes were independent of clinical measures of disease severity. In general, these young people scored relatively highly on the quality of life scale. For example the mean standardised score for physical functioning was 70 points, for respiratory symptoms was 63 points and for emotional state was 78 points. Increased levels of psychopathology and lack of hope for the future were however associated with lower ratings on a number of quality of life measures. Family cohesiveness, expressiveness and organization were associated with better psychological functioning in the young people. CONCLUSIONS: Adolescents with CF appear to be a psychologically well functioning and well-adjusted group. These findings support the importance of a more sophisticated model of well-being for adolescents with CF, which explores the young person's views on their quality of life and wider support frameworks rather than relying solely on measures of physical health to gauge well-being.

Muscle function and resting energy expenditure in female athletes with cystic fibrosis.

The pathophysiology of impaired exercise tolerance in patients with cystic fibrosis (CF) is not completely understood. The objective of this study was to compare exercise ability (at clinical and cellular levels) and resting energy expenditure in female athletes with CF compared with matched control subjects. Sixteen subjects and matched control subjects participated in the study. The girls with CF not only had a significantly greater resting energy expenditure (7.6% higher; p<0.05), their habitual daily activity was also significantly greater than that of control subjects (15% greater; p<0.01). Peak aerobic capacity was similar in both groups. However, peak anaerobic power was 20% less (p<0.05) in girls with CF. The 31P magnetic resonance spectroscopy studies demonstrated that there were no differences between the groups at rest, but at 25% total work output the girls with CF were less acidotic (CF, pH 6.99 [0.06]; control subjects, 6.90 [0.05]) and had a significantly lower inorganic phosphorus-to-phosphocreatine ratio (CF, 0.34 [0.07]; control subjects, 0.41 [0.08]). These differences continued to increase to maximal exercise. This study demonstrates that in spite of normal lung function and good nutritional status, females athletes with CF still had significant deficiencies in some measures of fitness and muscle metabolism compared with healthy athletes.

Validation of shuttle tests in children with cystic fibrosis.

Shuttle tests are simple, inexpensive field tests that have been used to estimate the cardiorespiratory status of children. It has yet to be validated in children with CF. The aim of this study was to assess the reproducibility and criterion validity of shuttle tests in children with cystic fibrosis (CF). Ninety-three CF patients aged 6 to 16 years of age with a wide range of disease severity performed the study. The 10-m shuttle test was used for children 7 years of age and younger and those deemed too chronically ill by their physicians to perform the longer test (n = 35.) All other children performed the 20-m shuttle test (n = 58). Reproducibility and criterion validity were assessed for each child over a two week period. Gas analysis was performed throughout testing using a polargraphic gas analyzer. The 10-m shuttle tests were reproducible (mean difference between tests VO(2) 2.41 mL/kg/min, CI 3.46,-0.18) and the difference from treadmill testing was not statistically significant (mean difference VO(2) 5.30 mL/kg/min, CI-7.46, 1.18). The 20-m shuttle tests were reproducible (mean difference between tests VO(2) 2.07 mL/kg/min, CI-3.90,0.60) and the difference from treadmill testing was not statistically significant (mean difference VO(2) 3.50 mL/kg/min, CI-4.90, 1.60). We conclude that when formal exercise testing with treadmill or cycle ergometer cannot be performed, the shuttle tests provide a reproducible and valid alternative.

The relationship between genotype and exercise tolerance in children with cystic fibrosis.

The relationship between fitness and genotype in children with cystic fibrosis (CF) and at least one copy of the DeltaF508 mutation was examined. Genotype was classified according to the second CF mutation. Fitness was measured by peak aerobic capacity (using a modified Bruce protocol during treadmill exercise) and anaerobic power (using the Wingate test on a cycle ergometer). The class of cystic fibrosis transmembrane regulator proteins (CFTR) mutation was statistically related with aerobic capacity, peak anaerobic power, body mass index, lung function (forced expiratory volume in one second), and disease severity as measured by the Shwachman score. Patients with mutations causing defective CFTR production (Class I) or processing (Class II) had a significantly lower peak aerobic capacity (28.6 +/- 4.2 ml/kg/min and 31.7 +/- 5.4 ml/kg/min, respectively) than those with a mutation conferring defective regulation of CFTR (Class III) (43.9 +/- 6.4 ml/kg/min). The peak anaerobic power in subjects with mutations inducing decreased CFTR conduction (Class IV) or CFTR mRNA (Class V), were significantly higher (11.4 +/- 1.7 and 11.6 +/- 1.5 watts/kg, respectively) than children with Class I (9.7 +/- 1.4 watts/kg), Class II (9.8 +/- 1.4 watts/kg), or Class III (10.5 +/- 1.8 watts/kg) mutations. There were no statistically significant differences in the lung function of patients with the different mutations. These results indicate a relationship between CF genotype and some measures of fitness, the mechanisms of which remain to be determined.