Cough in Children and Adults: Diagnosis, Assessment and Management (CICADA). Summary of an updated position statement on chronic cough in Australia.

INTRODUCTION: Cough is the most common symptom leading to medical consultation. Chronic cough results in significant health care costs, impairs quality of life, and may indicate the presence of a serious underlying condition. Here, we present a summary of an updated position statement on cough management in the clinical consultation. MAIN RECOMMENDATIONS: Assessment of children and adults requires a focused history of chronic cough to identify any red flag cough pointers that may indicate an underlying disease. Further assessment with examination should include a chest x-ray and spirometry (when age > 6 years). Separate paediatric and adult diagnostic management algorithms should be followed. Management of the underlying condition(s) should follow specific disease guidelines, as well as address adverse environmental exposures and patient/carer concerns. First Nations adults and children should be considered a high risk group. The full statement from the Thoracic Society of Australia and New Zealand and Lung Foundation Australia for managing chronic cough is available at https://lungfoundation.com.au/resources/cicada-full-position-statement. CHANGES IN MANAGEMENT AS A RESULT OF THIS STATEMENT: Algorithms for assessment and diagnosis of adult and paediatric chronic cough are recommended. High quality evidence supports the use of child-specific chronic cough management algorithms to improve clinical outcomes, but none exist in adults. Red flags that indicate serious underlying conditions requiring investigation or referral should be identified. Early and effective treatment of chronic wet/productive cough in children is critical. Culturally specific strategies for facilitating the management of chronic cough in First Nations populations should be adopted. If the chronic cough does not resolve or is unexplained, the patient should be referred to a respiratory specialist or cough clinic.

How does parent/self-reporting of common respiratory conditions compare with medical records among Aboriginal and Torres Strait Islander (Indigenous) children and young adults?

AIM: Self-reporting and/or data from medical records are frequently used in studies to ascertain health history. Data on the discrepancies between these information sources is lacking for Indigenous Australians. This study reports such data for selected respiratory and atopic conditions common among Indigenous Australians. METHODS: Data were extracted from the Indigenous respiratory reference value study, a multicentre cross-sectional study of Indigenous children and young adults (3-25 years) between June 2015 and November 2017. Only those living in rural/remote regions were included. Self-reported history was collected from parents (if participants <18 years) or participants. Medical records were manually reviewed. Participants with incomplete data (missing self-reported and/or medical record information) were excluded. Agreement between sources was examined using Cohen's kappa. RESULTS: Of 1097 participants, 889 (97.1% <18 years) had sufficient self-reported and medical record histories for comparison. Asthma was self-reported by 15.7% of participants and was reported in medical records for 10.3% (κ = 0.53, 95% confidence interval (CI) 0.45-0.61). For bronchiectasis, the reported rates were 1.5 and 0.7% (κ = 0.52, 95% CI 0.25-0.80), pneumonia 1.1 and 5.8% (κ = 0.15, 95% CI 0.02-0.27), allergic rhinitis 6.6 and 0.6% (κ = 0.05, 95% CI -0.03, 0.13) and eczema 5.8 and 6.2% (κ = 0.30, 95% CI 0.18-0.42). CONCLUSIONS: Within our cohort, agreement was moderate for asthma and bronchiectasis, fair for eczema and poor for pneumonia and allergic rhinitis. These results highlight the challenges associated with how best to obtain an accurate health history within Australian Indigenous rural/remote communities. Generalisability of findings and contributions of poor health knowledge and/or poor medical record documentation need further exploration.

Development of a quality improvement audit tool for the primary care of children with chronic wet cough using a modified Delphi consensus approach.

AIM: In the absence of quality indicators (QIs) for the management of chronic wet cough, our study's aim was to determine whether consensus on QIs reflecting good primary health care, prior to referral for children with chronic wet cough, can be achieved. METHODS: A questionnaire consisting of 10 QIs was developed by a clinical working group based on current evidence and guidelines on the management of chronic wet cough in children. Each indicator reflected the quality of care provided to children with chronic wet cough in primary care prior to referral. A modified Delphi consensus questionnaire was undertaken involving expert paediatric respiratory clinicians and general paediatricians who graded the importance of each indicator for the purposes above. We a priori defined that consensus was considered achieved if >75% agreed on the indicator. RESULTS: Twenty-two specialists (from Brisbane, Melbourne, Perth and Canberra) participated in the survey. The cumulative number of years of their respiratory experience was 324 and that of general clinical practice was 504. Consensus was achieved in all 10 QIs, with 6 reaching 100% agreement. Mean agreement for the 10 items was 97%. CONCLUSION: As complete consensus was achieved on these QIs, it can be used as a provisional clinical audit tool and can guide the development of a robust audit tool for primary care clinical practice to assist with quality improvement initiatives.

Tailoring asthma treatment on eosinophilic markers (exhaled nitric oxide or sputum eosinophils): a systematic review and meta-analysis.

BACKGROUND: Asthma guidelines guide health practitioners to adjust treatments to the minimum level required for asthma control. As many people with asthma have an eosinophilic endotype, tailoring asthma medications based on airway eosinophilic levels (sputum eosinophils or exhaled nitric oxide, FeNO) may improve asthma outcomes. OBJECTIVE: To synthesise the evidence from our updated Cochrane systematic reviews, for tailoring asthma medication based on eosinophilic inflammatory markers (sputum analysis and FeNO) for improving asthma-related outcomes in children and adults. DATA SOURCES: Cochrane reviews with standardised searches up to February 2017. STUDY SELECTION: The Cochrane reviews included randomised controlled comparisons of tailoring asthma medications based on sputum analysis or FeNO compared with controls (primarily clinical symptoms and/or spirometry/peak flow). RESULTS: The 16 included studies of FeNO-based management (seven in adults) and 6 of sputum-based management (five in adults) were clinically heterogeneous. On follow-up, participants randomised to the sputum eosinophils strategy (compared with controls) were significantly less likely to have exacerbations (62 vs 82/100 participants with ≥1 exacerbation; OR 0.36, 95% CI 0.21 to 0.62). For the FeNO strategy, the respective numbers were adults OR 0.60 (95% CI 0.43 to 0.84) and children 0.58 (95% CI 0.45 to 0.75). However, there were no significant group differences for either strategy on daily inhaled corticosteroids dose (at end of study), asthma control or lung function. CONCLUSION: Adjusting treatment based on airway eosinophilic markers reduced the likelihood of asthma exacerbations but had no significant impact on asthma control or lung function.

