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Abstract Background Gastroesophageal reflux disease (GORD) can cause respiratory disease in children from recurrent aspiration of gastric contents. GORD can be defined in several ways and one of the most common method is presence of reflux oesophagitis. In children with GORD and respiratory disease, airway neutrophilia has been described. However, there are no prospective studies that have examined airway cellularity in children with GORD but without respiratory disease. The aims of the study were to compare (1) BAL cellularity and lipid laden macrophage index (LLMI) and, (2) microbiology of BAL and gastric juices of children with GORD (G+) to those without (G-). Methods In 150 children aged Results BAL neutrophil% in G- group (n = 63) was marginally but significantly higher than that in the G+ group (n = 77), (median of 7.5 and 5 respectively, p = 0.002). Lipid laden macrophage index (LLMI), BAL percentages of lymphocyte, eosinophil and macrophage were similar between groups. Viral studies were negative in all, bacterial cultures positive in 20.7% of BALs and in 5.3% of gastric aspirates. BAL cultures did not reflect gastric aspirate cultures in all but one child. Conclusion In children without respiratory disease, GORD defined by presence of reflux oesophagitis, is not associated with BAL cellular profile or LLMI abnormality. Abnormal microbiology of the airways, when present, is not related to reflux oesophagitis and does not reflect that of gastric juices.

BACKGROUND: Chronic cough affects at least 7% of children, and the impact of this on families is significant. Although adult cough-specific quality-of-life (QOL) instruments have been shown to be a useful cough outcome measure, no suitable cough-specific QOL for parents of children with chronic cough exists. This article compares two methods of item reduction (clinical impact and psychometric) and reports on the statistical properties of both QOL instruments. METHOD: One hundred seventy children (97 boys and 73 girls; median age, 4 years; interquartile range, 3 to 7.25 years) and one of their parents participated. A preliminary 50-item parent cough-specific QOL (PC-QOL) questionnaire was developed from conversations with parents of children with chronic cough (ie, cough for > 3 weeks). Parents also completed generic QOL questionnaires (eg, Pediatric Quality of Life Inventory, version 4.0 [PedsQL4.0] and the 12-item Short Form Health Survey, version 2 [SF-12v2]). RESULTS: The clinical impact and psychometric method of item reduction resulted in 27-item and 26-item PC-QOL questionnaires, respectively, with approximately 50% of items overlapping. Internal consistency among the final items from both methods was excellent. Some evidence for concurrent and criterion validity of both methods was established as significant correlations were found between subscales of the PC-QOL questionnaire and the scales of the SF-12v2 and PedsQL4.0 scores. The PC-QOL questionnaire derived from both methods was sensitive to change following an intervention. CONCLUSION: Chronic cough significantly impacts on the QOL of both parents and children. Although the PC-QOL questionnaires derived from a clinical impact method and from a psychometric method contained different items, both versions were shown to be internally consistent and valid. Further testing is required to compare both final versions to objective and subjective cough measures. [ABSTRACT FROM AUTHOR]

Rationale: Conventionally considered irreversible, bronchiectasis has been demonstrated to be reversible in children in small studies. However, the factors associated with radiographic reversibility of bronchiectasis have yet to be defined. Objectives: In a large cohort of children with bronchiectasis, we aimed to determine: 1 ) if and to what extent bronchiectasis is reversible and 2 ) factors associated with radiographic chest high-resolution computed tomography (cHRCT) resolution. Methods: We identified children with bronchiectasis who had a repeat multidetector cHRCT scan between 2010 and 2021. We excluded those with cystic fibrosis, surgical pulmonary resection, traction bronchiectasis only, or lobar opacification. Measurements and Main Results: cHRCT scans were scored using the modified Reiff score (MRS) with a pediatric correction. Resolution was defined as an absence of abnormal bronchoarterial ratio (>0.8) on the second cHRCT scan. We included 142 children (median age, 5 years; IQR, 2.6-7.4). Inter- and intrarater agreement in MRSs was excellent (weighted κ = 0.83-0.86 and 0.95, respectively). There was radiographic resolution in 57 of 142 patients (40.1%), improvement in 56 of 142 (39.4%), and no change or worsening in 29 of 142 (20.4%). Pseudomonas aeruginosa ( PsA ) was absolutely associated with a lack of resolution. On multivariable regression, in those without PsA cultured, younger age at the time of diagnosis (risk ratio [RR], 0.94; 95% confidence interval [CI], 0.88-0.99), lower MRS (RR, 0.89; 95% CI, 0.82-0.97), and lower annual rate of exacerbations requiring intravenous antibiotic therapy (RR, 0.60; 95% CI, 0.37-0.98) increased the likelihood of radiographic resolution. Conclusions: This first large cohort confirms that bronchiectasis in children is often reversible with appropriate management. Younger children and those with lesser radiographic severity at diagnosis were most likely to exhibit radiographic reversibility, whereas those with PsA infection were least likely.

Background: The parent-proxy paediatric chronic cough quality of life questionnaire (PC-QoL) is a commonly used measure of spillover quality of life in parents of children with chronic cough. To date, spillover health utility in these parents is not routinely estimated largely due to the lack of a suitable instrument. Their perspective is not included in economic evaluations of interventions for their children. We explored developing a health state classification system based on the PC-QoL for measuring health utility spill over in this population., Methods: This study included PC-QoL 8-item responses of 653 parents participating in a prospective cohort study about paediatric chronic cough. Exploratory factor analysis (EFA) and Rasch analysis were used to examine dimensionality and select potential items and level structure., Results: EFA indicated that the PC-QoL had one underlying domain. Rasch analysis indicated threshold disordering in all items which improved when items were collapsed from seven to four levels. Two demonstrated differential item functioning (DIF) by diagnosis or ethnicity and were excluded from the final scale. This scale satisfied Rasch assumptions of local independence and unidimensionality and demonstrated acceptable fit to the Rasch model. It was presented to and modified by an expert panel and a consumer panel. The resulting classification system had six items, each with four levels., Discussion: The PC-QoL can conform to a Rasch model with minor modifications. It may be a good basis for the classification system of a child cough-specific PBM. A valuation study is required to estimate preference weights for each item and to estimate health utility in parents of children with chronic cough., (© 2024. The Author(s).)

Chronic cough in children is a common condition for which patients seek medical attention, and there are many etiologies. Of the various causes of chronic cough in children, protracted bacterial bronchitis (PBB) is one of the commonest causes, and bronchiectasis is one of the most serious. Together, they lie on different ends of the spectrum of chronic wet cough in children. Cough is often the only symptom present in children with PBB and bronchiectasis. This review highlights the role of cough as a marker for the presence of these conditions, as well as an outcome endpoint for treatment and research.

Objectives: To evaluate the suitability of the Global Lung Function Initiative (GLI)-2012 other/mixed and GLI-2022 global reference equations for evaluating the respiratory capacity of First Nations Australians., Design, Setting: Cross-sectional study; analysis of spirometry data collected by three prospective studies in Queensland, the Northern Territory, and Western Australia between March 2015 and December 2022., Participants: Opportunistically recruited First Nations participants in the Indigenous Respiratory Reference Values study (Queensland, Northern Territory; age, 3-25 years; 18 March 2015 - 24 November 2017), the Healthy Indigenous Lung Function Testing in Adults study (Queensland, Northern Territory; 18 years or older; 14 August 2019 - 15 December 2022) and the Many Healthy Lungs study (Western Australia; five years or older; 10 October 2018 - 7 November 2021)., Main Outcome Measures: Goodness of fit to spirometry data for each GLI reference equation, based on mean Z-score and its standard deviation, and proportions of participants with respiratory parameter values within 1.64 Z-scores of the mean value., Results: Acceptable and repeatable forced expiratory volume in the first second (FEV 1 ) values were available for 2700 First Nations participants in the three trials; 1467 were classified as healthy and included in our analysis (1062 children, 405 adults). Their median age was 12 years (interquartile range, 9-19 years; range, 3-91 years), 768 (52%) were female, and 1013 were tested in rural or remote areas (69%). Acceptable and repeatable forced vital capacity (FVC) values were available for 1294 of the healthy participants (88%). The GLI-2012 other/mixed and GLI-2022 global equations provided good fits to the spirometry data; the race-neutral GLI-2022 global equation better accounted for the influence of ageing on FEV 1 and FVC, and of height on FVC. Using the GLI-2012 other/mixed reference equation and after adjusting for age, sex, and height, mean FEV 1 (estimated difference, -0.34; 95% confidence interval [CI], -0.46 to -0.22) and FVC Z-scores (estimated difference, -0.45; 95% CI, -0.59 to -0.32) were lower for rural or remote than for urban participants, but their mean FEV 1 /FVC Z-score was higher (estimated difference, 0.14; 95% CI, 0.03-0.25)., Conclusion: The normal spirometry values of healthy First Nations Australians may be substantially higher than previously reported. Until more spirometry data are available for people in urban areas, the race-neutral GLI-2022 global or the GLI-2012 other/mixed reference equations can be used when assessing the respiratory function of First Nations Australians., (© 2024 The Authors. Medical Journal of Australia published by John Wiley & Sons Australia, Ltd on behalf of AMPCo Pty Ltd.)

