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Background: Early-life inflammation has long been recognised as a key pathophysiological process in the evolution of cystic fibrosis (CF) lung disease. Despite this, no CF-specific anti-inflammatory treatments have been developed. This is crucial even in the era of highly effective modulator therapy as recent evidence suggests that modulators alter, but may not fully resolve, pulmonary inflammation., Methods: In this study, we used clinical microbiology data, high-dimensional flow cytometry and multiplex immunoassays to compare pulmonary (bronchoalveolar lavage (BAL)) and systemic immunity in 70 preschool children with CF and a total of 32 age-matched preschool controls., Results: We show that inflammation in the early-life CF lung is characterised by innate cell infiltration (neutrophils: 31.31 vs 1.8% of BAL in CF compared with controls, FDRp=0.0001; eosinophils: 0.55 vs 0.06%, FDRp=0.001, and monocytes: 1.91 vs 0.45%, FDRp=0.004) and widespread upregulation of both traditional and type 2 inflammatory soluble signatures (40 analytes significantly elevated in BAL of CF compared with controls, all FDRp<0.1). Key targetable features of this response included pulmonary interleukin (IL)-8 and IL-13 which were most significantly associated with neutrophilic and eosinophilic infiltration, respectively (IL-8 and neutrophils; Spearman rho=0.68, FDRp=0.002: IL-13 and eosinophils; Spearman rho=0.75, FDRp=0.01). Signatures of type 2 inflammation, as identified by REACTOME pathway analysis, including IL-4, IL-13 and FGF-2, were highly elevated in both the lungs and circulation in early CF. When exploring the efficacy of Cystic Fibrosis Transmembrane Conductance Regulator modulators to resolve pulmonary and systemic inflammation in early life, we showed that different classes of modulators have varying effects on inflammation, with ivacaftor showing a more significant effect in the lungs and circulation than lumacaftor/ivacaftor. Finally, we showed that CF children with pathogen colonisation had similar levels of pulmonary inflammation as CF children without pathogen colonisation (no significant differences), and that inflammation was evident during infancy even without evidence of colonisation (as observed by significant increases in levels of SDF-1alpha, M-CSF, IL-2, IL-9, IL-12p40, IL-17, MCP-1 and LIGHT/TNFSF14, all FDRp<0.1), highlighting a role for intrinsic dysregulation of inflammation that begins in early life., Conclusions: We provide a rationale for targeted anti-inflammatory intervention in early-life CF., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2025. Re-use permitted under CC BY. Published by BMJ Group.)

Despite the central role of cytokines in mediating inflammation that underlies a range of childhood diseases, cytokine testing remains primarily limited to research settings and surrogate markers of inflammation are often used to inform clinical diagnostic and treatment decisions. There are currently no reference ranges available for cytokines in healthy children, either systemically (in blood) or at sites of disease (such as the lung). In our study, we aimed to develop an openly accessible dataset of cytokines in the airways and blood of healthy children spanning 1 to 16 years of age. We examined how cytokine concentration changes during childhood and assessed whether a core set of cytokine markers could be used to indirectly evaluate the response of a broad spectrum of inflammatory analytes. To develop our dataset, a total of 65 unique analytes were quantified in cell-free bronchoalveolar lavage (BAL) and plasma from 78 children. We showed that age profoundly impacts soluble immune analyte concentration in both sample types and identified a highly correlative core set of 10 analytes in BAL and 11 analytes in plasma capable of indirectly evaluating the response of up to 44 inflammatory mediators. This study addresses an urgent need to develop reference ranges for cytokines in healthy children to aid in diagnosis of disease, to determine eligibility for, and to monitor the effects of, cytokine-targeted monoclonal antibody therapy., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Objective: Asthma is the most common chronic disease among children. Dry-powder inhalers (DPIs) are effective for medication delivery in adults and adolescents, and provide a lower environmental footprint and more portability than a metered dose inhaler (MDI) with a spacer. They require a specific technique, and it is necessary to ascertain whether they can be used in younger age groups. We aimed to assess evidence regarding whether primary school-aged (5-11 years) children can use DPIs with adequate technique during both stable and acute asthma., Design: Ovid MEDLINE, Embase and PubMed were searched for studies assessing DPI use among children aged 5-11 years with asthma or wheeze. Results of studies were synthesised by study design and outcome measure., Results: 38 studies were identified for analysis. These were analysed in three groups: 1) 25 studies assessing children's ability to use DPIs by peak inspiratory flow measurement, 2) 10 studies assessing children's ability to use DPIs by physician assessment, and 3) three studies measuring the efficacy of DPIs compared with the gold standard (MDI with spacer). Five studies included children during acute exacerbations., Conclusion: The majority of primary school-aged children have the ability to use a DPI with adequate training, support and practice. Some younger children may have difficulties, and clinician assessment and ongoing review is crucial in determining which children are likely to benefit from a DPI. Consistent correct use and adherence remain as challenges, but these are also issues with an MDI plus spacer and do not appear to be significantly worse with DPIs. Evidence of the use of DPIs during acute illness is limited; more studies are required in this setting., Competing Interests: Conflict of interest: L. Fleming reports consulting fees and honoraria for lectures from AstraZeneca, Sanofi, GSK and Regeneron; all fees paid to her institution. Conflict of interest: R. Beasley reports institutional research funding from AstraZeneca, Genetech and Teva, and personal fees from AstraZeneca, Avillion, Cipla and Teva; and is Chair of the New Zealand adolescent and adult asthma guidelines. Conflict of interest: S. Shanthikumar reports honoraria for educational presentations from Sanofi and Vertex. Conflict of interest: There are no other conflicts of interest to declare., (Copyright ©The authors 2024.)

