The development of chronic cough in children following presentation to a tertiary paediatric emergency department with acute respiratory illness : study protocol for a prospective cohort study

Background Acute respiratory illness, a leading cause of cough in children, accounts for a substantial proportion of childhood morbidity and mortality worldwide. In some children acute cough progresses to chronic cough (> 4 weeks duration), impacting on morbidity and decreasing quality of life. Despite the importance of chronic cough as a cause of substantial childhood morbidity and associated economic, family and social costs, data on the prevalence, predictors, aetiology and natural history of the symptom are scarce. This study aims to comprehensively describe the epidemiology, aetiology and outcomes of cough during and after acute respiratory illness in children presenting to a tertiary paediatric emergency department. Methods/design A prospective cohort study of children aged <15 years attending the Royal Children's Hospital Emergency Department, Brisbane, for a respiratory illness that includes parent reported cough (wet or dry) as a symptom. The primary objective is to determine the prevalence and predictors of chronic cough (>= 4 weeks duration) post presentation with acute respiratory illness. Demographic, epidemiological, risk factor, microbiological and clinical data are completed at enrolment. Subjects complete daily cough dairies and weekly follow-up contacts for 28(+/-3) days to ascertain cough persistence. Children who continue to cough for 28 days post enrolment are referred to a paediatric respiratory physician for review. Primary analysis will be the proportion of children with persistent cough at day 28(+/-3). Multivariate analyses will be performed to evaluate variables independently associated with chronic cough at day 28(+/-3). Discussion Our protocol will be the first to comprehensively describe the natural history, epidemiology, aetiology and outcomes of cough during and after acute respiratory illness in children. The results will contribute to studies leading to the development of evidence-based clinical guidelines to improve the early detection and management of chronic cough in children during and after acute respiratory illness.

Validation of a parent-proxy quality of life questionnaire for paediatric chronic cough (PC-QOL)

Background Quality of life (QOL) measures are an important patient-relevant outcome measure for clinical studies. Currently there is no fully validated cough-specific QOL measure for paediatrics. The objective of this study was to validate a cough-specific QOL questionnaire for paediatric use. Method 43 children (28 males, 15 females; median age 29 months, IQR 20–41 months) newly referred for chronic cough participated. One parent of each child completed the 27-item Parent Cough-Specific QOL questionnaire (PC-QOL), and the generic child (Pediatric QOL Inventory 4.0 (PedsQL)) and parent QOL questionnaires (SF-12) and two cough-related measures (visual analogue score and verbal category descriptive score) on two occasions separated by 2–3 weeks. Cough counts were also objectively measured on both occasions. Results Internal consistency for both the domains and total PC-QOL at both test times was excellent (Cronbach alpha range 0.70–0.97). Evidence for repeatability and criterion validity was established, with significant correlations over time and significant relationships with the cough measures. The PC-QOL was sensitive to change across the test times and these changes were significantly related to changes in cough measures (PC-QOL with: verbal category descriptive score, rs=−0.37, p=0.016; visual analogue score, rs=−0.47, p=0.003). Significant correlations of the difference scores for the social domain of the PC-QOL and the domain and total scores of the PedsQL were also noted (rs=0.46, p=0.034). Conclusion The PC-QOL is a reliable and valid outcome measure that assesses QOL related to childhood cough at a given time point and measures changes in cough-specific QOL over time.

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.