Bronchiectasis, particularly in children, is an increasingly recognised yet neglected chronic lung disorder affecting individuals in both low-to-middle and high-income countries. It has a high disease burden and there is substantial inequity within and between settings. Furthermore, compared with other chronic lung diseases, considerably fewer resources are available for children with bronchiectasis. The need to prevent bronchiectasis and to reduce its burden also synchronously aligns with its high prevalence and economic costs to health services and society. Like many chronic lung diseases, bronchiectasis often originates early in childhood, highlighting the importance of reducing the disease burden in children. Concerted efforts are therefore needed to improve disease detection, clinical management and equity of care. Modifiable factors in the causal pathways of bronchiectasis, such as preventing severe and recurrent lower respiratory infections should be addressed, whilst also acknowledging the role played by social determinants of health. Here, we highlight the importance of early recognition/detection and optimal management of bronchiectasis in children, and outline our research, which is attempting to address important clinical knowledge gaps discussed in a recent workshop. The research is grouped under three themes focussing upon primary prevention, improving diagnosis and disease characterisation, and providing better management. Our hope is that others in multiple settings will undertake additional studies in this neglected field to further improve the lives of people with bronchiectasis. We also provide a resource list with links to help inform consumers and healthcare professionals about bronchiectasis and its recognition and management., (Copyright © 2024 The Authors. Published by Elsevier España, S.L.U. All rights reserved.)

Introduction: Elective flexible bronchoscopy (FB) is now widely available and standard practice for a variety of indications in children with respiratory conditions. However, there is limited evidence regarding the utility of elective FB in children. This systematic review (SRs) aimed to determine the utility of FB on its impact in clinical decision making and quality of life (QoL)., Methods: We searched Pubmed, Cochrane central register of controlled trials, Embase, World Health Organization Clinical Trials Registry Platform and Cochrane database of SRs from inception to April 20, 2023. We included SRs and randomized controlled trials (RCTs) that used parallel group design (comparing use of elective FB vs. no FB, or a wait-list approach [early FB vs. usual wait FB]) in children aged ≤ 18 years. Our protocol was prospectively registered and used Cochrane methodology for systemic reviews of interventions., Results: Our search identified 859 articles; 102 duplicates were removed, and 753 articles were excluded by title and abstract. Four full text articles were reviewed and subsequently excluded, as none met the inclusion criteria outlined in our patient, intervention, comparator, outcome measures framework., Conclusions: There is a paucity of high-quality RCT evidence to support the routine use of elective FB in children with respiratory conditions. However, available retrospective and a single prospective study demonstrate the high utility of FB in the elective pediatric setting., Registration: PROSPERO CRD42021291305., (© 2024 The Authors. Pediatric Pulmonology published by Wiley Periodicals LLC.)

Introduction: Bronchiectasis is a worldwide chronic lung disorder where exacerbations are common. It affects people of all ages, but especially Indigenous populations in high-income nations. Despite being a major contributor to chronic lung disease, there are no licensed therapies for bronchiectasis and there remain relatively few randomised controlled trials (RCTs) conducted in children and adults. Our RCT will address some of these unmet needs by evaluating whether the novel mucoactive agent, erdosteine, has a therapeutic role in children and adults with bronchiectasis.Our primary aim is to determine in children and adults aged 2-49 years with bronchiectasis whether regular erdosteine over a 12-month period reduces acute respiratory exacerbations compared with placebo. Our primary hypothesis is that people with bronchiectasis who regularly use erdosteine will have fewer exacerbations than those receiving placebo.Our secondary aims are to determine the effect of the trial medications on quality of life (QoL) and other clinical outcomes (exacerbation duration, time-to-next exacerbation, hospitalisations, lung function, adverse events). We will also assess the cost-effectiveness of the intervention., Methods and Analysis: We are undertaking an international multicentre, double-blind, placebo-RCT to evaluate whether 12 months of erdosteine is beneficial for children and adults with bronchiectasis. We will recruit 194 children and adults with bronchiectasis to a parallel, superiority RCT at eight sites across Australia, Malaysia and Philippines. Our primary endpoint is the rate of exacerbations over 12 months. Our main secondary outcomes are QoL, exacerbation duration, time-to-next exacerbation, hospitalisations and lung function., Ethics and Dissemination: The Human Research Ethics Committees (HREC) of Children's Health Queensland (for all Australian sites), University of Malaya Medical Centre (Malaysia) and St. Luke's Medical Centre (Philippines) approved the study. We will publish the results and share the outcomes with the academic and medical community, funding and relevant patient organisations., Trial Registration Number: ACTRN12621000315819., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY. Published by BMJ.)

Introduction: Elective flexible bronchoscopy (FB) is now widely available and standard practice for a variety of indications in children with respiratory conditions. However, there are no randomised controlled trials (RCTs) that have examined its benefits (or otherwise).Our primary aim is to determine the impact of FB on the parent-proxy quality-of-life (QoL) scores. Our secondary aims are to determine if undertaking FB leads to (a) change in management and (b) improvement of other relevant patient-reported outcome measures (PROMs). We also quantified the benefits of elective FB (using 10-point Likert scale). We hypothesised that undertaking elective FB will contribute to accurate diagnosis and therefore appropriate treatment, which will in turn improve QoL and will be deemed to be beneficial from patient and doctor perspectives., Methods and Analysis: Our parallel single-centre, single-blind RCT (commenced in May 2020) has a planned sample size of 114 children (aged <18 years) recruited from respiratory clinics at Queensland Children's Hospital, Brisbane, Australia. Children are randomised (1:1 concealed allocation) within two strata: age (≤2 vs >2 years) and indication for FB (chronic cough vs other indications) to either (a) early arm (intervention where FB undertaken within 2 weeks) or (b) delayed (control, FB undertaken at usual wait time). Our primary outcome is the difference between groups in their change in QoL at the T2 timepoint when the intervention group has had the FB and the control group has not. Our secondary outcomes are change in management, change in PROMs, adverse events and the Likert scales., Ethics and Dissemination: The human research ethics committee of the Queensland Children's Hospital granted ethical clearance (HREC/20/QCHQ/62394). Our RCT is conducted in accordance with Good Clinical Practice and the Australian legislation. Results will be disseminated through conference presentations, teaching avenues, workshops, websites and publications., Registration: Australia New Zealand Clinical Trial Registry ACTRN12620000610932., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY. Published by BMJ.)

Backgrounds: Understanding factors associated with anxiety of parents/carers of children with respiratory problems is clinically important yet there is relative paucity of data. In 106 children seen in the respiratory clinic of a pediatric hospital, we evaluated (a) the determinants for parental anxiety and (b) whether the anxiety scores correlate with quality-of-life (QoL) scores in the subset with chronic cough., Methods: We opportunistically re-analyzed data of our main study that examined the benefits of using spirometry for pediatric respiratory consultation where parents completed an anxiety questionnaire (State-Trait Anxiety Inventory, STAI) pre- and postconsultation. A subset (children with chronic cough) also completed the parent-proxy quality-of-life (PC-QoL) tool. We computed the association between clinical characteristics and anxiety scores using multivariable regression and between the two patient-reported outcome measures using Spearman's correlation., Results: The majority of parents/carers were women (n = 89, 84%). Most children (mean age = 10.9 years, SD = 3.7 years) were previously seen at the clinic (n = 67, 63.2%). In multivariate regression, parental anxiety score was significantly associated with reported presence of cough [coefficient β = 17.31 (95% confidence interval 9.62, 25.1)] and lower forced expiratory volume in first second (FEV 1 )/forced vital capacity (FVC) [-3.88 (-7.05, -0.71)] at preconsultation, but associated with cough only [coefficient β = 12.04 (5.24, 18.84)] at postconsultation, all p < .05. STAI strongly correlated with PC-QoL scores at pre- but only modestly at postconsultation (r s  = -.63 and -.39, respectively, p < .05)., Conclusion: Parental anxiety levels of children attending respiratory clinics are influenced by the presence of cough and low FEV 1 /FVC of their child and are associated with poorer QoL. These highlight the need for on-going research to reduce parental anxiety focusing on cough and lung function indices., (© 2023 The Authors. Pediatric Pulmonology published by Wiley Periodicals LLC.)