Background: Respiratory diseases are a common cause of morbidity and hospitalization for children. Despite this, treatment options are limited and are often ineffective. The development of curative or disease-modifying treatments for children relies on a better understanding of underlying immunity in the early airway., Objective: To establish a flow cytometry dataset for immune cells in the pediatric airway, we analyzed 180 samples from 68 children aged between 1 and 15 years. This included 5 tissues of the upper (nasal brushings, palatine tonsils, adenotonsil) and lower (bronchial brushings, bronchoalveolar lavage) airway, as well as whole blood for paired analysis of local and systemic immune response., Methods: Nasal, bronchial, and alveolar samples were analyzed using a 17-plex antibody panel that captures cells of immune and epithelial lineage, while tonsil, adenoid, and blood samples were analyzed using a 31-plex antibody panel that extensively phenotypes mononuclear immune cells. All protocols, panels, and data are openly available to facilitate implementation in pediatric clinical laboratories., Results: We provide age-specific airway cell data for infancy (0-2 years), preschool (3-5 years), childhood (6-10 years) and adolescence (11-15 years) for 37 cell populations. We show tissue-specific maturation of the airway immune system across childhood, further highlighting the importance of developing age-specific references of the pediatric airway. Intraindividual, cross-tissue analysis of paired samples revealed marked correlation in immune cell proportions between paired nasal-bronchial samples, paired tonsil-adenoid samples, and paired adenoid-blood samples, which may have implications for clinical testing., Conclusion: Our study advances knowledge of airway immunity from infancy through to adolescence and provides an openly available control dataset to aid in interpretation of clinical findings in samples obtained from children with respiratory diseases., Competing Interests: Disclosure statement Funded by a Chan Zuckerberg Initiative Single-Cell Biology grant (2021-237883). Disclosure of potential conflict of interest: The authors declare that they have no relevant conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Objectives: Haematopoietic cell transplant (HCT) is a cellular therapy for a group of high-risk children with cancer, immunodeficiency and metabolic disorders. Whilst curative for a child's underlying condition, HCT has significant risks associated, including lung injury. These complications are associated with increased post HCT mortality and require improved methods of risk stratification, diagnosis and treatment., Methods: Biomarkers measured in bronchoalveolar fluid and peripheral blood have been identified for both acute and chronic lung injury post HCT.This review evaluates the current research available investigating the use of these biomarkers to improve clinical care, with a focus on the paediatric cohort., Results: Elevated levels of cytokines such as IL-6, IL-8, G-CSF and TNF were identified as potential predictive biomarkers for the development of post HCT lung disease. The pulmonary microbiome was found to have strong potential as a biomarker pre and post HCT for the development of pulmonary complications. General limitations of the studies identified were study design, retrospective or single centre and not exclusively performed in the paediatric population., Conclusion: To translate biomarker discovery into clinical implementation further research is required, utilising larger cohorts of children in prospective trials to validate these biomarkers and determine how they can be translated into better outcomes for children post HCT., Competing Interests: The authors declare no conflicts of interest., (© 2024 The Author(s). Clinical & Translational Immunology published by John Wiley & Sons Australia, Ltd on behalf of Australian and New Zealand Society for Immunology, Inc.)

Objectives: Haematopoietic stem cell transplant (HCT) is a cellular therapy that, whilst curative for a child's underlying disease, carries significant risk of mortality, including because of pulmonary complications. The aims of this study were to describe the burden of pulmonary complications post-HCT in a cohort of Australian children and identify risk factors for the development of these complications., Methods: Patients were identified from the HCT databases at two paediatric transplant centres in Australia. Medical records were reviewed, and demographics, HCT characteristics and pulmonary complications documented. Relative risk ratio was used to identify risk factors for developing pulmonary complications prior to first transplant episode, and survival analysis performed to determine hazard ratio., Results: In total, 243 children underwent transplant during the study period, and pulmonary complications occurred in 48% (117/243) of children. Infectious complications were more common (55%) than non-infective complications (18%) and 26% of patients developed both. Risk factors for the development of pulmonary complications included the following: diagnoses of MPAL (RR 2.16, P  = 0.02), matched unrelated donor (RR1.34, P  = 0.03), peripheral blood (RR 1.36, P  = 0.028) or cord blood (RR 1.73, P  = 0.012) as the stem cell source and pre-existing lung disease (RR1.72, P  < 0.0001). Children with a post-HCT lung complication had a significantly increased risk of mortality compared with those who did not (HR 3.9, P  < 0.0001)., Conclusion: This study demonstrates pulmonary complications continue to occur frequently in children post-HCT and contribute significantly to mortality. Highlighting the need for improved strategies to identify patients at risk pre-transplant and enhanced treatments for those who develop lung disease., Competing Interests: The authors declare no conflict of interest., (© 2024 The Author(s). Clinical & Translational Immunology published by John Wiley & Sons Australia, Ltd on behalf of Australian and New Zealand Society for Immunology, Inc.)

Hematopoietic stem cell transplantation (HSCT) is undertaken in children with the aim of curing a range of malignant and nonmalignant conditions. Unfortunately, pulmonary complications, especially bronchiolitis obliterans syndrome (BOS), are significant sources of morbidity and mortality post-HSCT. Currently, criteria developed by a National Institutes of Health (NIH) working group are used to diagnose BOS in children post-HSCT. Unfortunately, during the development of a recent American Thoracic Society (ATS) Clinical Practice Guideline on this topic, it became apparent that the NIH criteria have significant limitations in the pediatric population, leading to late diagnosis of BOS. Specific limitations include use of an outdated pulmonary function testing reference equation, a reliance on spirometry, use of a fixed forced expiratory volume in 1 second (FEV 1 ) threshold, focus on obstructive defects defined by FEV 1 /vital capacity, and failure to acknowledge that BOS and infection can coexist. In this review, we summarize the evidence regarding the limitations of the current criteria. We also suggest potential evidence-based ideas for improving these criteria. Finally, we highlight a new proposed criteria for post-HSCT BOS in children that were developed by the authors of the recently published ATS clinical practice guideline, along with a pathway forward for improving timely diagnosis of BOS in children post-HSCT., (Copyright © 2024 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Background: Many children undergo allogeneic hematopoietic stem cell transplantation (HSCT) for the treatment of malignant and nonmalignant conditions. Unfortunately, pulmonary complications occur frequently post-HSCT, with bronchiolitis obliterans syndrome (BOS) being the most common noninfectious pulmonary complication. Current international guidelines contain conflicting recommendations regarding post-HSCT surveillance for BOS, and a recent NIH workshop highlighted the need for a standardized approach to post-HSCT monitoring. As such, this guideline provides an evidence-based approach to detection of post-HSCT BOS in children. Methods: A multinational, multidisciplinary panel of experts identified six questions regarding surveillance for, and evaluation of, post-HSCT BOS in children. A systematic review of the literature was undertaken to answer each question. The Grading of Recommendations, Assessment, Development, and Evaluation approach was used to rate the quality of evidence and the strength of recommendations. Results: The panel members considered the strength of each recommendation and evaluated the benefits and risks of applying the intervention. In formulating the recommendations, the panel considered patient and caregiver values, the cost of care, and feasibility. Recommendations addressing the role of screening pulmonary function testing and diagnostic tests in children with suspected post-HSCT BOS were made. Following a Delphi process, new diagnostic criteria for pediatric post-HSCT BOS were also proposed. Conclusions: This document provides an evidence-based approach to the detection of post-HSCT BOS in children while also highlighting considerations for the implementation of each recommendation. Further, the document describes important areas for future research.