Antibiotics for prolonged wet cough in children.

BACKGROUND: Cough is a frequent symptom presenting to doctors. The most common cause of childhood chronic (greater than fours weeks' duration) wet cough is protracted bacterial bronchitis (PBB) in some settings, although other more serious causes can also present this way. Timely and effective management of chronic wet or productive cough improves quality of life and clinical outcomes. Current international guidelines suggest a course of antibiotics is the first treatment of choice in the absence of signs or symptoms specific to an alternative diagnosis. This review sought to clarify the current evidence to support this recommendation. OBJECTIVES: To determine the efficacy of antibiotics in treating children with prolonged wet cough (excluding children with bronchiectasis or other known underlying respiratory illness) and to assess risk of harm due to adverse events. SEARCH METHODS: We undertook an updated search (from 2008 onwards) using the Cochrane Airways Group Specialised Register, Cochrane Register of Controlled Trials (CENTRAL), MEDLINE, Embase, trials registries, review articles and reference lists of relevant articles. The latest searches were performed in September 2017. SELECTION CRITERIA: We included randomised controlled trials (RCTs) comparing antibiotics with a placebo or a control group in children with chronic wet cough. We excluded cluster and cross-over trials. DATA COLLECTION AND ANALYSIS: We used standard methods as recommended by Cochrane. We reviewed results of searches against predetermined criteria for inclusion. Two independent review authors selected, extracted and assessed the data for inclusion. We contacted authors of eligible studies for further information as needed. We analysed data as 'intention to treat.' MAIN RESULTS: We identified three studies as eligible for inclusion in the review. Two were in the previous review and one new study was included. We considered the older studies to be at high or unclear risk of bias whereas we judged the newly included study at low risk of bias. The studies varied in treatment duration (from 7 to 14 days) and the antibiotic used (two studies used amoxicillin/clavulanate acid and one used erythromycin).We included 190 children (171 completed), mean ages ranged from 21 months to six years, in the meta-analyses. Analysis of all three trials (190 children) found that treatment with antibiotics reduced the proportion of children not cured at follow-up (primary outcome measure) (odds ratio (OR) 0.15, 95% confidence interval (CI) 0.07 to 0.31, using intention-to -treat analysis), which translated to a number needed to treat for an additional beneficial outcome (NNTB) of 3 (95% CI 2 to 4). We identified no significant heterogeneity (for both fixed-effect and random-effects model the I² statistic was 0%). Two older trials assessed progression of illness, defined by requirement for further antibiotics (125 children), which was significantly lower in the antibiotic group (OR 0.10, 95% CI 0.03 to 0.34; NNTB 4, 95% CI 3 to 5). All three trials (190 children) reported adverse events, which were not significantly increased in the antibiotic group compared to the control group (OR 1.88, 95% CI 0.62 to 5.69). We assessed the quality of evidence GRADE rating as moderate for all outcome measures, except adverse events which we assessed as low quality. AUTHORS' CONCLUSIONS: Evidence suggests antibiotics are efficacious for the treatment of children with chronic wet cough (greater than four weeks) with an NNTB of three. However, antibiotics have adverse effects and this review reported only uncertainty as to the risk of increased adverse effects when they were used in this setting. The inclusion of a more robust study strengthened the previous Cochrane review and its results.

Inhaled corticosteroids for bronchiectasis.

BACKGROUND: Bronchiectasis is being increasingly diagnosed and recognised as an important contributor to chronic lung disease in both adults and children in high- and low-income countries. It is characterised by irreversible dilatation of airways and is generally associated with airway inflammation and chronic bacterial infection. Medical management largely aims to reduce morbidity by controlling the symptoms, reduce exacerbation frequency, improve quality of life and prevent the progression of bronchiectasis. This is an update of a review first published in 2000. OBJECTIVES: To evaluate the efficacy and safety of inhaled corticosteroids (ICS) in children and adults with stable state bronchiectasis, specifically to assess whether the use of ICS: (1) reduces the severity and frequency of acute respiratory exacerbations; or (2) affects long-term pulmonary function decline. SEARCH METHODS: We searched the Cochrane Register of Controlled Trials (CENTRAL), the Cochrane Airways Group Register of trials, MEDLINE and Embase databases. We ran the latest literature search in June 2017. SELECTION CRITERIA: All randomised controlled trials (RCTs) comparing ICS with a placebo or no medication. We included children and adults with clinical or radiographic evidence of bronchiectasis, but excluded people with cystic fibrosis. DATA COLLECTION AND ANALYSIS: We reviewed search results against predetermined criteria for inclusion. In this update, two independent review authors assessed methodological quality and risk of bias in trials using established criteria and extracted data using standard pro forma. We analysed treatment as 'treatment received' and performed sensitivity analyses. MAIN RESULTS: The review included seven studies, involving 380 adults. Of the 380 randomised participants, 348 completed the studies.Due to differences in outcomes reported among the seven studies, we could only perform limited meta-analysis for both the short-term ICS use (6 months or less) and the longer-term ICS use (> 6 months).During stable state in the short-term group (ICS for 6 months or less), based on the two studies from which data could be included, there were no significant differences from baseline values in the forced expiratory volume in the first second (FEV1) at the end of the study (mean difference (MD) -0.09, 95% confidence interval (CI) -0.26 to 0.09) and forced vital capacity (FVC) (MD 0.01 L, 95% CI -0.16 to 0.17) in adults on ICS (compared to no ICS). Similarly, we did not find any significant difference in the average exacerbation frequency (MD 0.09, 95% CI -0.61 to 0.79) or health-related quality of life (HRQoL) total scores in adults on ICS when compared with no ICS, though data available were limited. Based on a single non-placebo controlled study from which we could not extract clinical data, there was marginal, though statistically significant improvement in sputum volume and dyspnoea scores on ICS.The single study on long-term outcomes (over 6 months) that examined lung function and other clinical outcomes, showed no significant effect of ICS on any of the outcomes. We could not draw any conclusion on adverse effects due to limited available data.Despite the authors of all seven studies stating they were double-blind, we judged one study (in the short duration ICS) as having a high risk of bias based on blinding, attrition and reporting of outcomes. The GRADE quality of evidence was low for all outcomes (due to non-placebo controlled trial, indirectness and imprecision with small numbers of participants and studies). AUTHORS' CONCLUSIONS: This updated review indicates that there is insufficient evidence to support the routine use of ICS in adults with stable state bronchiectasis. Further, we cannot draw any conclusion for the use of ICS in adults during an acute exacerbation or in children (for any state), as there were no studies.

