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Multiple breath nitrogen washout (MBNW) quantifies ventilation heterogeneity. Two distinct protocols are currently used for MBNW testing: "controlled breathing", with targeted tidal volume ( V T ) and respiratory rate (RR); and "free breathing", with no constraints on breathing pattern. Indices derived from the two protocols (functional residual capacity (FRC), lung clearance index (LCI), S cond , S acin ) have not been directly compared in adults. We aimed to determine whether MBNW indices are comparable between protocols, to identify factors underlying any between-protocol differences and to determine the between-session variabilities of each protocol. We performed MBNW testing by both protocols in 27 healthy adult volunteers, applying the currently proposed correction for V T to S cond and S acin derived from free breathing. To establish between-session variability, we repeated testing in 15 volunteers within 3 months. While FRC was comparable between controlled versus free breathing (3.17 (0.98) versus 3.18 (0.94) L, p=0.88), indices of ventilation heterogeneity derived from the two protocols were not, with poor correlation for S cond (r=0.18, p=0.36) and significant bias for S acin (0.057 (0.021) L -1 versus 0.085 (0.038) L -1 , p=0.0004). Between-protocol differences in S acin were related to differences in the breathing pattern, i.e. V T (p=0.004) and RR (p=0.01), rather than FRC. FRC and LCI showed good between-session repeatability, but S cond and S acin from free breathing showed poor repeatability with wide limits of agreement. These findings have implications for the ongoing clinical implementation of MBNW, as they demonstrate that S cond and S acin from free breathing, despite V T correction, are not equivalent to the controlled breathing protocol. The poor between-session repeatability of S cond during free breathing may limit its clinical utility., Competing Interests: Conflict of interest: B.M. Handley has nothing to disclose. Conflict of interest: E. Jeagal has nothing to disclose. Conflict of interest: R.E. Schoeffel has nothing to disclose. Conflict of interest: T. Badal has nothing to disclose. Conflict of interest: D.G. Chapman has nothing to disclose. Conflict of interest: C.E. Farrow has nothing to disclose. Conflict of interest: G.G. King reports fees for consultancy services (which include lectures and advisory board services), conference attendance support and unrestricted research grants from AstraZeneca, Boehringer Ingelheim, CycloPharm, GlaxoSmithKline, Novartis, Menarini and MundiPharma, and research grants and fellowships from the National Health & Medical Research Council and the Asthma Foundation, outside the submitted work. Conflict of interest: P.D. Robinson has nothing to disclose. Conflict of interest: S. Milne reports personal fees from Novartis and Boehringer Ingelheim outside the submitted work, and is supported by the MITACS Accelerate programme. Conflict of interest: C. Thamrin has nothing to disclose., (Copyright ©ERS 2021.)

Purpose: To develop a clinical practice guideline for systemic antifungal prophylaxis in pediatric patients with cancer and hematopoietic stem-cell transplantation (HSCT) recipients., Methods: Recommendations were developed by an international multidisciplinary panel that included a patient advocate. We conducted a systematic review of systemic antifungal prophylaxis in children and adults with cancer and HSCT recipients. The Grading of Recommendations Assessment, Development, and Evaluation approach was used to make strong or weak recommendations and to classify level of evidence as high, moderate, low, or very low. The panel considered directness of the data to pediatric patients., Results: There were 68 randomized trials included in the systematic review, of which 6 (9%) were conducted in a solely pediatric population. Strong recommendations were made to administer systemic antifungal prophylaxis to children and adolescents receiving treatment of acute myeloid leukemia, to those undergoing allogeneic HSCT pre-engraftment, and to those receiving systemic immunosuppression for graft-versus-host disease treatment. A strong recommendation was made to administer a mold-active agent with an echinocandin or a mold-active azole when systemic antifungal prophylaxis is warranted. For children younger than 13 years of age, an echinocandin, voriconazole, or itraconazole is suggested. Posaconazole may also be used in those age 13 years or older. A strong recommendation against routine administration of amphotericin as systemic antifungal prophylaxis was made., Conclusion: We developed a clinical practice guideline for systemic antifungal prophylaxis administration in pediatric patients with cancer and HSCT recipients. Implementation and assessment of guideline-concordant rates and impacts are important future steps.