Clinical pathways for chronic cough in children

Background Chronic cough (a cough lasting longer than four weeks) is a common problem internationally. Chronic cough has associated economic costs and is distressing to the child and to parents; ignoring cough may lead to delayed diagnosis and progression of serious underlying respiratory disease. Clinical guidelines have been shown to lead to efficient and effective patient care and can facilitate clinical decision making. Cough guidelines have been designed to facilitate the management of chronic cough. However, treatment recommendations vary, and specific clinical pathways for the treatment of chronic cough in children are important, as causes of and treatments for cough vary significantly from those in adults. Therefore, systematic evaluation of the use of evidence-based clinical pathways for the management of chronic cough in children would be beneficial for clinical practice and for patient care. Use of a management algorithm can improve clinical outcomes; such management guidelines can be found in the guidelines for cough provided by the American College of Chest Physicians (ACCP) and the British Thoracic Society (BTS). Objectives To evaluate the effectiveness of using a clinical pathway in the management of children with chronic cough. Search methods The Cochrane Register of Controlled Trials (CENTRAL), the Cochrane Airways Group Specialised Register, MEDLINE, EMBASE, review articles and reference lists of re levant articles were searched. The latest search was conducted in January 2014. Selection criteria All randomised controlled trials of parallel-group design comparing use versus non-use of a clinical pathway for treatment of chronic cough in children (< 18 years of age). Data collection and analysis Results of searches were reviewed against predetermined cr iteria for inclusion. Two review authors independently selected studies and performed data extraction in duplicate. Main results One study was included in the review. This multi-centre trial was based in five Australian hospitals and recruited 272 children with chronic cough. Children were randomly assigned to early (two weeks) or delayed (six weeks) referral to respiratory specialists who used a cough management pathway. When an intention-to-treat analysis was performed, clinical failure at six wee ks post randomisation (defined as < 75% improvement in cough score, or total resolution for fewer than three consecutive days) was significantly less in the early pathway arm compared with the control arm (odds ratio (OR) 0.35, 95% confidence interval (CI) 0.21 to 0.58). These results indicate that one additional child will be cured for e very five children treated via th e cough pathway (number needed to treat for an additional beneficial outcome (NNTB) = 5, 95% CI 3 to 9) at six weeks. Cough-specific parent-reported quality of life scores were significantly better in th e early-pathway group; the mean difference (MD) between groups was 0.60 (95% CI 0.19 to 1.01). Duration of cough post randomisation was significantly shorter in the intervention group (early-pathway arm) compared with the control group (delayed-pathway arm) (MD -2.70 weeks, 95% CI -4.26 to -1.14). Authors’ conclusions. Current evidence suggests that using a clinical algorithm for the management of children with ch r onic cough in h ospital outpatient settings is more effective than providing wait-list care. Futher high-quality randomised controlled trials are needed to perform ongoing evaluation of cough management pathways in general practitioner and other primary care settings.

Development of a children's acute cough specific quality of life questionnaire (Pac-Qol)

The high burden of parental concern in children with chronic cough has been well documented. Acute cough in children (lasting less than 2 weeks) also has a significant impact on families, reflected by the number of doctor visits for cough. Currently there is no validated acute cough specific quality of life (QOL) measure for children. The objective of this study is to develop and validate an acute cough specific QOL questionnaire (PAC-QOL) for paediatric use. Here we present our data on item selection. Methods Two independent focus groups were conducted to determine relevant items. Parents discussed the impact of their child’s current or previous episodes of acute cough on their child, themselves and their family functioning. Transcripts were analyzed to determine whether discussions had reached an item saturation point. Items were also compared against our previously validated parent-centred children’s chronic cough specific QOL questionnaire (PC-QOL), which was used as a model. The newly developed acute cough specific QOL questionnaire is designed to assess the level of frequency of parents’ feelings and worry related to their child’s acute cough, using a 24-h time-point reference. Results Newly identified acute cough specific items include parental worry around whether or not they should take their child to a doctor or emergency department, and frequency of seeking assistance from friends and family. Conclusions While there are similarities between items identified for both acute and chronic cough, there are distinct features. Further data will be collected for item reduction and validation of this children’s acute cough specific QOL questionnaire.

Defining the parental burden of acute cough in children

Despite the prevalence of acute cough in children (<2 weeks duration), the burden to parents and families is largely unknown. The objectives of this study were to determine the parental burden of children’s acute cough, and to evaluate psychological and other infl uences on the reported burden of acute cough in children. Methods Parents of children with a current acute cough (<2 weeks) at enrolment completed 4 questionnaires (state trait anxiety inventory (STAI); short form health survey (SF-8); depression, anxiety and stress 21-item scale (DASS21); and our preliminary 48-item parent acute cough specifi c quality of life (PAC-QOL48) questionnaire). In PAC-QOL48, lower scores refl ect worse QOL. Results Median age of the 104 children enrolled was 2.63 (IQR 1.42, 4.79) years, 54 were boys. Median length of cough at enrolment was 3 (IQR 2, 5) days. Median total PAC-QOL48 score of parents enrolled at presentation to the emergency department (n = 70) was signifi cantly worse than of parents enrolled through the community (n = 24) (p < 0.01). More than half (n = 55) had sought medical assistance more than once for the current acute coughing illness. PAC-QOL48 score was signifi cantly negatively correlated to verbal category descriptive and visual analogue scale cough scores (Spearman r = −0.26, p = 0.05 and r = −0.46, p = 0.01 respectively) and DASS21 total score (r = −0.36, p = 0.01), but not to child’s age. Conclusions Consistent with data on chronic cough, stress was the predominant factor of parental burden. This study highlights the ongoing need for clinicians to be cognizant of parental worries and concerns when their children are coughing, and for further research into safe and effective therapies for acute cough in children.

Do sex and atopy influence cough outcome measurements in children?