Caseworker-assigned discharge plans to prevent hospital readmission for acute exacerbations in children with chronic respiratory illness.

BACKGROUND: Chronic respiratory conditions are major causes of mortality and morbidity. Children with chronic health conditions have increased morbidity associated with their physical, emotional, and general well-being. Acute respiratory exacerbations (AREs) are common in children with chronic respiratory disease, often requiring admission to hospital. Reducing the frequency of AREs and recurrent hospitalisations is therefore an important goal in the individual and public health management of chronic respiratory illnesses in children. Discharge planning is used to decide what a person needs for transition from one level of care to another and is usually considered in the context of discharge from hospital to the home. Discharge planning from hospital for ongoing management of an illness has historically been referral to a general practitioner or allied health professional or self management by the individual and their family with limited communication between the hospital and patient once discharged. Effective discharge planning can decrease the risk of recurrent AREs requiring medical care. An individual caseworker-assigned discharge plan may further decrease exacerbations. OBJECTIVES: To evaluate the efficacy of individual caseworker-assigned discharge plans, as compared to non-caseworker-assigned plans, in preventing hospitalisation for AREs in children with chronic lung diseases such as asthma and bronchiectasis. SEARCH METHODS: We searched the Cochrane Airways Group Specialised Register of Trials, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, trials registries, and reference lists of articles. The latest searches were undertaken in November 2017. SELECTION CRITERIA: All randomised controlled trials comparing individual caseworker-assigned discharge planning compared to traditional discharge-planning approaches (including self management), and their effectiveness in reducing the subsequent need for emergency care for AREs (hospital admissions, emergency department visits, and/or unscheduled general practitioner visits) in children hospitalised with an acute exacerbation of chronic respiratory disease. We excluded studies that included children with cystic fibrosis. DATA COLLECTION AND ANALYSIS: We used standard Cochrane Review methodological approaches. Relevant studies were independently selected in duplicate. Two review authors independently assessed trial quality and extracted data. We contacted the authors of one study for further information. MAIN RESULTS: We included four studies involving a total of 773 randomised participants aged between 14 months and 16 years. All four studies involved children with asthma, with the case-planning undertaken by a trained nurse educator. However, the discharge planning/education differed among the studies. We could include data from only two studies (361 children) in the meta-analysis. Two further studies enrolled children in both inpatient and outpatient settings, and one of these studies also included children with acute wheezing illness (no previous asthma diagnosis); the data specific to this review could not be obtained. For the primary outcome of exacerbations requiring hospitalisation, those in the intervention group were significantly less likely to be rehospitalised (odds ratio (OR) 0.29, 95% confidence interval (CI) 0.16 to 0.50) compared to controls. This equates to 189 (95% CI 124 to 236) fewer admissions per 1000 children. No adverse events were reported in any study. In the context of substantial statistical heterogeneity between the two studies, there were no statistically significant effects on emergency department (OR 0.37, 95% CI 0.04 to 3.05) or general practitioner (OR 0.87, 95% CI 0.22 to 3.44) presentations. There were no data on cost-effectiveness, length of stay of subsequent hospitalisations, or adherence to medications. One study reported quality of life, with no significant differences observed between the intervention and control groups.We considered three of the studies to have an unclear risk of bias, primarily due to inadequate description of the blinding of participants and investigators. The fourth study was assessed as at high risk of bias as a single unblinded investigator was used. Using the GRADE system, we assessed the quality of the evidence as moderate for the outcome of hospitalisation and low for the outcomes of emergency department visits and general practitioner consultations. AUTHORS' CONCLUSIONS: Current evidence suggests that individual caseworker-assigned discharge plans, as compared to non-caseworker-assigned plans, may be beneficial in preventing hospital readmissions for acute exacerbations in children with asthma. There was no clear indication that the intervention reduces emergency department and general practitioner attendances for asthma, and there is an absence of data for children with other chronic respiratory conditions. Given the potential benefit and cost savings to the healthcare sector and families if hospitalisations and outpatient attendances can be reduced, there is a need for further randomised controlled trials encompassing different chronic respiratory illnesses, ethnicity, socio-economic settings, and cost-effectiveness, as well as defining the essential components of a complex intervention.

Tailored interventions based on sputum eosinophils versus clinical symptoms for asthma in children and adults.