Asthma and COPD make up the majority of obstructive airways diseases (OADs), which affects ∼11 % of the population. The main drugs used to treat OADs have not changed in the past five decades, with advancements mainly comprising variations on existing treatments. The recent biologics are beneficial to only specific subsets of patients. Part of this may lie in our inability to adequately characterise the tremendous heterogeneity in every aspect of OAD. The field is currently moving towards the concept of personalised medicine, based on a focus on treatable traits that are objective, measurable and modifiable. We propose extending this concept via the use of emerging clinical tools for comprehensive physiological phenotyping. We describe, based on published data, the evidence for the use of functional imaging, gas washout techniques and oscillometry, as well as potential future applications, to more comprehensively assess and predict treatment response in OADs. In this way, we hope to demonstrate how physiological phenotyping tools will improve the way in which drugs are prescribed, but most importantly, will facilitate development of new drugs for OADs., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

We have previously shown that functional residual capacity (FRC) and lung clearance index were significantly greater in sleeping healthy infants when measured by N 2 (nitrogen) washout using 100% O 2 (oxygen) versus 4% SF 6 (sulfur hexafluoride) washout using air. Following 100% O 2 exposure, tidal volumes decreased by over 30%, while end-expiratory lung volume (EELV, i.e., FRC) rose markedly based on ultrasonic flow meter assessments. In the present study to investigate the mechanism behind the observed changes, N 2 MBW was performed in 10 separate healthy full-term spontaneously sleeping infants, mean (range) 26 (18-31) weeks, with simultaneous EELV monitoring (respiratory inductance plethysmography, RIP) and oxygen uptake (V´O 2 ) assessment during prephase air breathing, during N 2 washout by exposure to 100% O 2 , and subsequently during air breathing. While flow meter signals suggested a rise in ELLV by mean (SD) 26 (9) ml over the washout period, RIP signals demonstrated no EELV change. V'O 2 /FRC ratio during air breathing was mean (SD) 0.43 (0.08)/min, approximately seven times higher than that calculated from adult data. We propose that our previously reported flow meter-based overestimation of EELV was in fact a physiological artifact caused by rapid and marked movement of O 2 across the alveolar capillary membrane into the blood and tissue during 100% O 2 exposure, without concomitant transfer of N 2 to the same degree in the opposite direction. This may be driven by the high observed O 2 consumption and resulting cardiac output encountered in infancy. Furthermore, the low resting lung volume in infancy may make this error in lung volume determination by N 2 washout relatively large., (© 2020 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society.)

Background: The lung clearance index (LCI), derived from the Multiple Breath Washout (MBW) test, is sensitive to treatment effects and compared with spirometry has higher feasibility in younger children and requires smaller sample sizes. As a result, the LCI has been endorsed by the European CF Society Clinical Trials Network for use as a primary outcome measure in CF clinical trials., Methods: Here we describe the implementation of standardised protocols for MBW test performance, data collection and quality control to successfully incorporate LCI as a novel outcome measure in a large multicentre phase III clinical trial., Results: Three regional (North America (NA), Europe (EU), Australia (AUS)) central over-reading centres (CORC) were established to provide a collaborative platform for MBW training, certification and quality control of data. One hundred and thirty-two naïve operators from 53 sites across NA, EU and AUS were successfully trained and certified to perform MBW testing.  Incorporation of a re-screening opportunity in the study protocol resulted a final screening feasibility rate of 93%, success remained high throughout the study resulting in an overall feasibility of MBW study data of 88.1% (1107/1257). MBW test acceptability was similar between geographical regions: NA (88%), EU (89%) and AUS (89%)., Conclusion: With this approach we achieved high MBW test feasibility and sustained collection of good quality data, demonstrating the utility of LCI as an effective primary endpoint in the first international phase III clinical trial to report LCI as the primary outcome., (Copyright © 2019. Published by Elsevier B.V.)