Pleural empyema is a serious complication of pneumonia in children. Negative bacterial cultures commonly impede optimal antibiotic therapy. To improve bacterial identification, we developed a molecular assay and evaluated its performance compared with bacterial culture. Our multiplex-quantitative PCR to detect Streptococcus pneumoniae, Streptococcus pyogenes, Staphylococcus aureus and Haemophilus influenzae was assessed using bacterial genomic DNA and laboratory-prepared samples (n = 267). To evaluate clinical performance, we conducted the Molecular Assessment of Thoracic Empyema (MATE) observational study, enrolling children hospitalised with empyema. Pleural fluids were tested by bacterial culture and multiplex-qPCR, and performance determined using a study gold standard. We determined clinical sensitivity and time-to-organism-identification to assess the potential of the multiplex-qPCR to reduce the duration of empiric untargeted antibiotic therapy. Using spiked samples, the multiplex-qPCR demonstrated 213/215 (99.1%) sensitivity and 52/52 (100%) specificity for all organisms. During May 2019-March 2023, 100 children were enrolled in the MATE study; median age was 3.9 years (IQR 2-5.6). A bacterial pathogen was identified in 90/100 (90%) specimens by multiplex-qPCR, and 24/100 (24%) by bacterial culture (P <0.001). Multiplex-qPCR identified a bacterial cause in 68/76 (90%) culture-negative specimens. S. pneumoniae was the most common pathogen, identified in 67/100 (67%) specimens. We estimate our multiplex-qPCR would have reduced the duration of untargeted antibiotic therapy in 61% of cases by a median 20 days (IQR 17.5-23, range 1-55). Multiplex-qPCR significantly increased pathogen detection compared with culture and may allow for reducing the duration of untargeted antibiotic therapy., Competing Interests: CS, EM, SR, CN and JJ are investigators on a Merck Investigator Studies Program grant funded by MSD on pneumococcal serotype epidemiology in children with empyema. CS, ED, CDN and EM are investigators on a clinical research collaboration with Pfizer unrelated to this work. ED is currently employed by Pfizer. The other authors declare that they have no competing interests., (Copyright: © 2024 Jacobson et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Asthma is the most common chronic respiratory illness among children in Australia. While childhood asthma prevalence varies by region, little is known about variations at the small geographic area level. Identifying small geographic area variations in asthma is critical for highlighting hotspots for targeted interventions. This study aimed to investigate small area-level variation, spatial clustering, and sociodemographic risk factors associated with childhood asthma prevalence in Australia., Methods: Data on self-reported (by parent/carer) asthma prevalence in children aged 0-14 years at statistical area level 2 (SA2, small geographic area) and selected sociodemographic features were extracted from the national Australian Household and Population Census 2021. A spatial cluster analysis was used to detect hotspots (i.e., areas and their neighbours with higher asthma prevalence than the entire study area average) of asthma prevalence. We also used a spatial Bayesian Poisson model to examine the relationship between sociodemographic features and asthma prevalence. All analyses were performed at the SA2 level., Results: Data were analysed from 4,621,716 children aged 0-14 years from 2,321 SA2s across the whole country. Overall, children's asthma prevalence was 6.27%, ranging from 0 to 16.5%, with significant hotspots of asthma prevalence in areas of greater socioeconomic disadvantage. Socioeconomically disadvantaged areas had significantly higher asthma prevalence than advantaged areas (prevalence ratio [PR] = 1.10, 95% credible interval [CrI] 1.06-1.14). Higher asthma prevalence was observed in areas with a higher proportion of Indigenous individuals (PR = 1.13, 95% CrI 1.10-1.17)., Conclusions: We identified significant geographic variation in asthma prevalence and sociodemographic predictors associated with the variation, which may help in designing targeted asthma management strategies and considerations for service enhancement for children in socially deprived areas., (© 2024. The Author(s).)

Suppurative lung disease and wheezing are common respiratory diseases of childhood, however, due to poor understanding of underlying pathobiology, there are limited treatment options and disease recurrence is common. We aimed to profile the pulmonary and systemic immune response in children with wheeze and chronic suppurative lung disease for identification of endotypes that can inform improved clinical management. We used clinical microbiology data, highly multiplexed flow cytometry and immunoassays to compare pulmonary [bronchoalveolar lavage (BAL)] and systemic immunity in children with lung disease and controls. Unsupervised analytical approaches were applied to BAL immune data to explore biological endotypes. We identified two endotypes that were analogous in both frequency and immune signature across both respiratory diseases. The hyper-inflammatory endotype had a 12-fold increase in neutrophil infiltration and upregulation of 14 soluble signatures associated with type 2 inflammation and cell recruitment to tissue. The non-inflammatory endotype was not significantly different from controls. We showed these endotypes are measurable in a clinical setting and can be defined by measuring only three immune factors in BAL. We identified hyper-inflammatory and non-inflammatory endotypes common across pediatric wheeze and chronic suppurative lung disease that, if validated in future studies, have the potential to inform clinical management., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Bronchiolitis obliterans syndrome (BOS) is a severe complication following hemopoietic stem cell transplantation (HSCT) and is often undetected until there is significant deterioration in pulmonary function. Lung clearance index (LCI 2.5 ) derived from the nitrogen multiple breath washout (N 2 MBW) test may be more feasible and sensitive than spirometry, which is currently used for surveillance and detection of BOS. We aimed to examine the feasibility of performing surveillance N 2 MBW in children post-HSCT, and in an exploratory analysis, determine if LCI 2.5 led to earlier detection of BOS when compared to spirometric indices. Participants aged 5 to 17 years were recruited prior to receiving HSCT into a prospective, single-center, feasibility study at the Royal Children's Hospital, Melbourne. N 2 MBW and spirometry were performed within the month prior to transplant and repeated at 3, 6, 9, and 12 months post-transplant. Data were also collected on the presence of graft-versus-host (GVHD) disease in any organ, including the lungs. Twenty-one (12 male) children with a mean age of 13.4 (range 9.2 to 17.1) years at recruitment participated in this study. Prior to HSCT, all participants had normal LCI 2.5 , while 16 (76%) demonstrated normal forced expiratory volume in 1 second (FEV 1 ). Ninety-nine percent of N 2 MBW tests were technically acceptable, compared with 66% of spirometry tests. Three participants developed BOS, while 2 participants died of other respiratory complications. At 6 and 12 months post-transplant, the BOS group had increases in LCI 2.5 ranging from 3 to 5 units and mean reductions in FEV 1 % predicted of 40% to 53% relative to pre HSCT values, respectively. In those who developed BOS, post-HSCT LCI 2.5 values were significantly worse when compared with the no BOS group (P < .001). Relative changes in LCI 2.5 and FEV 1 were both predictive of BOS at 6 months post HSCT. This study demonstrates that N 2 MBW is a more feasible test compared with spirometry in children post HSCT. However, in an exploratory analysis, LCI 2.5 did not lead to earlier detection of BOS, when compared to spirometry., (Copyright © 2024 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Primary idiopathic hypereosinophilic syndrome is a rare condition that can cause end-organ damage in multiple systems. The advent of targeted monoclonal antibodies, such as mepolizumab, provides a safe and effective steroid-sparing treatment. https://bit.ly/4bgDP1u., Competing Interests: Conflict of interest: J. Harrison reports roles as the Board Director of Cystic Fibrosis Community Care, and as a member of the Education and Training Committee of Thoracic Society Australia and New Zealand, outside the submitted work. The remaining authors have nothing to disclose., (Copyright ©ERS 2024.)