BACKGROUND: Asthma severity and control can be measured both subjectively and objectively. Sputum analysis for evaluation of percentage of sputum eosinophilia directly measures airway inflammation, and is one method of objectively monitoring asthma. Using sputum analysis to adjust or tailor asthma medications is potentially superior to traditional methods based on symptoms and spirometry. OBJECTIVES: To evaluate the efficacy of tailoring asthma interventions based on sputum analysis in comparison to traditional methods (usually symptom-based with or without spirometry/peak flow) for asthma-related outcomes in children and adults. SEARCH METHODS: We searched the Cochrane Airways Group Specialised Register of Trials, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, trials' registries, and reference lists of articles. The last search was conducted in February 2017. SELECTION CRITERIA: All randomised controlled comparisons of adjustment of asthma therapy based on sputum eosinophils compared to traditional methods (primarily clinical symptoms and spirometry/peak flow). DATA COLLECTION AND ANALYSIS: Results of searches were reviewed against pre-determined criteria for inclusion. In this update, two reviewers selected relevant studies, independently assessed trial quality and extracted the data. We contacted authors for further information when relevant. We analysed data as 'treatment received' and performed sensitivity analyses. MAIN RESULTS: Three new studies were added in this update, resulting in a total of six included studies (five in adults and one involving children/adolescents). These six studies were clinically and methodologically heterogeneous (use of medications, cut-off for percentage of sputum eosinophils and definition of asthma exacerbation). Of 374 participants randomised, 333 completed the trials. In the meta-analysis, there was a significant reduction in the occurrence of any exacerbations when treatment was based on sputum eosinophil counts, compared to that based on clinical symptoms with or without lung function; pooled odds ratio (OR) was 0.57 (95% confidence interval (CI) 0.38 to 0.86). The risk of having one or more exacerbations over 16 months was 82% in the control arm and 62% (95% CI 49% to 74%) in the sputum strategy arm, resulting in a number needed to treat to benefit (NNTB) of 6 (95% CI 4 to 13).There were also differences between the groups in the rate of exacerbation (any exacerbation per year) and severity of exacerbations defined by requirement for use of oral corticosteroids and hospitalisations: the risk of one or more hospitalisations over 16 months was 24% in controls compared to 8% (95% CI 3% to 21%) in the sputum arm. Data for clinical symptoms, quality of life and spirometry were not significantly different between groups. The mean dose of inhaled corticosteroids per day was also similar in both groups. However sputum induction was not always possible. The included studies did not record any adverse events.One study was not blinded and thus was considered to have a high risk of bias. However, when this study was removed in a sensitivity analysis, the difference between the groups for the primary outcome (exacerbations) remained statistically significant between groups. The GRADE quality of the evidence ranged from moderate (for the outcomes 'Occurrence of any exacerbation' and 'Hospitalisation' ) to low (for the outcome 'Mean dose of inhaled corticosteroids per person per day') due to the inconsistency in defining exacerbations and the small number of hospital admissions. AUTHORS' CONCLUSIONS: In this updated review, tailoring asthma interventions based on sputum eosinophils is beneficial in reducing the frequency of asthma exacerbations in adults with asthma. Adults with frequent exacerbations and severe asthma may derive the greatest benefit from this additional monitoring test, although we were unable to confirm this through subgroup analysis. There is insufficient data available to assess tailoring asthma medications based on sputum eosinophilia in children.Further robust RCTs need to be undertaken and these should include participants with different underlying asthma severities and endotypes.

A child chronic cough-specific quality of life measure: development and validation.

BACKGROUND: Quality of life (QoL) measures are an important patient-relevant outcome measure for clinical studies. Cough is the most common symptom that results in new medical consultations. Although adult and parent-proxy cough-specific QoL instruments have been shown to be a useful cough outcome measure, no suitable cough-specific QoL measure for children with chronic cough exists. We report on the statistical properties of a chronic cough-specific QoL (CC-QoL) questionnaire for children. METHOD: 130 children (median age 10 years, IQR 8-12 years; 65 girls) participated. A preliminary 37-item version was developed from conversations with children with chronic cough (>4 weeks). Children also completed generic QoL questionnaires (Pediatric QoL Inventory 4.0 (PedsQL4.0), Spence Children's Anxiety Scale (SCAS)) and cough diary scores. RESULTS: The clinical impact method of item reduction resulted in 16 items that had excellent internal consistency (Cronbach's α=0.94) among these items and also within each domain. Evidence for construct and criterion validity was established with significant correlations between CC-QoL subscales with cough scores, PedsQL and SCAS scores. CC-QoL scores were sensitive to change following an intervention and significant differences were noted between those children coughing and those who had ceased coughing. Minimum important difference (MID) for overall and domain CC-QoL ranged from 0.37-1.36 (distribution-based approach) to 1.11-1.58 (anchor-based approach). CONCLUSIONS: Chronic cough significantly impacts the QoL of children. The CC-QoL is a reliable, valid and sensitive to change outcome measure that assesses QoL from the child's perspective. Pending data from a confirmatory cohort, a MID for the CC-QoL of 1.1 is recommended when evaluating health status change.

Spirometry reference values in Indigenous Australians: a systematic review.