Background: Bronchiectasis, a previously neglected condition, now has renewed research interest. There are a few systematic reviews that have reported on the economic and societal burden of bronchiectasis in adults, but none have reported on children. We undertook this systematic review to estimate the economic burden of bronchiectasis in children and adults., Research Question: What is the health care resource utilization and economic burden of bronchiectasis in adults and children?, Study Design and Methods: We performed a systematic review identifying publications from Embase, PubMed, Web of Science, Cochrane (trials, reviews, and editorials), and EconLit about the economic burden and health care utilization in adults and children with bronchiectasis between January 1, 2001, and October 10, 2022. We used a narrative synthesis approach and estimated aggregate costs for several countries., Results: We identified 53 publications reporting on the economic burden and/or health care utilization of people with bronchiectasis. Total annual health care costs per adult patient ranged from 2021 $3,579 to $82,545 USD and were predominantly driven by hospitalization costs. Annual indirect costs including lost income because of illness (reported in only five studies) ranged from $1,311 to $2,898 USD. Total health care costs in children with bronchiectasis were $23,687 USD annually in the one study that estimated them. Additionally, one publication found that children with bronchiectasis missed 12 school days per year. We estimated aggregate annual health care costs for nine countries, ranging from $101.6 million per year in Singapore to $14.68 billion per year in the United States. We also estimated the aggregate cost of bronchiectasis in Australian children to be $17.77 million per year., Interpretation: This review highlights the substantial economic burden of bronchiectasis for patients and health systems. To our knowledge, it is the first systematic review to include the costs for children with bronchiectasis and their families. Future research to examine the economic impact of bronchiectasis in children and economically disadvantaged communities, and to further understand the indirect burden of bronchiectasis on individuals and the community, is needed., Competing Interests: Financial/Nonfinancial Disclosures The authors have reported to CHEST the following: J. D. C. has received research grants from AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Gilead Sciences, Grifols, Novartis, Insmed, and Trudell; and received consultancy or speaker fees from Antabio, AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Insmed, Janssen, Novartis, Pfizer, Trudell, and Zambon. A. B. C. reports multiple grants from NHMRC and other fees to the institution from work relating to IDMC membership of an unlicensed vaccine (GlaxoSmithKline), unlicensed monoclonal antibody for RSV (AstraZeneca), and a COVID-19 vaccine (Moderna), outside the submitted work; and fees to the institution from work relating to unlicensed therapies for bronchiectasis (inhaled antibiotics from Zambon and a molecule from Boehringer Ingelheim). P. C. G. has received grants from Chiesi, speaker fees from Insmed and GSK, and an advisory board fee from GlaxoSmithKline. None declared (J. M. R., V. G., S. K., N. K., F. H., J. M. M., S. M. M.)., (Copyright © 2023 American College of Chest Physicians. All rights reserved.)

Background: Respiratory exacerbations in children and adolescents with bronchiectasis are treated with antibiotics. However, antibiotics can have variable interindividual effects when treating exacerbations., Research Question: Can phenotypic features associated with symptom resolution after a 14-day course of oral antibiotics for a nonsevere exacerbation of bronchiectasis be identified?, Study Design and Methods: Combining data from two multicenter randomized controlled trials, we identified 217 children with bronchiectasis assigned to at least 14 days of oral antibiotics to treat nonsevere (nonhospitalized) exacerbations. Univariable and then multivariable logistic regression were used to identify factors associated with symptom resolution within 14 days of commencing antibiotics. Identified associations were re-evaluated by mediation analysis., Results: Of the 217 study participants (52% male patients), 41% were Indigenous (Australian First Nations, New Zealand Māori, or Pacific Islander). The median age was 6.6 years (interquartile range, 4.0-10.1 years). By day 14, symptoms had resolved in 130 children (responders), but persisted in the remaining 87 children (nonresponders). Multivariable analysis found those who were Indigenous (adjusted OR [AOR], 3.59; 95% CI, 1.35-9.54) or showed new abnormal auscultatory findings (AOR, 3.85; 95% CI, 1.56-9.52) were more likely to be responders, whereas those with multiple bronchiectatic lobes at diagnosis (AOR, 0.66; 95% CI, 0.46-0.95) or higher cough scores when starting exacerbation treatment (AOR, 0.55; 95% CI, 0.34-0.90) were more likely to be nonresponders. Detecting a respiratory virus at the beginning of an exacerbation was not associated with antibiotic failure at 14 days., Interpretation: Children with Indigenous ethnicity, milder bronchiectasis, mild exacerbations (low reported cough scores), or new abnormal auscultatory signs are more likely to respond to appropriate oral antibiotics than those without these features. These patient and exacerbation phenotypes may assist clinical management and development of biomarkers to identify those whose symptoms are more likely to resolve after 14 days of oral antibiotics., Trial Registry: Australian New Zealand Clinical Trials Registry; Nos.: ACTRN12612000011886 and ACTRN12612000010897; URL: https://www.anzctr.org.au., Competing Interests: Financial/Nonfinancial Disclosures The authors have reported to CHEST the following: A. B. C. reports other fees to her institution from work relating to independent data management committee membership for an unlicensed vaccine from GlaxoSmithKline, unlicensed monoclonal antibody for respiratory syncytial viruses from AstraZeneca and a COVID-19 vaccine from Moderna outside the submitted work and fees to her institution from work relating to unlicensed therapies for bronchiectasis: inhaled antibiotics from Zambon and a molecule from Boehringer Ingelheim. C. A. B. is a trustee of the BronchiectasisFoundation (no payment) and chairs the Clinical Advisory Panel for Cystic Fibrosis (no payment)., (Copyright © 2023 American College of Chest Physicians. All rights reserved.)

In children and adults, chronic cough is a common symptom presenting to health professionals worldwide. It is internationally accepted that children with chronic cough should be managed with pediatric specific management guidelines. The newly proposed clinical entity of 'cough hypersensitivity syndrome' has gained significant attention in adult literature. Given the significant differences between childhood and adult chronic cough, including in respiratory physiology and anatomy, and cough sensitivity, we address the suitability of the use of cough hypersensitivity syndrome in children. We explore these differences between childhood and adult chronic cough, explain what cough hypersensitivity is and highlight why the term cough hypersensitivity syndrome should not be used in children.