Sample multiplexing is often used to reduce cost and limit batch effects in single-cell RNA sequencing (scRNA-seq) experiments. A commonly used multiplexing technique involves tagging cells prior to pooling with a hashtag oligo (HTO) that can be sequenced along with the cells' RNA to determine their sample of origin. Several tools have been developed to demultiplex HTO sequencing data and assign cells to samples. In this study, we critically assess the performance of seven HTO demultiplexing tools: hashedDrops, HTODemux, GMM-Demux, demuxmix, deMULTIplex, BFF (bimodal flexible fitting) and HashSolo. The comparison uses data sets where each sample has also been demultiplexed using genetic variants from the RNA, enabling comparison of HTO demultiplexing techniques against complementary data from the genetic 'ground truth'. We find that all methods perform similarly where HTO labelling is of high quality, but methods that assume a bimodal count distribution perform poorly on lower quality data. We also suggest heuristic approaches for assessing the quality of HTO counts in an scRNA-seq experiment., (© The Author(s) 2023. Published by Oxford University Press on behalf of NAR Genomics and Bioinformatics.)

Background: Telehealth has been rapidly adopted by cystic fibrosis (CF) centers and ongoing use in routine CF care is endorsed by CF consumers. However, data describing CF clinician perceptions regarding telehealth are scarce. We aimed to describe clinician experiences and attitudes towards telehealth in CF care among health professionals across Australia., Methods: CF multidisciplinary health professionals from all CF clinics in Australia were sent an anonymous electronic survey., Results: Eighty-five responses were received representing 15 of 23 (65%) centers. Most clinicians reported using telehealth for routine clinic visits, and a range of other clinical encounters (69.9%). Telehealth was widely perceived as acceptable (91.8%), and clinicians were comfortable/very comfortable (81.2%) integrating telehealth into future CF care. Despite this, 64.1% of respondents considered telehealth clinics to be much worse than face-to-face clinics and 57.5% reported quality of care was somewhat/much worse using telehealth. Home spirometry was available in 73.7% of centers, however, only 26.7% of clinics could provide spirometers for >75% eligible patients. Growth and microbiology assessments were often missed in telehealth clinics and 75.7% reported a technical issue had prevented a telehealth consultation from occurring., Conclusions: Telehealth for CF in Australia is considered feasible and acceptable by CF clinicians, although use of telehealth varies widely between centers. Concerns exist around the impact of telehealth on health outcomes, especially given core assessments are frequently omitted. Guidelines may help ensure the benefits of telehealth are realized for people with CF without compromising the standard of care., (© 2023 The Authors. Pediatric Pulmonology published by Wiley Periodicals LLC.)

Myeloperoxidase (MPO) is released by neutrophils in inflamed tissues. MPO oxidizes chloride, bromide, and thiocyanate to produce hypochlorous acid (HOCl), hypobromous acid (HOBr), and hypothiocyanous acid (HOSCN), respectively. These oxidants are toxic to pathogens, but may also react with host cells to elicit biological activity and potential toxicity. In cystic fibrosis (CF) and related diseases, increased neutrophil inflammation leads to increased airway MPO and airway epithelial cell (AEC) exposure to its oxidants. In this study, we investigated how equal dose-rate exposures of MPO-derived oxidants differentially impact the metabolome of human AECs (BEAS-2B cells). We utilized enzymatic oxidant production with rate-limiting glucose oxidase (GOX) coupled to MPO, and chloride, bromide (Br - ), or thiocyanate (SCN - ) as substrates. AECs exposed to GOX/MPO/SCN - (favoring HOSCN) were viable after 24 h, while exposure to GOX/MPO (favoring HOCl) or GOX/MPO/Br - (favoring HOBr) developed cytotoxicity after 6 h. Cell glutathione and peroxiredoxin-3 oxidation were insufficient to explain these differences. However, untargeted metabolomics revealed GOX/MPO and GOX/MPO/Br - diverged significantly from GOX/MPO/SCN - for dozens of metabolites. We noted methionine sulfoxide and dehydromethionine were significantly increased in GOX/MPO- or GOX/MPO/Br - -treated cells, and analyzed them as potential biomarkers of lung damage in bronchoalveolar lavage fluid from 5-year-olds with CF (n = 27). Both metabolites were associated with increasing bronchiectasis, neutrophils, and MPO activity. This suggests MPO production of HOCl and/or HOBr may contribute to inflammatory lung damage in early CF. In summary, our in vitro model enabled unbiased identification of exposure-specific metabolite products which may serve as biomarkers of lung damage in vivo. Continued research with this exposure model may yield additional oxidant-specific biomarkers and reveal explicit mechanisms of oxidant byproduct formation and cellular redox signaling., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Objectives: To (1) describe primary health care utilization and (2) estimate the effect of primary care early follow-up, continuity, regularity, frequency, and long consultations on asthma hospital readmission, including secondary outcomes of emergency (ED) presentations, asthma preventer adherence, and use of rescue oral corticosteroids within 12 months., Methods: An Australian multi-site cohort study of 767 children aged 3-18 years admitted with asthma between 2017 and 2018, followed up for at least 12 months with outcome and primary care exposure data obtained through linked administrative datasets. We estimated the effect of primary care utilization through a modified Poisson regression adjusting for child age, asthma severity, socioeconomic status and self-reported GP characteristics., Results: The median number of general practitioner (GP) consultations, unique GPs and clinics visited was 9, 5, and 4, respectively. GP care was irregular and lacked continuity, only 152 (19.8%) children visited their usual GP on more than 60% of occasions. After adjusting for confounders, there was overall weak indication of effects due to any of the exposures. Increased frequency of GP visits was associated with reduced readmissions (4-14 visits associated with risk ratio of 0.71, 95% CI 0.50-1.00, p  = 0.05) and ED presentations (>14 visits associated risk ratio 0.62, 95% CI 0.42-0.91, p  = 0.02)., Conclusions: Our study demonstrates that primary care use by children with asthma is often irregular and lacking in continuity. This highlights the importance of improving accessibility, consistency in care, and streamlining discharge communication from acute health services.