OBJECTIVES: To evaluate published spirometry data for Australian Aboriginal and Torres Strait Islander (Indigenous) peoples to determine (i) whether their ethnicity influenced spirometry results; and (ii) if any reliable spirometry reference values exist for Indigenous Australians. STUDY DESIGN: Systematic review of published and grey literature. DATA SOURCES: PubMed and Cochrane Library databases, references of included articles and appropriate grey literature. Last searches were conducted in April 2016. STUDY SELECTION: We included any study that performed spirometry on healthy Indigenous Australians and compared their results with those from people of European ancestry. Two authors independently screened titles and abstracts and then reviewed potentially relevant full-text articles for possible inclusion. We used PRISMA systematic review reporting methods to collate data. DATA SYNTHESIS: Of a possible 125 studies, 18 full-text articles were reviewed, but only nine fulfilled the inclusion criteria. None specified Torres Strait Islander inclusion. All studies reported lower spirometry values (as much as 30% lower) for Aboriginal people compared with non-Indigenous people. Five studies developed spirometry reference values for Indigenous Australians; however, none adhered to all participant inclusion and exclusion criteria outlined by the American Thoracic Society and European Respiratory Society. Hence, reported results and subsequent reference values may not be a true representation of spirometry values in healthy Indigenous people. CONCLUSIONS: The lower spirometry values reported for Indigenous Australians may be due to study limitations. Furthermore, there are currently no reliable spirometry reference values for Indigenous Australians that adhere to current guidelines. Developing a set of Indigenous Australian reference values will improve the accuracy of test interpretation and aid in the diagnosis of respiratory disease in this population.

Exhaled nitric oxide levels to guide treatment for children with asthma.

BACKGROUND: Asthma guidelines aim to guide health practitioners to optimise treatment for patients to minimise symptoms, improve or maintain good lung function, and prevent acute exacerbations. The principle of asthma guidelines is based on a step-up or step-down regimen of asthma medications to maximise health using minimum doses. Fractional exhaled nitric oxide (FeNO) is a marker of eosinophilic inflammation and tailoring asthma medications in accordance to airway eosinophilic levels may improve asthma outcomes such as indices of control or reduce exacerbations, or both. OBJECTIVES: To evaluate the efficacy of tailoring asthma interventions based on fractional exhaled nitric oxide (FeNO), in comparison to not using FeNO, that is, management based on clinical symptoms (with or without spirometry/peak flow) or asthma guidelines (or both), for asthma-related outcomes in children. SEARCH METHODS: We searched the Cochrane Airways Group Specialised Register of Trials, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase and reference lists of articles. The last searches were in June 2016. SELECTION CRITERIA: All randomised controlled trials (RCTs) comparing adjustment of asthma medications based on FeNO levels compared to those not using FeNO, that is, management based on clinical symptoms or asthma guidelines (or both) involving children. DATA COLLECTION AND ANALYSIS: We reviewed results of searches against predetermined criteria for inclusion. Two review authors independently selected relevant studies, assessed trial quality and extracted data. We contacted study authors for further information with responses provided from three. MAIN RESULTS: The review included nine studies; these studies differed in a variety of ways including definition of asthma exacerbations, FeNO cut-off levels used (12 parts per billion (ppb) to 30 ppb), the way in which FeNO was used to adjust therapy and duration of study (6 to 12 months). Of 1426 children randomised, 1329 completed the studies. The inclusion criteria for the participants in each study varied but all had a diagnosis of asthma. There was a significant difference in the number of children having one or more asthma exacerbations over the study period, they were significantly lower in the FeNO group in comparison to the control group (odds ratio (OR) 0.58, 95% confidence interval (CI) 0.45 to 0.75; 1279 participants; 8 studies). The number needed to treat for an additional beneficial outcome (NNTB) over 52 weeks was 9 (95% CI 6 to 15). There was no difference between the groups when comparing exacerbation rates (mean difference (MD) -0.37, 95% CI -0.8 to 0.06; 736 participants; 4 studies; I2 = 67%). The number of children in the FeNO group requiring oral corticosteroid courses was lower in comparison to the children in the control group (OR 0.63, 95% CI 0.48 to 0.83; 1169 participants; 7 studies; I2 = 0%). There was no statistically significant difference between the groups for exacerbations requiring hospitalisation (OR 0.75, 95% CI 0.41 to 1.36; 1110 participants; 6 studies; I2 = 0%). There were no significant differences between the groups for any of the secondary outcomes (forced expiratory volume in one second (FEV1), FeNO levels, symptom scores or inhaled corticosteroid doses at final visit). The included studies recorded no adverse events.Three studies had inadequate blinding and were thus considered to have a high risk of bias. However, when these studies were removed in subgroup analysis, the difference between the groups for the primary outcome (exacerbations) remained statistically significant. The GRADE quality of the evidence ranged from moderate (for the outcome 'Number of participants who had one or more exacerbations over the study period') to very low (for the outcome 'Exacerbation rates'), based on lack of blinding, statistical heterogeneity and imprecision. AUTHORS' CONCLUSIONS: In this updated review with five new included studies, tailoring asthma medications based on FeNO levels (in comparison with primarily guideline management) significantly decreased the number of children who had one or more exacerbations over the study period but did not impact on the day-to-day clinical symptoms or inhaled corticosteroid doses. Therefore, the use of FeNO to guide asthma therapy in children may be beneficial in a subset of children, it cannot be universally recommended for all children with asthma.Further RCTs need to be conducted and these should encompass different asthma severities, different settings including primary care and less affluent settings, and consider different FeNO cut-offs.

Exhaled nitric oxide levels to guide treatment for adults with asthma.