Early childhood respiratory infections, including pneumonia, are an important global public health issue, with more than 40 million annual cases resulting in approximately 650 000 deaths. A growing number of published studies have examined the effects of early childhood lower respiratory tract infections (LRTIs) or pneumonia on lung function, particularly as part of large early-life exposure studies. To our knowledge, there is no published systematic review of these data. We searched PubMed, Embase, and Web of Science for studies published between database inception and May 12, 2022. Case-control, cohort, and cross-sectional studies were included if they reported forced expiratory volume in 1 s (FEV 1 ) or forced vital capacity (FVC) values of participants older than 5 years. Article titles and abstracts were screened in Rayyan before retrieval, assessment, and data extraction of the full text. Primary outcome measures were differences in mean FEV 1 or FVC values between exposed groups (ie, children aged ≤5 years with LRTIs) and non-exposed groups. This study is registered with PROSPERO, CRD42021265295. Database searches yielded 3070 articles, and 14 studies were included in this systematic review, providing a total of 23 276 participants, including 9969 children and 13 307 adults. Eight of 14 articles reported significant reductions in FEV 1 values, and six of 12 studies reported reductions in FVC values in children and adults with a history of early childhood LRTIs or pneumonia, compared with unexposed controls (p<0·05). Most studies reporting reductions in lung function described deficits consistent with a restrictive spirometry pattern. Only two of 14 studies reported data from low-income and middle-income countries or disadvantaged populations in middle-income and high-income countries, and there were scarce data available on the effect of LRTI severity and recurrence on lung function. LRTIs in early childhood could be associated with a restrictive spirometry pattern in later childhood and adulthood. Data are needed from low-income and middle-income nations, and from disadvantaged populations in middle-income and high-income countries in which early childhood respiratory infection burden is disproportionately high. Data are also needed on the effect of LRTI severity and recurrence on future lung function., Competing Interests: Declaration of interests ABC reports multiple grants from the Australian National Health and Medical Research Council (NHMRC), and other fees to the institution from work relating to independent data monitoring committee membership of an unlicensed vaccine (GlaxoSmithKline), an unlicensed monoclonal antibody for RSV (AstraZeneca), and a COVID-19 vaccine (Moderna), outside the submitted work; and fees to the institution from work relating to unlicensed therapies for bronchiectasis (inhaled antibiotics from Zambon and a molecule from Boehringer Ingelheim). JLP reports investigator-initiated funding from GlaxoSmithKline for unrelated research. SCD reports investigator-initiated funding from GlaxoSmithKline for unrelated research, and further investigator-initiated funding from AstraZeneca. MSM reports other grants from Children's Hospital Foundation., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Introduction: There is limited evidence on the efficacy of using spirometry routinely in paediatric practice for improving outcomes., Objective: To determine whether the routine use of spirometry alters clinical decisions and patient-related outcome measures for children managed by respiratory paediatricians., Methods: We undertook a parallel open-label randomised controlled trial involving children (aged 4-18 years) able to perform spirometry in a specialist children's hospital in Australia. Children were randomised to either routine use of spirometry (intervention) or clinical review without use of spirometry (control) for one clinic visit. The primary outcomes were the (a) proportion of children with 'any change in clinical decisions' and (b) 'change score' in clinical decisions. Secondary outcomes were change in patient-related outcome measures assessed by State-Trait Anxiety Inventory (STAI) and Parent-Proxy QoL questionnaire for paediatric chronic cough (PC-QoL)., Results: Of 136 eligible children, 106 were randomised. Compared with controls, the intervention group had significantly higher proportion of children with 'any change in clinical decisions' (n=54/54 (100%) vs n=34/52 (65.4%), p<0.001) and higher clinical decision 'change score' (median=2 (IQR 1-4) vs 1 (0-2), p<0.001). Also, improvement was significantly greater in the intervention group for overall STAI score (median=-5 (IQR -10 to -2) vs -2.5 (-8.5, 0), p=0.021) and PC-QoL social domain (median=3 (IQR 0 to 5) vs 0 (-1, 1), p=0.017)., Conclusion: The routine use of spirometry in children evaluated for respiratory issues at clinical outpatient review is beneficial for optimising clinical management and improving parent psychosocial well-being., Registration: Australia and New Zealand Clinical Trials Registry ACTRN12619001686190., Competing Interests: Competing interests: No competing interests to declare., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Fractional exhaled nitric oxide (Feno), used as a biomarker, is influenced by several factors including ethnicity. Normative data are essential for interpretation, and currently single cutoff values are used in children and adults., Research Question: Accounting for factors that influence Feno, (1) what are appropriate predicted and upper limit of normal (ULN) Feno values in an underserved population (First Nations Australians), (2) how do these values compare with age-based interpretive guidelines, and (3) what factors influence Feno and what is the size of the effect?, Study Design and Methods: Feno data of First Nations Australians (age < 16 years, n = 862; age ≥ 16 years, n = 348) were obtained. Medical history using participant questionnaires and medical records were used to define healthy participants. Flexible regression using spline functions, as used by the Global Lung Function Initiative, were used to generate predicted and ULN values., Results: Look-up tables for predicted and ULN values using age (4-76 years) and height (100-200 cm) were generated and are supplied with a calculator for clinician use. In healthy First Nations children (age < 18 years), ULN values ranged between 25 and 60 parts per billion (ppb) when considering only biologically plausible age and height combinations. For healthy adults, ULN values ranged between 39 and 88 ppb. Neither the current Feno interpretation guidelines, nor the currently recommended cutoff of 50 ppb for First Nations children 16 years of age or younger were appropriate for use in this cohort. Our modelling revealed that predicted and ULN values of healthy participants varied nonlinearly with age and height., Interpretation: Because single pediatric, adult, or all-age Feno cutoff values used by current interpretive guidelines to define abnormality fail to account for factors that modify Feno values, we propose predicted and ULN values for First Nations Australians 4 to 76 years of age. Creating age- and height-adjusted predicted and ULN values could be considered for other ethnicities., (Copyright © 2022 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Purpose: Low diffusing capacity of the lung for carbon monoxide (D LCO ) and spirometry values are associated with increased mortality risk. However, associations between mortality risk and cardiovascular disease with the transfer coefficient of the lung for carbon monoxide (K CO ) and alveolar volume (V A ) are unknown. This cohort study: (i) evaluated whether D LCO , K CO , and V A abnormalities are independently associated with cardiovascular morbidity and/or elevated mortality risk and, (ii) compared these associations with those using spirometry values., Methods: Gas-diffusing capacity and spirometry data of 1165 adults seen at specialist respiratory outreach clinics over an 8-year period (241 with cardiovascular disease; 108 deceased) were analysed using multivariable Cox and logistic regression., Results: D LCO , K CO , and V A values below the lower limit of normal (< - 1.64 Z-scores) were associated with elevated cardiovascular disease prevalence [respective odds ratios of 1.83 (95% CI 1.31-2.55), 1.56 (95% CI 1.08-2.25), 2.20 (95% CI 1.60-3.01)] and increased all-cause mortality risk [respective hazard ratios of 2.99 (95% CI 1.83-4.90), 2.14 (95% CI 1.38-3.32), 2.75 (95% CI 1.18-2.58)], after adjustment for factors including age, personal smoking, and respiratory disease. Compared to similar levels of spirometry abnormality, D LCO , K CO , and V A were associated with similar or greater mortality risk, and similar cardiovascular disease prevalence. Analysis of only those patients with clinical normal spirometry values (n = 544) showed these associations persisted for D LCO ., Conclusion: Low D LCO , K CO , and V A measurements are associated with cardiovascular disease prevalence. As risk factors of all-cause mortality, they are more sensitive than spirometry even among patients with no diagnosed respiratory disease., (© 2022. The Author(s).)

Background: There is little data on patterns of spirometry curves in children with tracheomalacia but convex inflection on flow-volume curves (identified as the 'knee') is thought to represent tracheomalacia., Objectives: To determine (a) the prevalence of tracheomalacia in children with the 'knee' pattern on spirometry, and (b) whether spirometry parameters and visual characteristics of the 'knee' can identify presence/absence or severity of tracheomalacia., Patients/methods: We reviewed the spirometry undertaken at Queensland Children's Hospital between 2016 and 2019 and retrieved spirometry with the 'knee' pattern in the flow-volume curves. Flexible bronchoscopy videos of these children were reviewed for tracheomalacia diagnosis and severity in a blinded manner. We also evaluated several 'knee' characteristics (onset of inflection, angle of inflection, a scoop before plateau, plateau progression), spirometry parameters and tracheomalacia severity., Results: Of the 78 children with the 'knee', 51 (65.4%) had tracheomalacia. Spirometry values were significantly lower in those with tracheomalacia, compared to those without (predicted FEV 1  = 86.1% vs 99.9%, FVC = 95.1% vs 104%, FEF 25-75%  = 68.6% vs 89.6%, all p < 0.02). A scoop before plateau was significantly associated with tracheomalacia (66.7% vs 40.7%, p = 0.03). There was no significant difference in spirometry parameters or the 'knee' characteristics between children with mild versus moderate-to-severe tracheomalacia., Conclusion: Most but not all children with the 'knee' pattern have flexible bronchoscopy-defined tracheomalacia. Those with tracheomalacia had lower spirometry values and the presence of a scoop before plateau was the most characteristic feature. A prospective longitudinal study is required to determine the diagnostic value of spirometry flow-volume curve characteristics in children., Competing Interests: Declaration of competing interest None., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Spirometry provides a quantitative measure of lung function and its use is recommended as an adjunct to enhance pediatric respiratory healthcare in many clinical practice guidelines. However, there is limited evidence confirming the benefits (or otherwise) of using spirometry from either clinician or patient perspectives. This systematic review aimed to determine the impact of spirometry on change in clinical decision making and patient-reported outcome measures. We searched PubMed, Embase, Cochrane Central Register of Controlled Trials, www.clinicaltrials.gov, and World Health Organization International Clinical Trials Registry Platform, from inception to July 2021. We included randomized controlled trials (RCTs) comparing the use versus non-use of spirometry during standard clinical review in children aged <18 years with respiratory problems in clinics. We used Cochrane methodology. The search identified 3475 articles; 8 full-text articles were reviewed but only 1 study fulfilled the inclusion criteria. The single study involved two cluster RCTs of spirometry for children with asthma in general practice. The included study did not find any significant intergroup difference at the 12-month follow-up for asthma-related quality-of-life and clinical endpoints. However, the findings were limited by methodological weaknesses and high risks of bias. With a paucity of data, the clinical benefits of spirometry remain unclear. Thus, there is a clear need for RCTs that provide high-quality evidence to support the routine use of spirometry in children with suspected or known lung disease. Pending the availability of better evidence, we recommend that clinicians adhere to the current clinical practice recommendations., (© 2022 The Authors. Pediatric Pulmonology published by Wiley Periodicals LLC.)