Objectives: To (1) describe the dispensing of asthma preventers at hospital discharge and estimate its effect on hospital readmissions, and (2) estimate the effect of community asthma preventer dispensing on readmissions for the subgroup of children who were not prescribed an asthma preventer at discharge., Design: Multisite cohort study with linked administrative data., Participants: Children aged 3-18 years admitted with asthma to a tertiary paediatric, mixed paediatric and adult, or regional hospital between 2017 and 2018., Main Outcome Measure: Hospital readmission for asthma within 12 months., Results: Of the 767 participants, 201 (26.2%) were newly prescribed or requested to continue with asthma preventers. Of these, only 91 (45.3%) dispensed their discharge prescription within 3 days or had an active prescription. There was no evidence for a protective effect of discharge asthma preventer dispensing on asthma hospital readmissions within 12 months (OR 1.17, 95% CI 0.69 to 1.97, p=0.57). Of the 566 children who were not prescribed asthma preventers at discharge, 269 (47.5%) had one or more prescriptions dispensed in the community within 12 months. Participants who were in the protected period (asthma preventer dispensed) had reduced risk of an asthma hospital readmission (HR 0.61, 95% CI 0.36 to 1.02, p=0.06), including preschool children (HR 0.48, 95% CI 0.25, 0.93, p=0.03) on subgroup analysis., Conclusions: There was a low rate for prescribing and dispensing of hospital discharge asthma preventers and no protective effect was found for its impact on readmissions. A protective effect on readmissions was found for community asthma preventer dispensing., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

The ongoing development and integration of telehealth within CF care has been accelerated in response to the Covid-19 pandemic, with many centres publishing their experiences. Now, as the restrictions of the pandemic ease, the use of telehealth appears to be waning, with many centres returning to routine traditional face-to-face services. For most, telehealth is not integrated into clinical care models, and there is a lack of guidance on how to integrate such a service into clinical care. The aims of this systematic review were to first identify manuscripts which may inform best CF telehealth practices, and second, to analyse these finding to determine how the CF community may use telehealth to improve care for patients, families, and Multidisciplinary Teams into the future. To achieve this, the PRISMA review methodology was utilised, in combination with a modified novel scoring system that consolidates expert weighting from key CF stakeholders, allowing for the manuscripts to be placed in a hierarchy in accordance with their scientific robustness. From the 39 found manuscripts, the top ten are presented and further analysed. The top ten manuscripts are exemplars of where telehealth is used effectively within CF care at this time, and demonstrate specific use cases of its potential best practices. However, there is a lack of guidance for implementation and clinical decision making, which remains an area for improvement. Thus, it is suggested that further work explores and provides guidance for standardised implementation into CF clinical practice., Competing Interests: Declaration of Competing Interest The authors have no conflicts of interest to declare., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

In response to the COVID-19 pandemic telehealth utilisation amongst the Cystic Fibrosis (CF) population increased. Our aim was to assess the impact of CF telehealth clinics on CF outcomes. We conducted a retrospective chart review of patients seen in the CF clinic at the Royal Children's Hospital (Victoria, Australia). In this review we compared spirometry, microbiology and anthropometry in the year preceding the pandemic to during the pandemic, and to the first in-person appointment in 2021. 214 patients were included. First in-person FEV 1 was median 5.4% below individuals' best FEV 1 in 12 months prior to lockdown and decreased by >10% in 46 (31.9%) patients. There were no significant findings with regards to microbiology or anthropometry. The reduction in FEV 1 observed on return to in-person appointments highlights the importance of ongoing improvement of telehealth-based care along with continued face-to-face review for the paediatric CF population., (Copyright © 2023. Published by Elsevier B.V.)

Cystic Fibrosis (CF) is a chronic life-limiting condition that affects multiple organs within the body. Patients must adhere to strict medication regimens, physiotherapy, diet, and attend regular clinic appointments to manage their condition effectively. This necessary but burdensome requirement has prompted investigations into how different digital health technologies can enhance current care by providing the opportunity to virtually monitor patients. This review explores how virtual monitoring has been harnessed for assessment or performance of physiotherapy/exercise, diet/nutrition, symptom monitoring, medication adherence, and wellbeing/mental-health in people with CF. This review will also briefly discuss the potential future of CF virtual monitoring and some common barriers to its current adoption and implementation within CF. Due to the multifaceted nature of CF, it is anticipated that this review will be relevant to not only the CF community, but also those investigating and developing digital health solutions for the management of other chronic diseases., 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., (© 2023 Vagg, Deasy, Chapman, Ranganathan, Plant and Shanthikumar.)