BACKGROUND: Asthma guidelines aim to guide health practitioners to optimise treatment for patients so as to minimise symptoms, improve or maintain good lung function, and prevent acute exacerbations or flare-ups. The principle of asthma guidelines is based on a step-up or step-down regimen of asthma medications to maximise good health outcomes using minimum medications. Asthma maintenance therapies reduce airway inflammation that is usually eosinophilic. Tailoring asthma medications in accordance with airway eosinophilic levels may improve asthma outcomes such as indices of control or reduce exacerbations or both. Fractional exhaled nitric oxide (FeNO) is a marker of eosinophilic inflammation, and as it is easy to measure, has an advantage over other measurements of eosinophilic inflammation (for example sputum eosinophils). OBJECTIVES: To evaluate the efficacy of tailoring asthma interventions based on exhaled nitric oxide (FeNO), in comparison to not using FeNO, that is management based on clinical symptoms (with or without spirometry/peak flow) or asthma guidelines or both, for asthma-related outcomes in adults. SEARCH METHODS: We searched the Cochrane Airways Group Specialised Register of Trials, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, and reference lists of articles. The last searches were undertaken in June 2016. SELECTION CRITERIA: All randomised controlled trials (RCTs) comparing adjustment of asthma medications based on exhaled nitric oxide levels compared to not using FeNO, that is management based on clinical symptoms (with or without spirometry/peak flow) or asthma guidelines or both. DATA COLLECTION AND ANALYSIS: We reviewed results of searches against predetermined criteria for inclusion. We independently selected relevant studies in duplicate. Two review authors independently assessed trial quality and extracted data. We contacted study authors for further information, receiving responses from four. MAIN RESULTS: We included seven adult studies; these studies differed in a variety of ways including definition of asthma exacerbations, FeNO cutoff levels used (15 to 35 ppb), the way in which FeNO was used to adjust therapy, and duration of study (4 to 12 months). Of 1700 randomised participants, 1546 completed the trials. The mean ages of the participants ranged from 28 to 54 years old. The inclusion criteria for the participants in each study varied, but all had a diagnosis of asthma and required asthma medications. In the meta-analysis, there was a significant difference in the primary outcome of asthma exacerbations between the groups, favouring the FeNO group. The number of people having one or more asthma exacerbations was significantly lower in the FeNO group compared to the control group (odds ratio (OR) 0.60, 95% confidence interval (CI) 0.43 to 0.84). The number needed to treat to benefit (NNTB) over 52 weeks was 12 (95% CI 8 to 32). Those in the FeNO group were also significantly more likely to have a lower exacerbation rate than the controls (rate ratio 0.59, 95% CI 0.45 to 0.77). However, we did not find a difference between the groups for exacerbations requiring hospitalisation (OR 0.14, 95% CI 0.01 to 2.67) or rescue oral corticosteroids (OR 0.86, 95% CI 0.50 to 1.48). There was also no significant difference between groups for any of the secondary outcomes (FEV1, FeNO levels, symptoms scores, or inhaled corticosteroid doses at final visit).We considered three included studies that had inadequate blinding to have a high risk of bias. However, when these studies were excluded from the meta-analysis, the difference between the groups for the primary outcomes (exacerbations) remained statistically significant. The GRADE quality of the evidence ranged from moderate (for the outcome 'exacerbations') to very low (for the outcome 'inhaled corticosteroid dose at final visit') based on the lack of blinding and statistical heterogeneity. Six of the seven studies were industry supported, but the company had no role in the study design or data analyses. AUTHORS' CONCLUSIONS: With new studies included since the last version of this review, which included adults and children, this updated meta-analysis in adults with asthma showed that tailoring asthma medications based on FeNO levels (compared with primarily on clinical symptoms) decreased the frequency of asthma exacerbations but did not impact on day-to-day clinical symptoms, end-of-study FeNO levels, or inhaled corticosteroid dose. Thus, the universal use of FeNO to help guide therapy in adults with asthma cannot be advocated. As the main benefit shown in the studies in this review was a reduction in asthma exacerbations, the intervention may be most useful in adults who have frequent exacerbations. Further RCTs encompassing different asthma severity, ethnic groups in less affluent settings, and taking into account different FeNO cutoffs are required.

Codeine versus placebo for chronic cough in children.

BACKGROUND: Cough in children is a commonly experienced symptom that is associated with increased health service utilisation and burden to parents. The presence of chronic (equal to or more than four weeks) cough in children may indicate a serious underlying condition such as inhaled foreign body or bronchiectasis. Codeine (and derivative)-based medications are sometimes used to treat cough due to their antitussive properties. However, there are inherent risks associated with the use of these medications such as respiratory drive suppression, anaesthetic-induced anaphylaxis, and addiction. Metabolic response and dosage variability place children at increased risk of experiencing such side effects. A systematic review evaluating the quality of the available literature would be useful to inform management practices. OBJECTIVES: To evaluate the safety and efficacy of codeine (and derivatives) in the treatment of chronic cough in children. SEARCH METHODS: We searched the Cochrane Airways Group Register of Trials, Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE (1946 to 8 June 2016), EMBASE (1974 to 8 June 2016), the online trials registries of the World Health Organization and ClinicalTrials.gov, and the bibliographic references of publications. We imposed no language restrictions. SELECTION CRITERIA: We considered studies eligible for analysis when: the participant population included children aged less than 18 years with chronic cough (duration equal to or more than four weeks at the time of intervention); and the study design evaluated codeine or codeine-based derivatives against placebo through a randomised controlled trial. DATA COLLECTION AND ANALYSIS: Two review authors independently screened the search results to determine eligibility against a standardised criteria, and we had a pre-planned method for analysis. MAIN RESULTS: We identified a total of 556 records, of which 486 records were excluded on the basis of title and abstract. We retrieved the remaining 70 references in full to determine eligibility. No studies fulfilled the inclusion criteria of this review, and thus we found no evidence to support or oppose the use of codeine or derivatives as antitussive agents for chronic cough in children.While chronic cough is not the same as acute cough, systematic reviews on the use of codeine efficacy for acute cough in children conclude an overall lack of evidence to support or oppose the use of over-the-counter cough and cold medications containing codeine (or derivatives) for treatment of acute cough in children. The lack of sufficient evidence to support the use of these medications has been consistently reaffirmed by medical experts in international chronic cough guidelines and by governing medical and pharmaceutical authorities in the USA, Europe, Canada, New Zealand, and Australia. Due to the lack of sufficient evidence to support efficacy, and the known risks associated with use - in particular the increased risks for children - these medications are now not recommended for children less than 12 years of age and children between 12 to 18 years with respiratory conditions. AUTHORS' CONCLUSIONS: This review has highlighted the absence of any randomised controlled trials evaluating codeine-based medications in the treatment of childhood chronic cough. Given the potential adverse events of respiratory suppression and opioid toxicity, national therapeutic regulatory authorities recommend the contraindication of access to codeine in children less than 12 years of age. We suggest that clinical practice adhere to clinical practice guidelines and thus refrain from using codeine or its derivatives to treat cough in children. Aetiological-based management practices continue to be advocated for children with chronic cough.