Objectives: Spirometry is easily accessible yet there is limited data in children with tracheomalacia. Availability of such data may inform clinical practice. We aimed to describe spirometry indices of children with tracheomalacia, including Empey index and flow-volume curve pattern, and determine whether these indices relate with bronchoscopic features., Methods: From the database of children with tracheomalacia diagnosed during 2016-2019, we reviewed their flexible bronchoscopy and spirometry data in a blinded manner. We specially evaluated several spirometry indices and tracheomalacia features (cross-sectional lumen reduction, malacic length, and presence of bronchomalacia) and determined their association using multivariable regression., Results: Of 53 children with tracheomalacia, the mean (SD) peak expiratory flow (PEF) was below the normal range [68.9 percent of predicted value (23.08)]. However, all other spirometry parameters were within normal range [Z-score forced expired volume in 1 s (FEV 1 ) = -1.18 (1.39), forced vital capacity (FVC) = -0.61 (1.46), forced expiratory flow between 25% and 75% of vital capacity​​​​​​ (FEF 25%-75% ) = -1.43 (1.10), FEV 1 /FVC = -1.04 (1.08)], Empey Index = 8.21 (1.59). The most common flow-volume curve pattern was the "knee" pattern (n = 39, 73.6%). Multivariable linear regression identified the presence of bronchomalacia was significantly associated with lower flows: FEV 1 [coefficient (95% CI) -0.78 (-1.54, -0.02)], FEF 25%-75% [-0.61 (-1.22, 0)], and PEF [-12.69 (-21.13, -4.25)], all p ≤ 0.05. Other bronchoscopic-defined tracheomalacia features examined (cross-sectional lumen reduction, malacic length) were not significantly associated with spirometry indices., Conclusion: The "knee" pattern in spirometry flow-volume curve is common in children with tracheomalacia but other indices, including Empey index, cannot be used to characterize tracheomalacia. Spirometry indices were not significantly associated with bronchoscopic tracheomalacia features but children with tracheobronchomalacia have significantly lower flow than those with tracheomalacia alone., (© 2022 The Authors. Pediatric Pulmonology published by Wiley Periodicals LLC.)

Introduction: Primary ciliary dyskinesia (PCD) is a rare, progressive, inherited ciliopathic disorder, which is incurable and frequently complicated by the development of bronchiectasis. There are few randomised controlled trials (RCTs) involving children and adults with PCD and thus evidence of efficacy for interventions are usually extrapolated from people with cystic fibrosis. Our planned RCT seeks to address some of these unmet needs by employing a currently prescribed (but unapproved for long-term use in PCD) macrolide antibiotic (azithromycin) and a novel mucolytic agent (erdosteine). The primary aim of our RCT is to determine whether regular oral azithromycin and erdosteine over a 12-month period reduces acute respiratory exacerbations among children and adults with PCD. Our primary hypothesis is that: people with PCD who regularly use oral azithromycin and/or erdosteine will have fewer exacerbations than those receiving the corresponding placebo medications. Our secondary aims are to determine the effect of the trial medications on PCD-specific quality-of-life (QoL) and other clinical outcomes (lung function, time-to-next exacerbation, hospitalisations) and nasopharyngeal bacterial carriage and antimicrobial resistance., Methods and Analysis: We are currently undertaking a multicentre, double-blind, double-dummy RCT to evaluate whether 12 months of azithromycin and/or erdosteine is beneficial for children and adults with PCD. We plan to recruit 104 children and adults with PCD to a parallel, 2×2 partial factorial superiority RCT at five sites across Australia. Our primary endpoint is the rate of exacerbations over 12 months. Our main secondary outcomes are QoL, lung function and nasopharyngeal carriage by respiratory bacterial pathogens and their associated azithromycin resistance., Ethics and Dissemination: Our RCT is conducted in accordance with Good Clinical Practice and the Australian legislation and National Health and Medical Research Council guidelines for ethical conduct of Research, including that for First Nations Australians., Trial Registration Number: ACTRN12619000564156., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Chronic cough is a common symptom of many underlying respiratory and non-respiratory disorders and may be associated with less serious causes, such as gastroesophageal reflux and nasal diseases. Chronic cough in children differs from that in adults with respect to its etiologies and management since it can indicate a symptom of an underlying disease in children. Guidelines for managing chronic cough in children are based on recording the history, followed by physical examination, chest radiography, and spirometry. Thus, taking accurate respiratory history for coughing helps delineate the pathophysiological basis of the cause of chronic cough. Detailed history taking enhances the evaluation and treatment, and facilitates a tailored diagnostic identification of likely diagnoses. While studies have described evidence-based red flags in children with chronic cough, the value of skilled physicians regarding history taking has received less attention for the best patient care. In the present article, we outline the major questions comprising a detailed history taking for chronic cough in children., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Kantar, Marchant, Song, Shields, Chatziparasidis, Zacharasiewicz, Moeller and Chang.)

Background: Preventing and/or reducing acute lower respiratory infections (ALRIs) in young children will lead to substantial short and long-term clinical benefits. While immunisation with pneumococcal conjugate vaccines (PCV) reduces paediatric ALRIs, its efficacy for reducing infant ALRIs following maternal immunisation has not been studied. Compared to other PCVs, the 10-valent pneumococcal- Haemophilus influenzae Protein D conjugate vaccine (PHiD-CV) is unique as it includes target antigens from two common lower airway pathogens, pneumococcal capsular polysaccharides and protein D, which is a conserved H. influenzae outer membrane lipoprotein. Aims: The primary aim of this randomised controlled trial (RCT) is to determine whether vaccinating pregnant women with PHiD-CV (compared to controls) reduces ALRIs in their infants' first year of life. Our secondary aims are to evaluate the impact of maternal PHiD-CV vaccination on different ALRI definitions and, in a subgroup, the infants' nasopharyngeal carriage of pneumococci and H. influenzae , and their immune responses to pneumococcal vaccine type serotypes and protein D. Methods: We are undertaking a parallel, multicentre, superiority RCT (1:1 allocation) at four sites across two countries (Australia, Malaysia). Healthy pregnant Australian First Nation or Malaysian women aged 17-40 years with singleton pregnancies between 27 +6 and 34 +6 weeks gestation are randomly assigned to receive either a single dose of PHiD-CV or usual care. Treatment allocation is concealed. Study outcome assessors are blinded to treatment arms. Our primary outcome is the rate of medically attended ALRIs by 12-months of age. Blood and nasopharyngeal swabs are collected from infants at birth, and at ages 6- and 12-months (in a subset). Our planned sample size ( n = 292) provides 88% power (includes 10% anticipated loss to follow-up). Discussion: Results from this RCT potentially leads to prevention of early and recurrent ALRIs and thus preservation of lung health during the infant's vulnerable period when lung growth is maximum. The multicentre nature of our study increases the generalisability of its future findings and is complemented by assessing the microbiological and immunological outcomes in a subset of infants. Clinical Trial Registration: https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=374381, identifier: ACTRN12618000150246., Competing Interests: KG participated in a rotavirus strain outbreak advisory board for GlaxoSmithKline, Rixensart, Belgium. ABC has received fees to the institution from work relating to IDMC membership of an unlicensed vaccine (GSK), and a COVID-19 vaccine (Moderna) outside the submitted work. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Chang, Toombs, Chatfield, Mitchell, Fong, Binks, Smith-Vaughan, Pizzutto, Lust, Morris, Marchant, Yerkovich, O'Farrell, Torzillo, Maclennan, Simon, Unger, Ellepola, Odendahl, Marshall, Swamy and Grimwood.)