Objective: Explore gaps and opportunities in primary care for children following a hospital admission for asthma., Design: Exploratory mixed-methods, using linked hospital and primary care administration data., Setting: Eligible children, aged 3-18 years, admitted to one of three hospitals in Victoria, Australia between 2017 and 2018 with a clinical diagnosis of asthma., Results: 767 caregivers of eligible children participated, 39 caregivers completed a semistructured interview and 277 general practitioners (GPs) caring for 360 children completed a survey. Over 90% (n=706) of caregivers reported their child had a regular GP. However, few (14.1%, n=108) attended a GP in the 24 hours prior to index admission or in the 7 days after (35.8%, n=275). Children readmitted for asthma (34.2%, n=263), compared with those not readmitted (65.8%, n=504), were less likely to have visited a GP in the non-acute phase of their asthma in the 12 months after index admission (22.1% vs 42.1%, respectively), and their GP was more likely to report not knowing the child had an asthma admission (52.8% vs 39.2%, respectively). Fewer GPs reported being extremely confident managing children with poorly controlled asthma (11.9%, n=43) or post-discharge (16.7%, n=60), compared with children with well-controlled asthma (36.4%, n=131), with no difference by child readmission status., Conclusions: Given the exploratory design and descriptive approach, it is unknown if the differences by child readmission status have any causal relationship with readmission. Nonetheless, improving preventative patterns of primary care visits, timely communication between hospitals and primary care providers, and guideline concordant care by GPs are needed., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Human immunodeficiency virus (HIV) in children and adolescents remains an important health challenge in many countries and is commonly associated with lung disease. The introduction of antiretroviral therapy (ART) has greatly improved survival but chronic lung disease is a common ongoing challenge. We conducted a scoping review of studies that have reported lung function in school-aged children and adolescents living with HIV., Methods: A systematic literature search was performed by searching Medline, Embase, and PubMed databases, limited to articles published between 2011 and 2021 in English language. Inclusion criteria were studies involving participants living with HIV aged 5-18 years and having spirometry data. The primary outcome was lung function as measured by spirometry., Results: Twenty-one studies were included in the review. Most study participants were living in the sub-Saharan African region. The prevalence of reduced forced expiratory volume in 1 s (FEV 1 ) ranged from 25.3% to 73% across studies, reduced forced vital capacity (FVC) ranged from 10% to 42% and reduced FEV 1 /FVC ranged from 3% to 26%. The mean z-score of FEV 1 ranged from -2.19 to -0.73, mean zFEV 1 /FVC ranged from -0.74 to 0.2, and mean FVC ranged from -1.86 to -0.63., Conclusion: There is a high prevalence of lung function impairment in children and adolescents living with HIV, which persists in the ART era. Further studies are needed of interventions that might improve lung function in these vulnerable populations., (© 2023 The Authors. Pediatric Pulmonology published by Wiley Periodicals LLC.)

Objectives: To (a) identify rates of hospital readmission and emergency department (ED) re-presentation for asthma within a 12-month period, (b) estimate the effects of modifiable hospital, general practitioner (GP) and home environmental factors on hospital readmission, ED re-presentations and rescue oral corticosteroid use., Methods: We recruited 767 children aged 3-18 years who were admitted to 3 hospitals in Victoria, Australia between 2017 and 2018 with a validated diagnosis of asthma on chart review. Primary outcome was hospital readmission with asthma within 12 months of index admission. Secondary outcomes were ED re-presentation for asthma and rescue oral corticosteroid use. All outcomes were identified through linked administrative datasets. Their caregivers and 277 nominated GPs completed study surveys regarding the home environment and their usual asthma management practices respectively., Results: Within 12 months of an index admission for asthma 263 (34.3%) participants were readmitted to a hospital for asthma, with participants between the ages of 3-5 years accounting for 69.2% of those readmitted. The estimated effect of GP reported guideline discordant care on the odds of readmission was OR 1.57, 95% CI 1.00-2.47, p  = 0.05. None of the hospital or home environmental factors appeared to be associated with hospital readmissions., Conclusions: Hospital readmissions among Australian children with asthma are increasing, and linked datasets are important for objectively identifying the health services burden of asthma. They also confirm the important role of the GP in the management of pediatric asthma.

Purpose of Review: Haematopoietic stem cell transplant (HSCT) remains the only curative treatment option for many children with relapsed leukaemia, primary immunodeficiencies and haemoglobinopathies. Unfortunately, infectious and noninfectious pulmonary complications following HSCT continue to cause significant morbidity and mortality. This review will focus on recent advances in the field that enhance clinically available diagnostic tools and the role of novel diagnostic techniques., Recent Findings: Research continues to highlight the role of standard diagnostic modalities, including imaging using computed topography chest and Fluorodeoxyglucose-positron emission tomography (FDG-PET) in the diagnosis of posttransplant pulmonary infections. Similarly, bronchoalveolar lavage using bronchoscopy to obtain samples for microbiological analysis remains an important tool in the clinical and diagnostic algorithm for these children. The application of more novel diagnostic techniques such as metagenomic next-generation sequencing and the use of specific biomarkers remain potential future tools in children in whom the aetiology of posttransplant lung disease is unknown. The impact of the pulmonary microbiome on infectious and noninfectious pulmonary disease post HSCT is a future research direction., Summary: Pulmonary infectious complications post HSCT remain a devastating complication for children and their families. Despite improvements in standard and novel diagnostic modalities, the aetiology of pulmonary disease remains unknown for many patients. There is an urgent need for ongoing collaborative research to bridge this critical knowledge gap and lead to better patient outcomes., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Lower airway sampling is important in the assessment of lower respiratory tract infection in children with cancer or posthematopoietic stem cell transplant and can be done via bronchoalveolar lavage (BAL). Clinicians can struggle with balancing the benefits of BAL against the risks. This study aimed to define the diagnostic and clinical utility of BAL in this population., Methods: A single-center retrospective review of BAL performed in children with cancer or posthematopoietic stem cell transplant. Data extracted included demographics, BAL method and results and antimicrobial treatment. Variables significantly associated with diagnostic yield, diagnostic impact (confirmation or exclusion of infection), and clinical impact (any change in antimicrobial or nonantimicrobial therapy) were assessed in both univariate and multivariate analysis., Results: Seventy-three BAL episodes were included. In 26 (35.6%) episodes, a pathogen was identified on BAL. Forty-nine (67%) BAL episodes had a diagnostic impact and 15 (21%) had a clinical impact. Late BAL (&gt;72 hours) compared with early BAL (odds ratio 3.27; 95% CI: 1.03-10.86), and flexible bronchoscopy compared with nonbronchoscopic lavage (odds ratio 6.10; 95% CI: 1.90-24.0), were more likely to have a diagnostic impact on multivariate analysis. No associations were found for clinical impact., Conclusions: One-third of BAL episodes identified a pathogen, two-thirds had a diagnostic impact, and almost a quarter of episodes impacted antimicrobial prescribing. The method and timing of BAL may be important, with flexible bronchoscopy 6-fold more likely and late BAL 3-fold more likely to have a diagnostic impact., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Pleural effusion is rare in cystic fibrosis. Infection leading to pleural effusion is likely to be polymicrobial, including contributory fungal infection; microbiology of pleural fluid is commonly discordant with sputum. https://bit.ly/3MJXrhk., Competing Interests: Conflict of interest: The authors do not identify any conflicts of interest., (Copyright ©ERS 2022.)