Adenovirus species C is associated with chronic suppurative lung diseases in children.

BACKGROUND: The role of human adenoviruses (HAdVs) in chronic respiratory disease pathogenesis is recognized. However, no studies have performed molecular sequencing of HAdVs from the lower airways of children with chronic endobronchial suppuration. We thus examined the major HAdV genotypes/species, and relationships to bacterial coinfection, in children with protracted bacterial bronchitis (PBB) and mild bronchiectasis (BE). METHODS: Bronchoalveolar lavage (BAL) samples of 245 children with PBB or mild (cylindrical) BE were included in this prospective cohort study. HAdVs were genotyped (when possible) in those whose BAL had HAdV detected (HAdV(+)). Presence of bacterial infection (defined as ≥10(4) colony-forming units/mL) was compared between BAL HAdV(+) and HAdV negative (HAdV(-)) groups. Immune function tests were performed including blood lymphocyte subsets in a random subgroup. RESULTS: Species C HAdVs were identified in 23 of 24 (96%) HAdV(+) children; 13 (57%) were HAdV-1 and 10 (43%) were HAdV-2. An HAdV(+) BAL was significantly associated with bacterial coinfection with Haemophilus influenzae, Moraxella catarrhalis, or Streptococcus pneumoniae (odds ratio [OR], 3.27; 95% confidence interval, 1.38-7.75; P = .007) and negatively associated with Staphylococcus aureus infection (P = .03). Young age was related to increased rates of HAdV(+). Blood CD16 and CD56 natural killer cells were significantly more likely to be elevated in those with HAdV (80%) compared with those without (56.1%) (P = .027). CONCLUSIONS: HAdV-C is the major HAdV species detected in the lower airways of children with PBB and BE. Younger age appears to be an important risk factor for HAdV(+) of the lower airways and influences the likelihood of bacterial coinfection.

Pulmonary innate immunity in children with protracted bacterial bronchitis.

OBJECTIVE: To determine bronchoalveolar lavage (BAL) levels of 3 innate immunity components (human ß-defensin-2 [hBD2], mannose-binding lectin [MBL], and surfactant protein-A [SP-A]), the relationship with airway neutrophilia and infection, and cytokine production of stimulated BAL cells in children with current protracted bacterial bronchitis (PBB), children with resolved PBB (PBB well), and controls. STUDY DESIGN: BAL of 102 children (mean age 2.8 years) fulfilling predefined criteria of current PBB (n = 61), PBB well (n = 20), and controls (n = 21) was cultured (quantitative bacteriology) and viruses examined by polymerase chain reaction. hBD2, MBL, and SP-A were measured, and cytokine production by lipopolysaccharide-stimulated BAL cells was determined. RESULTS: Median hBD2 and MBL levels were significantly higher in the current PBB group (hBD2 = 164.4, IQR 0-435.5 pg/mL; MBL = 1.7, 0.4-4 ng/mL) than in the PBB well group (hBD2 = 0, IQR 0-85.2; MBL = 0.6, IQR 0.03-2.9) and controls (hBD2 = 3.6, IQR 0-126; MBL = 0.4, IQR 0.02-79). hBD2 was significantly higher in children with airway infection (n = 54; median 76.9, IQR 0-397.3) compared with those without (n = 48; 0, IQR 0-236.3), P= .04. SP-A levels and cytokine production of stimulated BAL cells were similar between groups. CONCLUSION: In children's airways, hBD2, but not MBL and SP-A, relates to inflammation and infection. In children with PBB, mechanisms involving airway hBD2 and MBL are augmented. These pulmonary innate immunity components and the ability of BAL cells to respond to stimuli are unlikely to be deficient.

Soluble receptor for advanced glycation end products (sRAGE) is present at high concentrations in the lungs of children and varies with age and the pattern of lung inflammation.

BACKGROUND AND OBJECTIVE: The soluble receptor for advanced glycation end products (sRAGE) plays an important role in inflammation. Few studies have looked at sRAGE levels in human lungs, and there is no information in children. Therefore, this study aimed to compare bronchoalveolar lavage fluid (BALF) and plasma sRAGE concentrations in children in relation to age and inflammation. METHODS: BAL was performed in 76 children, and BALF and plasma sRAGE levels were determined by enzyme-linked immunosorbent assay. RESULTS: sRAGE levels were fourfold higher in BALF than in plasma (P < 0.001). BALF sRAGE was inversely proportional to age (r = -0.333, P = 0.008) and serum immunoglobulin A (r = -0.283, P = 0.028). Plasma sRAGE showed a positive correlation to the percentage of BAL macrophages and negative correlation to the percentage of neutrophils and lymphocytes (P < 0.05). Multivariate linear regression analysis identified that the percentage of BAL lymphocytes and neutrophils were significant independent predictors of plasma sRAGE levels, while age and the percentage of BAL macrophages independently predicted BALF sRAGE levels. CONCLUSIONS: In children, sRAGE is present at higher concentrations in the lung compared with blood. It appears that sRAGE varies with age, and hence future studies of sRAGE in paediatric lung disease require age matching. The significant relationship between sRAGE and lung inflammation warrants further research.

Chronic wet cough in Australian children: Societal costs and quality of life.