Introduction: Bronchiectasis is no longer considered rare or irreversible in children, yet it remains relatively under-researched and neglected in respiratory health globally. Bronchiectasis (including chronic suppurative lung disease) causes substantial morbidity for patients and significant impact on caregivers, especially during acute respiratory exacerbations. In other chronic respiratory diseases (eg, asthma), empowering consumers with an individualised plan for management of acute exacerbations improves clinical outcomes. However, in the absence of any such data specific to bronchiectasis, action management plans are rarely currently used in children or adults with bronchiectasis. We hypothesise that providing an individualised bronchiectasis action management plan (BAMP) to children with bronchiectasis reduces non-scheduled doctor consultations, compared with not having a BAMP., Methods and Analysis: This multicentre, parallel, double-blind, randomised trial involving three urban Australian hospitals commenced in June 2018 and will include 198 children, aged <19 years with bronchiectasis who had 2 or more exacerbations in the previous 18 months. Children will be randomised to having an individualised BAMP or standard care (a decoy clinic letter). Primary caregivers will then be followed up monthly for 12 months. The primary outcome is the rate of acute non-scheduled doctor visits for respiratory exacerbations by 12 months. The main secondary outcomes are cough-specific quality of life scores at 6 and 12 months, overall exacerbation rate over 12 months, and proportion of children who received timely influenza vaccination by 30 May annually., Ethics and Dissemination: The Human Research Ethics Committees of the Northern Territory Department of Health and Menzies School of Heath Research and Queensland Children's Hospital approved the study. The results of the trial will be submitted for publication and the BAMP made available free online., Trial Registration Number: Australia and New Zealand Clinical Trials Register ACTRN12618000604202., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Bronchiectasis is a neglected chronic respiratory condition. In children optimal appropriate management can halt the disease process, and in some cases reverse the radiological abnormality. This requires many facets, including parental/carer bronchiectasis-specific knowledge, for which there is currently no such published data. Further, the importance of patient voices in guiding clinical research is becoming increasingly appreciated. To address these issues, we aimed to describe the voices of parents of children with bronchiectasis relating to (a) burden of illness and quality of life (QoL), (b) their major worries/concerns and (c) understanding/management of exacerbations. The parents of 152 children with bronchiectasis (median age = 5.8 years, range 3.5-8.4) recruited from the Queensland Children's Hospital (Australia) completed questionnaires, including a parent-proxy cough-specific QoL. We found that parents of children with bronchiectasis had impaired QoL (median 4.38, range 3.13-5.63) and a high disease burden with median 7.0 (range 4.0-10.0) doctor visits in 12-months. Parental knowledge varied with only 41% understanding appropriate management of an exacerbation. The highest worry/concern expressed were long-term effects ( n = 42, 29.8%) and perceived declining health ( n = 36, 25.5%). Our study has highlighted the need for improved education, high parental burden and areas of concern/worry which may inform development of a bronchiectasis-specific paediatric QoL tool.

Background: Some but not all previous studies report that pneumonia in children aged less than five years is associated with lower lung function and elevated risk of respiratory disease. To date, none have explored these associations in at-risk populations such as First Nations Australians, whose incidence of early childhood pneumonia is among the highest reported in the world., Methods: This cross-sectional study included 1276 First Nations Australian children/young adults aged 5-25 years recruited from regional/remote Queensland and Northern Territory communities and schools. Associations between pneumonia and both spirometry values and asthma were investigated using linear and logistic regression., Results: Early childhood pneumonia was associated with lower FEV1 and FVC Z-scores, but not FEV1/FVC% Z-scores, when occurring before age three (FEV1 β = -0.42, [95%CI -0.79, -0.04]; FVC β = -0.62, [95%CI -1.14, -0.09]), and between three and five years (β = -0.50, [95%CI -0.88, -0.12]; β = -0.63, [95%CI -1.17, -0.10]), compared to those who never had pneumonia. Similarly, pneumonia occurring when aged before age three years (OR = 3.68, 95%CI 1.96-6.93) and three to five years (OR = 4.81, 95%CI 1.46-15.8) was associated with increased risk of asthma in later childhood., Conclusions: Early childhood pneumonia is associated with lung function deficits and increased asthma risk in later childhood/early adulthood in First Nations Australians. The disproportionate impact of pneumonia on at-risk children must be addressed as a priority.

We describe the prevalence and risk factors for protracted bacterial bronchitis (PBB) following healthcare presentation for an acute cough illness in children. Data from three studies of the development of chronic cough (CC) in children were combined. PBB was defined as a wet cough of at least 4-weeks duration with no identified specific cause of cough that resolved following 2-4 weeks of appropriate antibiotics. Anterior nasal swabs were tested for 17 viruses and bacteria by polymerase chain reaction. The study included 903 children. Childcare attendance (adjusted relative risk (aRR) = 2.32, 95% CI 1.48-3.63), prior history of chronic cough (aRR = 2.63, 95% CI 1.72-4.01) and age <2-years (<12-months: aRR = 4.31, 95% CI 1.42-13.10; 12-<24 months: aRR = 2.00, 95% CI 1.35-2.96) increased risk of PBB. Baseline diagnoses of asthma/reactive airways disease (aRR = 0.30, 95% CI 0.26-0.35) or bronchiolitis (aRR = 0.15, 95% CI 0.06-0.38) decreased risk. M. catarrhalis was the most common organism (52.4%) identified in all children (PBB = 72.1%; no PBB = 50.2%, p < 0.001). We provide the first data on risks for PBB in children following acute illness and a hypothesis for studies to further investigate the relationship with wheeze-related illnesses. Clinicians and parents/guardians should be aware of these risks and seek early review if a wet cough lasting more than 4-weeks develops the post-acute illness.

Background: Spirometry values of First Nations Australian children are lower than White children. One explanation relates to differences in the sitting-height/standing-height ratio (Cormic Index), as this accounts for up to half the observed differences in spirometry values between White children and other ethnicities. We investigated whether the Cormic Index of First Nations children differs from White children and if this explains the lower spirometry values of First Nations children., Methods: First Nations children (n = 619) aged 8-16 years were recruited from nine Queensland communities. Their spirometry and Cormic Index data were compared to that of White children (n = 907) aged 8-16 years from the NHANES III dataset., Results: FEV 1 and FVC of First Nations children was 8% lower for children aged 8-11.9 years and 9%-10% lower for children aged 12-16 years. The Cormic Index was statistically lower in the First Nations 8-11.9 years group (median = 0.515, interquartile range [IQR]: 0.506-0.525) compared with White children (0.519, IQR: 0.511-0.527), and this difference was greater in the 12-16 years group (0.505, IQR: 0.492-0.516; 0.520, IQR: 0.510-0.529). Adjusting for age, sex, and standing height, lower Cormic Index of First Nations children accounts for 14% (95% confidence interval [CI]: 7%-21%) of FEV 1 and 15% (95% CI: 8%-21%) of FVC differences in the younger group, and 26% (95% CI: 16%-37%) of FEV 1 and 31% (95% CI: 19%-42%) of FVC differences in the older group., Conclusion: Ethnic differences in Cormic Index partly account for why healthy First Nations Australian children have lower spirometry values than White children. As childhood spirometry values impact adult health, other contributing factors require attention., (© 2021 Wiley Periodicals LLC.)