Aim: Paediatric intensive care unit (PICU) admissions for empyema increased following the 13-valent pneumococcal conjugate vaccine (PCV13). We describe the clinical characteristics, management and outcomes for children with empyema and compare incidence before and after PCV13., Methods: Retrospective study of patients <18 years admitted to The Royal Children's Hospital Melbourne PICU with empyema between January 2016 and July 2019. We investigated the incidence of empyema during two time periods: 2007-2010 (pre-PCV13) and 2016-2019 (post-PCV13)., Results: Seventy-one children (1.9% of all PICU admissions) were admitted to PICU with empyema between 2016 and 2019. Sixty-one (86%) had unilateral disease, 11 (16%) presented with shock and 44 (62%) were ventilated. Streptococcus pneumoniae and group A Streptococcus were the most commonly identified pathogens. Forty-five (63%) were managed with video-assisted thoracoscopic surgery (VATS). There was a 31% reduction in empyema hospitalisations as a proportion of all hospitalisations (IRR 0.69, 95% CI 0.59-0.8), but a 2.8-fold increase in empyema PICU admissions as a proportion of all PICU admissions (95% CI 2.2-3.5, P < 0.001). For the PICU cohort, this was accompanied by reduction in PIM2 probability of death (median 1% vs. 1.9%, P = 0.02) and duration of intubation (median 69 h vs. 126.5 h, P = 0.045)., Conclusions: In children with empyema in PICU 62% required ventilation, 16% had features of shock and 63% received VATS. Empyema admissions, as a proportion of all PICU admissions, increased in the era post-PCV13 compared to pre-PCV13 despite no increase in illness severity at admission., (© 2022 The Authors. Journal of Paediatrics and Child Health published by John Wiley & Sons Australia, Ltd on behalf of Paediatrics and Child Health Division (The Royal Australasian College of Physicians).)

Background: Hematopoietic Stem Cell Transplant (HSCT) is an established treatment for malignant and non-malignant conditions and pulmonary disease is a leading cause of late term morbidity and mortality. Accurate and early detection of pulmonary complications is a critical step in improving long term outcomes. Existing guidelines for surveillance of pulmonary complications post-HSCT contain conflicting recommendations., Aim: To determine the breadth of current practice in monitoring for pulmonary complications of pediatric HSCT., Methods: An institutional review board approved, online, anonymous multiple-choice survey was distributed to HSCT and pulmonary physicians from the United States of America and Australasia using the REDcap platform. The survey was developed by members of the American Thoracic Society Working Group on Complications of Childhood Cancer, and was designed to assess patient management and service design., Results: A total of 40 (34.8%) responses were received. The majority (62.5%) were pulmonologists, and 82.5% were from the United States of America. In all, 67.5% reported having a protocol for monitoring pulmonary complications and 50.0% reported adhering "well" or "very well" to protocols. Pulmonary function tests (PFTs) most commonly involved spirometry and diffusion capacity for carbon monoxide. The frequency of PFTs varied depending on time post-HSCT and presence of complications. In all, 55.0% reported a set threshold for a clinically significant change in PFT., Conclusions: These results illustrate current variation in surveillance for pulmonary complications of pediatric HSCT. The results of this survey will inform development of future guidelines for monitoring of pulmonary complications after pediatric HSCT., (© 2021 The Authors. Cancer Reports published by Wiley Periodicals LLC.)

Aim: Establishing the underlying cause in a child with chronic suppurative lung disease (CSLD) allows for targeted treatment and screening for associated complications. One cause of CSLD is primary ciliary dyskinesia (PCD). Testing for PCD requires specialist expertise which is not widely available. Computed tomography (CT) scans are commonly performed when assessing CSLD. Identifying PCD-specific signs on CT would help clinicians in deciding when to refer for specialist testing. One potential PCD-specific sign we have observed is fissure adjacent partial lobe atelectasis (FAPLA). We aimed to assess if FAPLA is commonly found in CT of PCD patients., Methods: Fifty-eight CT scans from 42 adult and child PCD patients were analysed. The presence and distribution of FAPLA were noted, and its association to sputum culture and other signs commonly seen in CSLD (bronchiectasis, bronchial wall thickening, air trapping and mucus plugging)., Results: FAPLA was found in 13 of 40 participants in their earliest CT scan. The prevalence of FAPLA was similar in children and adults. FAPLA involved the right middle lobe in all 13 cases and was systematically associated with ≥1 other structural change. There was no association between FAPLA and bacterial isolation from sputum., Conclusion: FAPLA was found in 32.5% PCD scans, without difference between children and adults in terms of frequency. Future work will determine if it is a PCD-specific sign by assessing whether it is also found in other CSLD processes and analysing more scans from children with PCD to determine how early this sign develops., (© 2021 Paediatrics and Child Health Division (The Royal Australasian College of Physicians).)

In epigenome-wide association studies analysing DNA methylation from samples containing multiple cell types, it is essential to adjust the analysis for cell type composition. One well established strategy for achieving this is reference-based cell type deconvolution, which relies on knowledge of the DNA methylation profiles of purified constituent cell types. These are then used to estimate the cell type proportions of each sample, which can then be incorporated to adjust the association analysis. Bronchoalveolar lavage is commonly used to sample the lung in clinical practice and contains a mixture of different cell types that can vary in proportion across samples, affecting the overall methylation profile. A current barrier to the use of bronchoalveolar lavage in DNA methylation-based research is the lack of reference DNA methylation profiles for each of the constituent cell types, thus making reference-based cell composition estimation difficult. Herein, we use bronchoalveolar lavage samples collected from children with cystic fibrosis to define DNA methylation profiles for the four most common and clinically relevant cell types: alveolar macrophages, granulocytes, lymphocytes and alveolar epithelial cells. We then demonstrate the use of these methylation profiles in conjunction with an established reference-based methylation deconvolution method to estimate the cell type composition of two different tissue types; a publicly available dataset derived from artificial blood-based cell mixtures and further bronchoalveolar lavage samples. The reference DNA methylation profiles developed in this work can be used for future reference-based cell type composition estimation of bronchoalveolar lavage. This will facilitate the use of this tissue in studies examining the role of DNA methylation in lung health and disease., 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 © 2021 Shanthikumar, Neeland, Saffery, Ranganathan, Oshlack and Maksimovic.)