INTRODUCTION: Children with chronic wet cough regularly use the health system, experience considerable variability in care, have reduced quality of life (QoL), and, left untreated, poorer health outcomes. Despite this, little is known about the associated economic burden. This study aimed to quantify the cost of chronic wet cough among Australian children from the perspectives of families and the health system. METHODS: A cost of illness study was conducted at the Queensland Children's Hospital, Brisbane, using data on 91 children newly referred to a respiratory specialist between July 2015 and January 2017 with a history of chronic wet cough (>4 weeks) of unknown etiology. Administrative and parent-reported data were used to estimate costs (reported in 2019 Australian Dollars [AUD]) for up to 12 months before and following initial pulmonology consultation. QoL was assessed for the same periods. RESULTS: Mean cost per child-month during the average 9.8 months of observation preceding pulmonology consultation was AUD689 (95% confidence interval [CI] 534-844) increasing to AUD1339 (95% CI 1051-1628) during the average 11.9 months following pulmonology consultation. This translated to a total of AUD1.9 million across the study period, with families bearing 26.4% of costs. Aspiration and bronchiectasis were associated with higher total costs. For all etiologies, cough-specific QoL improved following pulmonology consultation, while direct medical costs declined. CONCLUSION: Childhood chronic wet cough is associated with substantial societal costs. The observed cost decrease after specialist diagnosis suggests that early referral to a respiratory specialist may have economic benefits, in addition to the known health benefits.

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, r(s)=-0.37, p=0.016; visual analogue score, r(s)=-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 (r(s)=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.

The impact of viral respiratory infection on the severity and recovery from an asthma exacerbation.

BACKGROUND: : Viral respiratory illness triggers asthma exacerbations, but the influence of respiratory illness on the acute severity and recovery of childhood asthma is unknown. Our objective was to evaluate the impact of a concurrent acute respiratory illness (based on a clinical definition and PCR detection of a panel of respiratory viruses, Mycoplasma pneumoniae and Chlamydia pneumoniae) on the severity and resolution of symptoms in children with a nonhospitalized exacerbation of asthma. METHODS: : Subjects were children aged 2 to 15 years presenting to an emergency department for an acute asthma exacerbation and not hospitalized. Acute respiratory illness (ARI) was clinically defined. Nasopharyngeal aspirates (NPA) were examined for respiratory viruses, Chlamydia and Mycoplasma using PCR. The primary outcome was quality of life (QOL) on presentation, day 7 and day 14. Secondary outcomes were acute asthma severity score, asthma diary, and cough diary scores on days 5, 7, 10, and 14. RESULTS: : On multivariate regression, presence of ARI was statistically but not clinically significantly associated with QOL score on presentation (B = -0.36, P = 0.025). By day 7 and 14, there was no difference between groups. Asthma diary score was significantly higher in children with ARI (B = 0.41, P = 0.039) on day 5 but not on presentation or subsequent days. Respiratory viruses were detected in 54% of the 78 NPAs obtained. There was no difference in the any of the asthma outcomes of children grouped by positive or negative NPA. CONCLUSIONS: : The presence of a viral respiratory illness has a modest influence on asthma severity, and does not influence recovery from a nonhospitalized asthma exacerbation.

Tailored interventions based on exhaled nitric oxide versus clinical symptoms for asthma in children and adults.

BACKGROUND: The measurement of severity and control of asthma in both children and adults can be based on subjective or objective measures. It has been advocated that fractional exhaled nitric oxide (FeNO) can be used to monitor airway inflammation as it correlates with some markers of asthma. Interventions for asthma therapies have been traditionally based on symptoms and/or spirometry. OBJECTIVES: To evaluate the efficacy of tailoring asthma interventions based on exhaled nitric oxide in comparison to clinical symptoms (with or without spirometry/peak flow) for asthma related outcomes in children and adults. SEARCH STRATEGY: We searched the Cochrane Airways Group Specialised Register of Trials, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE and reference lists of articles. The last search was completed in February 2009. SELECTION CRITERIA: All randomised controlled comparisons of adjustment of asthma therapy based on exhaled nitric oxide compared to traditional methods (primarily clinical symptoms and spirometry/peak flow). DATA COLLECTION AND ANALYSIS: Results of searches were reviewed against pre-determined criteria for inclusion. Relevant studies were independently selected in duplicate. Two authors independently assessed trial quality and extracted data. Authors were contacted for further information with response from one. MAIN RESULTS: Two studies have been added for this update, which now includes six (2 adults and 4 children/adolescent) studies; these studies differed in a variety of ways including definition of asthma exacerbations, FeNO cut off levels, the way in which FeNO was used to adjust therapy and duration of study. Of 1053 participants randomised, 1010 completed the trials. In the meta-analysis, there was no significant difference between groups for the primary outcome of asthma exacerbations or for other outcomes (clinical symptoms, FeNO level and spirometry). In post-hoc analysis, a significant reduction in mean final daily dose inhaled corticosteroid per adult was found in the group where treatment was based on FeNO in comparison to clinical symptoms, (mean difference -450 mcg; 95% CI -677 to -223 mcg budesonide equivalent/day). However, the total amount of inhaled corticosteroid used in one of the adult studies was 11% greater in the FeNO arm. In contrast, in the paediatric studies, there was a significant increase in inhaled corticosteroid dose in the FeNO strategy arm (mean difference of 140 mcg; 95% CI 29 to 251, mcg budesonide equivalent/day). AUTHORS' CONCLUSIONS: Tailoring the dose of inhaled corticosteroids based on exhaled nitric oxide in comparison to clinical symptoms was carried out in different ways in the six studies and found only modest benefit at best and potentially higher doses of inhaled corticosteroids in children. The role of utilising exhaled nitric oxide to tailor the dose of inhaled corticosteroids cannot be routinely recommended for clinical practice at this stage and remains uncertain.