Background Despite the commonality of cough and its burden, there are no published data on the relationship between atopy or sex on objectively measured cough frequency or subjective cough scores in children. In 202 children with and without cough, we determined the effect of sex and atopy on validated cough outcome measurements (cough receptor sensitivity [CRS], objective cough counts, and cough scores). We hypothesized that in contrast to adult data, sex does not influence cough outcome measures, and atopy is not a determinant of these cough measurements. Methods We combined data from four previous studies. Atopy (skin prick test), the concentration of capsaicin causing two and five or more coughs (C2 and C5, respectively), objectively measured cough frequency, and cough scores were determined and their relationship explored. The children’s (93 girls, 109 boys) mean age was 10.6 years (SD 2.9), and 56% had atopy. Results In multivariate analysis, CRS was influenced by age (C2 coefficient, 5.9; P = .034; C5 coefficient, 29.1; P = .0001). Atopy and sex did not significantly influence any of the cough outcomes (cough counts, C2, C5, cough score) in control subjects and children with cough. Conclusions Atopy does not influence important cough outcome measures in children with and without chronic cough. However, age, but not sex, influences CRS in children. Unlike adult data, sex does not affect objective counts or cough score in children with and without chronic cough. Studies on cough in children should be age matched, but matching for atopic status and sex is less important.

An objective study of acid reflux and cough in children using an ambulatory pHmetry-cough logger

Objective There are no objective ambulatory studies on the temporal relationship between reflux and cough in children. Commercial pHmetry loggers have slow capture rates (0.25 Hz) that limit objective quantification of reflux and cough. The authors aimed to evaluate if there is a temporal association between cough and acid pH in ambulatory children with chronic cough. setting and patients The authors studied children (aged <14 years) with chronic cough, suspected of acid reflux and considered for pHmetry using a specifically built ambulatory pHmetry–cough logger that enabled the simultaneous ambulatory recording of cough and pH with a fast (10 Hz) capture rate. Main outcome measures Coughs within (before and after) 10, 30, 60 and 120 s of a reflux episode (pH<4 for >0.5 s). Results Analysis of 5628 coughs in 20 children. Most coughs (83.9%) were independent of a reflux event. Cough–reflux (median 19, IQR 3–45) and reflux–cough (24.5, 13–51) sequences were equally likely to occur within 120 s. Within the 10 and 30 s time frame, reflux–cough (10 s=median 2.5, IQR 0–7.25; 30 s=6.5, 1.25–22.25) sequences were significantly less frequent than reflux–no cough (10 s=27, IQR 15–65; 30 s=24.5, 14.5–55.5) sequences, (p=0.0001 and p=0.001, respectively). No differences were found for 60 and 120 s time frame. Cough–reflux sequence (median 1.0, IQR 0–8) within 10 s was significantly less (p=0.0001) than no cough–reflux sequences (median 29.5, 15–67), within 30 s (p=0.006) and 60 s (p=0.048) but not within 120 s (p=0.47). Conclusions In children with chronic cough and suspected of having gastro-oesophageal reflux disease, the temporal relationship between acid reflux and cough is unlikely causal.

Cough and exhaled nitric oxide levels : what happens with exercise?

Cough associated with exertion is often used as a surrogate marker of asthma. However, to date there are no studies that have objectively measured cough in association with exercise in children. Our primary aim was to examine whether children with a pre-existing cough have an increase in cough frequency during and post-exercise. We hypothesized that children with any coughing illness will have an increase in cough frequency post-exercise regardless of the presence of exercise-induced broncho-constriction (EIB) or atopy. In addition, we hypothesized that Fractional exhaled nitric oxide (FeNO) levels decreases post-exercise regardless of the presence of EIB or atopy. Children with chronic cough and a control group without cough undertook an exercise challenge, FeNO measurements and a skin prick test, and wore a 24-h voice recorder to objectively measure cough frequency. The association between recorded cough frequency, exercise, atopy, and presence of EIB was tested. We also determined if the change in FeNO post exercise related to atopy or EIB. Of the 50 children recruited (35 with cough, 15 control), 7 had EIB. Children with cough had a significant increase in cough counts (median 7.0, inter-quartile ranges, 0.5, 24.5) compared to controls (2.0, IQR 0, 5.0, p = 0.028) post-exercise. Presence of atopy or EIB did not influence cough frequency. FeNO level was significantly lower post-exercise in both groups but the change was not influenced by atopy or EIB. Cough post-exertion is likely a generic response in children with a current cough. FeNO level decreases post-exercise irrespective of the presence of atopy or EIB. A larger study is necessary confirm or refute our findings.