Background: There are limited data in pediatric populations evaluating whether chronic cardiorespiratory conditions are associated with increased risk of coronavirus disease 2019 (COVID-19). We aimed to compare the rates of chronic cardiac and respiratory disease in children testing positive severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2[+]) compared with those testing negative (SARS-CoV-2[-]) at our institution., Method: Prospective cohort with nested case-control study of all children tested by polymerase chain reaction (PCR) for SARS-CoV-2 by nasopharyngeal/oropharyngeal sampling between March and October 2020. Children were identified prospectively via laboratory notification with age and sex-matching of SARS-CoV-2[+] to SARS-CoV-2[-] (1:2). Clinical data were extracted from the electronic medical record., Results: In total, 179 SARS-CoV-2[+] children (44% females, median age 3.5 years, range: 0.1-19.0 years) were matched to 391 SARS-CoV-2[-] children (42% female, median age 3.7 years, range: 0.1-18.3 years). The commonest comorbidities showed similar frequencies in the SARS-CoV-2[+] and [-] groups: asthma (n = 9, 5% vs. n = 17, 4.4%, p = 0.71), congenital heart disease (n = 6, 3.4% vs. n = 7, 1.8%, p = 0.25) and obstructive sleep apnoea (n = 4, 2.2% vs. n = 10, 2.3%, p = 0.82). In the SARS-CoV-2[+] group, the prevalence of symptomatic disease was similar among children with and without cardiorespiratory comorbidities (n = 12, 75% vs. n = 103, 57%, p = 0.35). A high proportion of children hospitalized with SARS-CoV-2 infection had cardiac comorbidities (23.8%)., Conclusions: In this single site data set, rates of pre-existing cardiorespiratory disease were similar in SARS-CoV-2[+] and SARS-CoV-2[-] children. Rates of symptomatic infection were similar between children with and without cardiorespiratory comorbidity. High rates of comorbid cardiac disease were observed among hospitalized children with COVID-19 warranting further research to inform vaccine prioritization., (© 2021 Wiley Periodicals LLC.)

Purpose of Review: At many institutions, the Covid-19 pandemic made it necessary to rapidly change the way services are provided to patients, including those with cystic fibrosis (CF). The purpose of this review is to explore the past, present and future of telehealth and virtual monitoring in CF and to highlight certain challenges/considerations in developing such services., Recent Findings: The Covid-19 pandemic has proven that telehealth and virtual monitoring are a feasible means for safely providing services to CF patients when traditional care is not possible. However, both telehealth and virtual monitoring can also provide further support in the future in a post-covid era through a hybrid-model incorporating traditional care, remote data collection and sophisticated platforms to manage and share data with CF teams., Summary: We provide a detailed overview of telehealth and virtual monitoring including examples of how paediatric and adult CF services adapted to the need for rapid change. Such services have proven popular with people with CF meaning that co-design with stakeholders will likely improve systems further. In the future, telehealth and virtual monitoring will become more sophisticated by harnessing increasingly powerful technologies such as artificial intelligence, connected monitoring devices and wearables. In this review, we harmonise definitions and terminologies before highlighting considerations and limitations for the future of telehealth and virtual monitoring in CF., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc.)

The immune landscape of the paediatric respiratory system remains largely uncharacterised and as a result, the mechanisms of globally important childhood respiratory diseases remain poorly understood. In this work, we used high parameter flow cytometry and inflammatory cytokine profiling to map the local [bronchoalveolar lavage (BAL)] and systemic (whole blood) immune response in preschool aged children with cystic fibrosis (CF) and aged-matched healthy controls. We demonstrate that children with CF show pulmonary infiltration of CD66b + granulocytes and increased levels of MIP-1α, MIG, MCP-1, IL-8, and IL-6 in BAL relative to healthy control children. Proportions of systemic neutrophils positively correlated with age in children with CF, whilst systemic CD4 T cells and B cells were inversely associated with age. Inflammatory cells in the BAL from both CF and healthy children expressed higher levels of activation and migration markers relative to their systemic counterparts. This work highlights the utility of multiplex immune profiling and advanced analytical pipelines to understand mechanisms of lung disease in childhood., 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 © 2021 Shanthikumar, Ranganathan, Saffery and Neeland.)

Background: With the emergence of cystic fibrosis transmembrane conductance regulator (CFTR) modulators, forced expiratory volume in 1 s (FEV 1 ) may become a less sensitive measure of pulmonary disease progression in children with cystic fibrosis (CF). Increasing evidence shows that peak oxygen uptake (VO 2peak ) is a strong predictor of prognosis in CF. The primary aim of this study was to describe the associations between peak oxygen uptake, lung function, and bronchiectasis in children with CF in the era of CFTR modulators., Methods: Spirometry and a maximal cardiopulmonary exercise test (CPET) were performed on the same day and compared to markers of disease severity. Markers of disease severity included a number of pulmonary exacerbations resulting in hospital admission within the preceding 12 months, body mass index, Pseudomonas aeruginosa (PsA) infection, and bronchiectasis., Results: Fifty-two subjects (24 female) with CF participated in the study with a mean (SD) age of 13.8 (2.4) years, range 8-18 years. Forty-nine participants met satisfactory criteria for a maximal CPET. A significant correlation was found between relative VO 2peak %predicted and FEV 1 %predicted (r = .546, p < .001). A total of 4/49 children demonstrated an impaired aerobic capacity despite normal spirometry. Participants who had experienced one or more pulmonary exacerbations in the previous 12 months had a significantly lower relative VO 2peak %predicted (p = .02)., Conclusions: In children with CF who have mild pulmonary disease, there is significant correlation between FEV 1 and VO 2peak . In all, 8.2% of participants had an abnormal CPET result despite normal spirometry, and preceding pulmonary exacerbations were associated with poorer CPET outcomes. CPET may offer important prognostic information for clinical decision making in this new era of CFTR modulators., (© 2021 Wiley Periodicals LLC.)