Purpose: Acute cough in children has a significant impact on the child and family. Relevant quality of life (QoL) instruments are essential for high-quality clinical research. This study aimed to (1) revalidate the 16-item Parent-proxy Children's Acute Cough-specific QoL questionnaire (PAC-QoL 16 ) using a different dataset (i.e., different children), (2) confirm the minimally important difference (MID), and (3) develop and validate a short form., Methods: Three datasets from two sources were utilized, comprising of 332 children with acute cough (< 2 weeks duration); the first dataset (n = 83, 54 boys; median age 2.04 years, IQR 1.08-4.06 years) was used for revalidation, the second dataset (n = 238, 141 boys; median age 2.17 years, IQR 1.21-4.21 years) was used to develop the short form, and the third dataset (n = 94, 62 boys; median age, 1.75 years, IQR 0.90-3.63 years) was used to confirm the short form. Psychometric properties were investigated., Results: Six items were found to account for 96.4% of the variance in the PAC-QoL 16 . The PAC-QoL 16 and short form (PAC-QoL 6 ) scales correlated with cough scores (r s  ≤ - 0.40, p < 0.001), were internally consistent (Cronbach α = 0.94 and 0.87, respectively) and demonstrated sensitivity to change over time. A MID of 0.71 to 1.11 is recommended., Conclusion: Both the PAC-QoL 16 and newly developed short form (PAC-QoL 6 ) are reliable and valid outcome measures that assess children's acute cough-specific QoL at a given time point, are easy to interpret and reflect changes over time. The new short form addresses the need for outcome measures to be as time effective as possible without loss of information., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Protracted bacterial bronchitis (PBB) is a leading cause of chronic wet cough in children. The current standard treatment in European and American guidelines is 2 weeks of antibiotics, but the optimal duration of therapy is unknown. We describe the first randomised controlled trial to assess the duration of antibiotic treatment in children with chronic wet cough and suspected PBB. We hypothesise that 4 weeks of amoxicillin-clavulanate is superior to 2 weeks for improving clinical outcomes., Methods: Our parallel, double-blind, placebo-controlled, randomised controlled trial was completed in four Australian hospitals. Children aged 2 months to 19 years with chronic (>4 weeks duration) wet cough, and suspected PBB were randomly assigned (1:1) using permuted block randomisation (stratified by age and site) to 4 weeks of amoxicillin-clavulanate (25-35 mg/kg twice daily oral suspension; 4-week group) or 2 weeks of amoxicillin-clavulanate followed by 2 weeks of placebo (2-week group). The children, caregivers, all the study coordinators, and investigators were masked to treatment assignment until data analysis was completed. The primary outcome was clinical cure (cough resolution) by day 28. Secondary outcomes were recurrence of PBB at 6 months, time to next exacerbation, change in Parent-proxy Cough-Specific Quality-of-Life (PC-QoL) score from baseline to day 28 and from day 28 to 7 months, adverse events, nasal swab bacteriology, and antimicrobial resistance. Analyses followed the intention-to-treat principle. This trial is complete and registered with Australian/New Zealand Registry, ACTRN12616001725459., Findings: Between March 8, 2017, and Sept 30, 2019, 106 children were randomly assigned (52 in the 4-week group, median age 2·2 years [IQR 1·3-4·1]; 54 in the 2-week group, median age 1·7 years [1·2-3·8]) with 90 children completing the 4-week treatment. By day 28, the primary endpoint of clinical cure in the 4-week group (32 [62%] of 52 patients) was not significantly different to the 2-week group (38 [70%] of 54 patients; adjusted relative risk 0·87 [95% CI 0·60 to 1·28]; p=0·49). Time to next wet cough exacerbation was significantly longer in the 4-week group than the 2-week group (median 150 days [IQR 38-181] vs 36 days [15-181]; adjusted hazard ratio 0·47 [0·25 to 0·90]; p=0·02). The rate of recurrence of PBB at 6 months was 17 (53%) of 32 patients in the 4-week group vs 28 (74%) of 38 patients in the 2-week group, but the difference between the groups was not significant (adjusted odds ratio 0·39 [0·14 to 1·04]; p=0·07). PC-QoL significantly improved from baseline to day 28 in both groups, but there was no significant difference between them (mean difference in change -0·2 [95% CI -1·0 to 0·6]; p=0·64). From day 28 to 7 months, median PC-QoL remained stable in both groups with no difference in change between them. Data on respiratory pathogens and antimicrobial resistance (paired swabs available for 48 children) were similar between groups. Adverse events occurred in 13 (25%) children in the 2-week group and ten (19%) in the 4-week group (p=0·57)., Interpretation: A 4-week course of amoxicillin-clavulanate for treating children with chronic wet cough and suspected PBB confers little advantage compared with a 2-week course in achieving clinical cure by 28 days. However, as a 4-week duration led to a longer cough-free period, identifying children who would benefit from a longer antibiotic course is a priority., Funding: Queensland Children's Hospital Foundation., Competing Interests: Declaration of interests ABC reports grants from the National Health and Medical Research Council, Australia (NHMRC), other fees to the institution from work relating to being an independent data monitoring committee member of an unlicensed vaccine (GlaxoSmithKline [GSK]) and an advisory member of the study design for an unlicensed molecule for chronic cough (Merck), outside of the submitted work. AS reports personal fees from Vertex Pharmaceuticals, outside of the submitted work. JWU reports personal fees from AstraZeneca, GSK, Novartis, and Sanofi, outside of the submitted work. All other authors declare no competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Introduction: Although spirometry has been available for decades, it is underused in paediatric practice, other than in specialist clinics. This is unsurprising as there is limited evidence on the benefit of routine spirometry in improving clinical decision making and/or outcomes for children. We hypothesised that using spirometry for children being evaluated for respiratory diseases impacts on clinical decision making and/or improves patient-related outcome measures (PROMs) and/or quality of life (QoL), compared with not using spirometry., Methods and Analysis: We are undertaking a randomised controlled trial (commenced in March 2020) that will include 106 children (aged 4-18 years) recruited from respiratory clinics at Queensland Children's Hospital, Australia. Inclusion criteria are able to perform reliable spirometry and a parent/guardian who can complete questionnaire(s). Children (1:1 allocation) are randomised to clinical medical review with spirometry (intervention group) or without spirometry (control group) within strata of consultation status (new/review), and cough condition (present/absent). The primary outcome is change in clinical decision making. The secondary outcomes are change in PROM scores, opinions regarding spirometry and degree of diagnosis certainty. Intergroup differences of these outcomes will be determined by χ 2 test or unpaired t-test (or Mann-Whitney if not normally distributed). Change in outcomes within the control group after review of spirometry will also be assessed by McNemar's test or paired t-test/Wilcoxon signed-rank test., Ethics and Dissemination: The Human Research Ethics Committee of the Queensland Children's Hospital approved the study. The trial results will be disseminated through conference presentations, teaching avenues and publications., Trial Registration Number: ACTRN12619001686190; Pre-results., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: Northern Territory (NT)-based clinical service data suggest substantial lung function impairment amongst First Nations adults as young as 18-40 years. Our objectives were to describe the burden of disease and lung function of adults living in regional-remote Queensland, identify determinants of lung function, and evaluate the impact of a specialist respiratory outreach service on lung function., Methods: Retrospective 8-year cohort study (February 2012-March 2020) of 1113 First Nations Australian adults (and 648 non-First Nations adults) referred to respiratory outreach clinics in regional-remote Queensland., Results: In the combined cohort, the forced expiratory volume in 1 s (FEV 1 ) was clinically abnormal for 54% of First Nations patients (51% of non-First Nations patients), forced vital capacity (FVC) for 46% (36%), FEV 1 /FVC% for 30% (36%), and gas diffusing capacity (D LCO ) for 44% (37%). A respiratory diagnosis was assigned by a respiratory physician in 78% of First Nations (76% non-First Nations) patients. Smoking, household smoke exposure, underweight BMI, and respiratory disease were associated with reduced lung function. In the 40% of patients (709/1765) followed up, FEV 1 and FVC significantly improved (mean change: zFEV 1  = 0.15 [95% CI 0.10-0.20]; zFVC = 0.25 [0.20, 0.31]), and FEV 1 /FVC% significantly reduced (mean =  - 0.10 [95%CI - 0.07 to - 0.03]), with no significant change in D LCO . Patients with COPD had lower FEV 1 improvement, whilst underweight and obese patients had lower FVC improvement., Conclusion: Regional-remote First Nations adult Queenslanders have higher lung function than previously reported, with no lung function decline observed at follow-up visit, including for those with respiratory disease., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

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., (© 2021 Wiley Periodicals LLC.)

Background: Spirometric lung function impairment is an independent predictor of respiratory and cardiovascular disease, and mortality across a broad range of socioeconomic backgrounds and environmental settings. No contemporary studies have explored these relationships in a predominantly regional/remote First Nations population, whose health outcomes are worse than for non-First Nations populations, and First Nations people living in urban centres., Methods: This was a retrospective cohort study of 1,734 adults (1,113 First Nations) referred to specialist respiratory outreach clinics in the state of Queensland, Australia from February 2012 to March 2020. Regression modelling was used to test associations between lung function and mortality and cardiovascular disease., Findings: At the time of analysis (August 2020), 189 patients had died: 88 (47%) from respiratory causes and 38 (20%) from cardiovascular causes. When compared to patients with forced expiratory volume in one second (FEV 1 ) and forced vital capacity (FVC) Z-scores of >0 to -1, patients with Z-scores <-1 were at elevated mortality risk (HR=3•2, 95%CI 1•4-7•4; HR=2•6, 95%CI 1•3-5•1), and elevated cardiovascular disease risk (OR=1•5, 95%CI 1•1-2•2; OR=1•6, 95%CI 1•2-2•3). FEV 1 /FVC% Z-scores <-1 were associated with increased overall mortality (HR=1•6, 95%CI 1•1-2•3), but not cardiovascular disease (OR=1•1, 95%CI 0•8-1•4). These associations were not affected by First Nations status., Interpretation: Reduced lung function even within the clinically normal range is associated with increased mortality, and cardiovascular disease in First Nations Australians. These findings highlight the importance of lung function optimisation and inform the need for future investment to improve outcomes in First Nations populations., Funding: None., Competing Interests: The authors received no specific funding for this work. AJC is supported by a National Health and Medical Research Council (NHMRC) Postgraduate Scholarship (APP2003334), had full access to all the data in the study and had final responsibility for the decision to submit for publication. JM reports grants from the Children's Hospital Foundation (RPC0772019) during the conduct of the study. ABC reports grants from the NHMRC (APP1154302) and Children's Health Foundation (top-up #50286); other fees to the institution from work relating to being a IDMC Member of an unlicensed vaccine (GSK), and an advisory member of study design for unlicensed molecule for chronic cough (Merck) outside the submitted work. TB reports grants from during the conduct of the study; AD is a paid employee of Metro North Hospital and Health Services which also administers the Indigenous Respiratory Outreach (IROC) Program for Queensland Health, and provides clinical services to IROC clinics. KF reports grants from Various competitive funding bodies, non-financial support from Industry, occasional honorariums from various Universities, various international funding bodies, and Cochrane Clinical Answers, occasional royalty from UpToDate, outside the submitted work; and Paid employee of Metro North Hospital and Health Services which also administers the IROC program for Queensland Health. MM reports other from Children's Hospital Foundation, and grants from the NHMRC during the conduct of the study., (© 2021 The Authors.)