Cough and reflux esophagitis in children: their co-existence and airway cellularity

Background There are no prospective studies that have examined for chronic cough in children without lung disease but with gastroesophageal reflux (GER). In otherwise healthy children undergoing flexible upper gastrointestinal endoscopy (esophago-gastroscopy), the aims of the study were to (1) define the frequency of cough in relation to symptoms of GER, (2) examine if children with cough and reflux esophagitis (RE) have different airway cellularity and microbiology in bronchoalveolar lavage (BAL) when compared to those without. Methods Data specific for chronic cough (>4-weeks), symptoms of GER and cough severity were collected. Children aged <16-years (n = 150) were defined as 'coughers' (C+) if a history of cough in association with their GER symptoms was elicited before BAL were obtained during elective esophago-gastroscopy. Presence of esophagitis on esophageal biopsies was considered reflux esophagitis positive (E+). Results C+ (n = 69) were just as likely as C- (n = 81) to have esophagitis, odds ratio 0.87 (95%CI 0.46, 1.7). Median neutrophil percentage in BAL was significantly different between groups; highest in C+E- (7, IQR 28) and lowest in C-E+ (5, IQR 6). BAL positive bacterial culture occurred in 20.7% and were more likely present in current coughers (OR 3.37, 95%CI 1.39, 8.08). Airway neutrophilia (median 20%, IQR 34) was significantly higher in those with BAL positive bacterial cultures than those without (5%, 4; p = 0.0001). Conclusion In children without lung disease, the common co-existence of cough with symptoms of GER is independent of the occurrence of esophagitis. Airway neutrophilia when present in these children is more likely to be related to airway bacterial infection and not to esophagitis.

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.

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 ACTRN12612000010897. http://www.anzctr.org.au/trial_view.aspx?id=347879

The respiratory health of urban Indigenous children aged less than 5 years: Study protocol for a prospective cohort study

Background Despite the burden of acute respiratory illnesses (ARI) among Aboriginal and Torres Strait Islander children being a substantial cause of childhood morbidity and associated costs to families, communities and the health system, data on disease burden in urban children are lacking. Consequently evidence-based decision-making, data management guidelines, health resourcing for primary health care services and prevention strategies are lacking. This study aims to comprehensively describe the epidemiology, impact and outcomes of ARI in urban Aboriginal and Torres Strait Islander children (hereafter referred to as Indigenous) in the greater Brisbane area. Methods/design A prospective cohort study of Indigenous children aged less than five years registered with a primary health care service in Northern Brisbane, Queensland, Australia. Children are recruited at time of presentation to the service for any reason. Demographic, epidemiological, risk factor, microbiological, economic and clinical data are collected at enrolment. Enrolled children are followed for 12 months during which time ARI events, changes in child characteristics over time and monthly nasal swabs are collected. Children who develop an ARI with cough as a symptom during the study period are more intensely followed-up for 28(±3) days including weekly nasal swabs and parent completed cough diary cards. Children with persistent cough at day 28 post-ARI are reviewed by a paediatrician. Discussion Our study will be one of the first to comprehensively evaluate the natural history, epidemiology, aetiology, economic impact and outcomes of ARIs in this population. The results will inform studies for the development of evidence-based guidelines to improve the early detection, prevention and management of chronic cough and setting of priorities in children during and after ARI.

Randomised controlled trial of amoxycillin clavulanate in children with chronic wet cough

Background Despite guideline recommendations, there are no published randomised controlled trial data on the efficacy of antibiotics for chronic wet cough in children. The majority of children with chronic wet cough have protracted bacterial bronchitis (PBB), a recognised condition in multiple national guidelines. The authors conducted a parallel 1:1 placebo randomised controlled trial to test the hypothesis that a 2-week course of amoxycillin clavulanate is efficacious in the treatment of children with chronic wet cough. Methods 50 children (median age 1.9 years, IQR 0.9–5.1) with chronic (>3 weeks) wet cough were randomised to 2 weeks of twice daily oral amoxycillin clavulanate (22.5 mg/kg/dose) or placebo. The primary outcome was ‘cough resolution’ defined as a >75% reduction in the validated verbal category descriptive cough score within 14 days of treatment compared with baseline scores, or cessation of cough for >3 days. In selected children, flexible bronchoscopy and bronchoalveolar lavage (BAL) were undertaken at baseline. Results Cough resolution rates (48%) were significantly higher in children who received amoxycillin clavulanate compared with those who received placebo (16%), p=0.016. The observed difference between proportions was 0.32 (95% CI 0.08 to 0.56). Post treatment, median verbal category descriptive score in the amoxycillin clavulanate group of 0.5 (IQR 0.0–2.0) was significantly lower than in the placebo group, 2.25 (IQR 1.15–2.9) (p=0.02). Pre-treatment BAL data were consistent with PBB in the majority of children, with no significant difference between groups. Conclusion A 2-week course of amoxycillin clavulanate will achieve cough resolution in a significant number of children with chronic wet cough. BAL data support the diagnosis of PBB in the majority of these children.