Background: Bacteremia and other invasive bacterial infections are common among children with cancer receiving intensive chemotherapy and in pediatric recipients of hematopoietic stem cell transplantation (HSCT). Systemic antibacterial prophylaxis is one approach that can be used to reduce the risk of these infections. Our purpose was to develop a clinical practice guideline (CPG) for systemic antibacterial prophylaxis administration in pediatric patients with cancer and those undergoing HSCT., Methods: An international and multidisciplinary panel was convened with representation from pediatric hematology/oncology and HSCT, pediatric infectious diseases (including antibiotic stewardship), nursing, pharmacy, a patient advocate, and a CPG methodologist. The panel used the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach to generate recommendations based on the results of a systematic review of the literature., Results: The systematic review identified 114 eligible randomized trials of antibiotic prophylaxis. The panel made a weak recommendation for systemic antibacterial prophylaxis for children receiving intensive chemotherapy for acute myeloid leukemia and relapsed acute lymphoblastic leukemia (ALL). Weak recommendations against the routine use of systemic antibacterial prophylaxis were made for children undergoing induction chemotherapy for ALL, autologous HSCT and allogeneic HSCT. A strong recommendation against its routine use was made for children whose therapy is not expected to result in prolonged severe neutropenia. If used, prophylaxis with levofloxacin was recommended during severe neutropenia., Conclusions: We present a CPG for systemic antibacterial prophylaxis administration in pediatric cancer and HSCT patients. Future research should evaluate the long-term effectiveness and adverse effects of prophylaxis., (© The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America.)

Terms used to label types of clinical recommendations and guidance are applied inconsistently and do not reflect the methods used to create each type. Here, the international Pediatric Oncology Supportive Care Guideline Network proposes a lexicon for types of recommendations and guidance documents. A lexicon describing three types of recommendations (clinical practice guideline-derived, good practice statement, and expert opinion statement) and two types of guidance documents (clinical practice guideline and expert opinion) is presented. Consistent use of this lexicon will allow pediatric oncology clinicians to readily appreciate the methods used to create clinical guidance., (© 2020 Wiley Periodicals, Inc.)

Background: Uncontrolled severe asthma in children is burdensome and challenging to manage. This study aims to describe outcomes in children with uncontrolled severe asthma managed in a nurse-led severe asthma clinic (SAC)., Methods: This retrospective analysis uses data collected from children referred by a paediatric respiratory specialist to a nurse-led SAC for uncontrolled severe asthma between 2014 and 2019. The pre-clinical assessments included a home visit to assess modifiable factors that could be addressed to improve control. A comprehensive lung function analysis was conducted at each visit. Interventions were personalised and included biologic agents. Statistical analysis was performed using nonparametric, two-tailed Mann-Whitney U-test, the parametric Student's t-test, or analysis of variance (ANOVA) as appropriate., Results: Twenty-three children with a median age of 12 years were seen once, and 16 were followed up. Compared to a non-asthmatic (NA) and asthmatic (A) age-matched cohort, children with severe asthma (SA) had a lower FEV1, and FVC% predicted before and after bronchodilator inhalation, and a higher mean Lung Clearance Index [LCI] (10.5 [SA] versus 7.3 [NA] versus 7.6 [A], p = 0.003). Almost 80% of children with SA had an abnormal LCI, and 48% had a reduced FEV1% at the first SAC visit. Asthma control and FEV1% predicted significantly improved at a follow-up visit, while LCI remained abnormal in the majority of children (83%)., Conclusion: Over time, many children with severe asthma showed improved clinical outcomes and lung function while lung ventilation inhomogeneities persisted. Future appropriately controlled studies are required to determine if a nurse-led multidisciplinary SAC is associated with better outcomes.