Introduction: Cough is an important contributor to the health burden of children and their families. There are limited data describing healthcare utilization and medication use over the course of a cough illness beyond the initial presentation. Our primary objective was to describe medication and healthcare use in children with a respiratory illness with cough as a symptom over the course of the illness., Methods: A cohort study of children aged less than 15-years presenting to three primary healthcare centers and three emergency departments with a cough illness between July 7, 2015 and October 6, 2018. Children with immunosuppression, known chronic lung diseases (except asthma) and those requiring hospitalization at screening were excluded. The primary outcomes were cough-related frequency and type of healthcare seeking and medication use up to 28 days following enrolment., Results: Data for 465 children were analyzed; median age 2.2-years (interquartile range = 1.1-5.3). Cough at Day 28 persisted in 117 children (25.2%). Overall, 436 (94%) children received medications in the week before and/or 4 weeks following enrolment. Half with upper respiratory tract infections were prescribed antibiotics. Among children with no diagnosis of asthma, reactive airways disease or croup (n = 404), 16.8% were given steroids. Fifty-eight percent of children sought healthcare at least once before their baseline presentation (median = 1, range = 0-20) and 49.7% had at least one further presentation in the following 28 days., Conclusions: High healthcare utilization, inappropriate medication use, and suboptimal parent knowledge regarding cough suggests targeted education is needed to improve management and reduce cough burden., (© 2021 Wiley Periodicals LLC.)

Background: Management strategies based on airway inflammation phenotypes are increasingly used for adults with asthma. While sputum-based phenotypes are relatively stable in adults with asthma, there is little such data in childhood asthma. Hence, we aimed to evaluate the stability of sputum inflammatory phenotypes in children with asthma both in the stable and during exacerbation phases., Methods: Sputum cellularity data from two previous prospective studies involving children with asthma were re-evaluated and categorized into two inflammatory phenotypes: eosinophilic (>2.5% eosinophils) and noneosinophilic (≤2.5% eosinophils). Baseline values and follow-up sputum inflammatory phenotype classification were compared in children with asthma during stable and exacerbation phases., Results: Thirteen of 32 children (41%) with stable asthma demonstrated a change in sputum inflammatory phenotype 8 weeks later. In a different second cohort, both sputum eosinophils and neutrophils percentages increased and peaked on Day 1 of asthma exacerbation, but compared with baseline, 22% (2/9) and 13% (1/8) of these children had their sputum phenotype categorization changed on Day 1 and Day 3 of exacerbation, respectively., Conclusion: In children with asthma, sputum inflammatory phenotypes are variable in both stable and exacerbation phases, in contrast to data in adults., (© 2021 Wiley Periodicals LLC.)

Objectives: Maximal inspiratory pressure (MIP) and maximal expiratory pressure (MEP) could be useful clinical parameters in monitoring many conditions including cystic fibrosis (CF). However, current protocols for undertaking the measurements lack standardization including the number of repeated attempts to achieve best values. We aimed to (a) determine the optimum number of attempts to achieve best MIP/MEP values, and (b) evaluate if the number of attempts is consistent across two different test days., Methods: We analyzed data of a previous randomized controlled trial involving the effect of singing on respiratory muscle strength in 35 children with CF. On two different days (T1, T2) children performed MIP/MEP with at least ten attempts each to achieve < 10% repeatability., Results: All children achieved repeatable MIP/MEP values within 10-11 attempts with 24 (68.6%) and 26 (74.3%) of these achieving best values of MIP and MEP, respectively, at attempts 6-11. Median values of the pressures by three, five, eight and all attempts significantly increased with more attempts (all p < 0.05). At T2, 56% required fewer attempts to achieve best values, but 32% required more attempts, indicating that the number of attempts required was inconsistent between test days., Conclusion: It is likely that at least ten attempts (best two within < 10% variability) is required to achieve best and reliable MIP/MEP in children with CF. A larger sample size in children with CF and various conditions is required to consolidate these findings.

Background and Objective: Long-term data on children with PBB has been identified as a research priority. We describe the 5-year outcomes for children with PBB to ascertain the presence of chronic respiratory disease (bronchiectasis, recurrent PBB and asthma) and identify the risk factors for these., Methods: Prospective cohort study was undertaken at the Queensland Children's Hospital, Brisbane, Australia, of 166 children with PBB and 28 controls (undergoing bronchoscopy for symptoms other than chronic wet cough). Monitoring was by monthly contact via research staff. Clinical review, spirometry and CT chest were performed as clinically indicated., Results: A total of 194 children were included in the analysis. Median duration of follow-up was 59 months (IQR: 50-71 months) post-index PBB episode, 67.5% had ongoing symptoms and 9.6% had bronchiectasis. Significant predictors of bronchiectasis were recurrent PBB in year 1 of follow-up (OR adj = 9.6, 95% CI: 1.8-50.1) and the presence of Haemophilus influenzae in the BAL (OR adj = 5.1, 95% CI: 1.4-19.1). Clinician-diagnosed asthma at final follow-up was present in 27.1% of children with PBB. A significant BDR (FEV 1 improvement >12%) was obtained in 63.5% of the children who underwent reversibility testing. Positive allergen-specific IgE (OR adj = 14.8, 95% CI: 2.2-100.8) at baseline and bronchomalacia (OR adj = 5.9, 95% CI: 1.2-29.7) were significant predictors of asthma diagnosis. Spirometry parameters were in the normal range., Conclusion: As a significant proportion of children with PBB have ongoing symptoms at 5 years, and outcomes include bronchiectasis and asthma, they should be carefully followed up clinically. Defining biomarkers, endotypes and mechanistic studies elucidating the different outcomes are now required., (© 2020 Asian Pacific Society of Respirology.)

Background and Objective: Despite paediatric bronchiectasis being recognized increasingly worldwide, prior reports of hospitalization costs for bronchiectasis in children are lacking. This study aimed to (i) identify health service costs of hospitalizations and (ii) factors associated with these costs in children admitted to an Australian paediatric hospital following an acute exacerbation of their bronchiectasis., Methods: Demographic and hospital resource use data were prospectively recorded for 100 hospitalizations in 80 children aged <18 years admitted consecutively to the QCH, Brisbane, Australia. Costs (2016 AUD) were obtained from the hospital's Finance Department. Linear regressions, with bootstrap resampling to quantify uncertainty, were used to estimate factors affecting cost of hospitalization., Results: The 100 hospitalizations (48 males) had a median (IQR) age of 6.04 (4.04-9.85) years. Their mean (SD) LOS was 12.30 (4.60) days. The mean (SD) direct health service cost was AUD 30 182 (13 998) per hospitalization. The greatest contributor to costs was health professional wages, accounting for 70% of the cost per episode. LOS, younger age at admission and number of bronchiectatic lobes affected were associated with higher costs, whilst HITH service was associated with lower cost. The cost to families on average was AUD 2669.50 (SD: 991.50) per hospitalization when accounting for lost wages and opportunity cost., Conclusion: The per episode healthcare cost burden of hospitalizations for paediatric bronchiectasis exacerbations is substantial. Interventions that prevent hospitalized exacerbations and reduce severity of childhood bronchiectasis with even moderate effectiveness are likely to result in substantial hospital costs savings., (© 2020 Asian Pacific Society of Respirology.)