Despite ototoxicity being a prevalent consequence of cisplatin chemotherapy, little guidance exists on interventions to prevent this permanent and progressive adverse event. To develop a clinical practice guideline for the prevention of cisplatin-induced ototoxicity in children and adolescents with cancer, we convened an international, multidisciplinary panel of experts and patient advocates to update a systematic review of randomised trials for the prevention of cisplatin-induced ototoxicity. The systematic review identified 27 eligible adult and paediatric trials that evaluated amifostine, sodium diethyldithiocarbamate or disulfiram, systemic sodium thiosulfate, intratympanic therapies, and cisplatin infusion duration. Regarding systemic sodium thiosulfate, the panel made a strong recommendation for administration in non-metastatic hepatoblastoma, a weak recommendation for administration in other non-metastatic cancers, and a weak recommendation against its routine use in metastatic cancers. Amifostine, sodium diethyldithiocarbamate, and intratympanic therapy should not be routinely used. Cisplatin infusion duration should not be altered as a means to reduce ototoxicity. Further research to determine the safety of sodium thiosulfate in patients with metastatic cancer is encouraged., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Objectives: Telehealth and home spirometry feasibility for children has been established, but their impact on cystic fibrosis (CF) disease progression remains unassessed. We aimed to evaluate the effects of telehealth and home spirometry on CF disease progression and care., Methods: Children with CF aged 5-17 years from all Swedish CF centers were provided with home spirometers. A minimum of two in-person visits were replaced with telemedicine visits and participants were instructed to conduct home spirometry before visits. Linear mixed-effects models were used to compare annual CF disease trajectories during the intervention period and prepandemic period (1 January 2019 to 28 February 2020). Participants and caregivers completed study questionnaires., Results: A total of 59 individuals completed the study over a mean (SD) period of 6.8 (1.4) months, made 3.1 (1.0) physical visits and 2.2 (0.6) telehealth visits per patient year during the study period. The mean difference (95% CI) between the intervention and prepandemic period progression rate for FEV 1 %, lung clearance index and BMI were -0.4 (-1.3 to 0.5, p = 0.39), 0.11 (-0.07 to 0.28, p = 0.25) and -0.02 (-0.13 to 0.08, p = 0.70), respectively. There were no major shifts in the incidence of airway pathogens, sputum cultures, or antibiotics use between the periods (p > 0.05). The intervention did not increase stress. Almost all participants and caregivers expressed a desire to continue with home spirometry and telemedicine., Conclusion: Combining telehealth and physical visits with access to home spirometry demonstrated comparable effectiveness as exclusively in-person care with enhanced flexibility and personalization of CF care., (© 2024 The Author(s). Pediatric Pulmonology published by Wiley Periodicals LLC.)

Inert gas washout methods have been shown to detect pathological changes in the small airways that occur in the early stages of obstructive lung diseases such as asthma and COPD. Numerical lung models support the analysis of characteristic washout curves, but are limited in their ability to simulate the complexity of lung anatomy over an appropriate time period. Therefore, the interpretation of patient-specific washout data remains a challenge. A new numerical lung model is presented in which electrical components describe the anatomical and physiological characteristics of the lung as well as gas-specific properties. To verify that the model is able to reproduce characteristic washout curves, the phase 3 slopes (S 3 ) of helium washouts are simulated using simple asymmetric lung anatomies consisting of two parallel connected lung units with volume ratios of 1.25 0.75 , 1.50 0.50 , and 1.75 0.25 and a total volume flow of 250 ml/s which are evaluated for asymmetries in both the convection- and diffusion-dominated zone of the lung. The results show that the model is able to reproduce the S 3 for helium and thus the processes underlying the washout methods, so that electrical components can be used to model these methods. This approach could form the basis of a hardware-based real-time simulator., (© 2024. The Author(s).)

Background: Supportive care clinical practice guidelines (CPGs) facilitate the incorporation of the best available evidence into pediatric cancer care. We aimed to assess the impact of the work of the Children's Oncology Group (COG) Supportive Care Guideline Task Force on institutional supportive care practices., Procedure: An online survey was distributed to representatives at 209 COG sites to assess the awareness, use, and helpfulness of COG-endorsed supportive care CPGs. Availability of institutional policies regarding 13 topics addressed by current COG-endorsed CPGs was also assessed. Respondents described their institutional processes for developing supportive care policies., Results: Representatives from 92 COG sites responded to the survey, and 78% (72/92) were "very aware" of the COG-endorsed supportive care CPGs. On average, sites had policies that addressed seven COG-endorsed supportive care CPG topics (median = 7, range: 0-12). Only 45% (41/92) of sites reported having institutional processes for developing supportive care policies. Of these, most (76%, 31/41) reported that the COG-endorsed CPGs have a medium or large impact on policy development. Compared with sites without processes for supportive care policy development, sites with established processes had policies on a greater number of topics aligned with current COG-endorsed CPG topics (mean = 6.6, range: 0-12 vs mean = 7.9, range: 2-12; p = 0.027)., Conclusions: Most site respondents were aware of the COG-endorsed supportive care CPGs. Less than half of the COG sites represented in the survey have processes in place to implement supportive care policies. Improvement in local implementation is required to ensure that patients at COG sites receive evidence-based supportive care., (© 2024 Wiley Periodicals LLC.)

Rationale: Lung T1 MRI is a potential method to assess cystic fibrosis (CF) lung disease that is safe, quick, and widely available, but there are no data in children with mild CF lung disease., Objective: Assess the ability of lung T1 MRI to detect abnormalities in children with mild CF lung disease., Methods: We performed T1 MRI, multiple breath washout (MBW), chest computed tomography (CT), and spirometry in a cohort of 45 children with mild CF lung disease (6-11 years of age)., Main Results: Despite mean normal ppFEV1 values, the majority of children with CF in this study exhibited mild lung disease evident in lung clearance index (LCI) measured by MBW, chest CT Brody scores, and percent normal lung perfusion (%NLP) measured by T1 MRI. The %NLP correlated with chest CT Brody scores, as did LCI, but %NLP and LCI did not correlate with each other. Analysis of the Brody subscores showed that %NLP and LCI largely correlated with different Brody subscores., Conclusions: T1 MRI can detect mild CF lung disease in children and correlates with chest CT findings. The %NLP from T1 MRI and LCI correlate with different chest CT Brody subscores, suggesting they provide complementary information about CF lung disease., (© 2024 The Authors. Pediatric Pulmonology published by Wiley Periodicals LLC.)

Background: Molecular diagnostics may enable early, noninvasive detection of invasive fungal disease (IFD) in immunocompromised patients. Cell-free deoxyribonucleic acid (cfDNA) fungal polymerase chain reaction (PCR) assays were recently incorporated into institutional prolonged febrile neutropenia pathways. We aimed to evaluate the performance of plasma cfDNA PCR panels (mold and Candida panels) in pediatric oncology and hematopoietic stem cell transplant (HSCT) patients with clinical concern for IFD., Methods: This single-center, observational study assessed plasma cfDNA fungal PCR performance for noninvasive IFD detection in hospitalized pediatric oncology and HSCT patients. The primary outcome was IFD diagnosis per published consensus definitions within 1 month. Positive and negative agreement between plasma cfDNA fungal PCR and consensus definitions were calculated. We also described test turnaround time and patient survival., Results: From October 2021 to 2022, 54 patients underwent 60 evaluations with 11 proven/probable IFD cases. Comparing plasma cfDNA fungal PCRs to consensus definitions for proven/probable IFD, there was 73% positive agreement and 96% negative agreement. Two proven/probable cases with negative PCRs were caused by organisms not included on either panel. Median time to cfDNA fungal PCR result was 35 hours (interquartile range: 19-69) in eight proven/probable cases detected by cfDNA fungal PCR. There were 17 deaths among 54 patients, and IFD contributed to 45% of deaths in patients with proven/probable IFD., Conclusions: Plasma cfDNA fungal PCRs detected relevant molds or yeast in most cases classified as proven/probable IFD. However, this targeted approach missed some cases. More studies are required to determine optimal utilization of molecular diagnostics in pediatric patients., (© 2024 Wiley Periodicals LLC.)

Objective: Vomiting is a common and distressing acute side effect of chemotherapy, negatively impacting quality of life, nutritional status, and the ability of patients to tolerate further treatment. Standardized guidelines have been developed to improve control of nausea and vomiting. We aimed to determine the benefit of adherence to clinical practice guidelines (CPGs) on complete control of acute chemotherapy-induced vomiting in newly diagnosed pediatric patients with cancer., Methods: An electronic dashboard of pediatric patients newly diagnosed with cancer at Phoenix Children's Hospital between August 2019 and January 2021 and receiving their first cycle of chemotherapy was utilized to monitor chemotherapy regimen, antiemetic medications, and vomiting episodes. Blocks were classified as guideline-inconsistent, guideline-consistent, or guideline-consistent PLUS if additional prophylactic antiemetic medications were utilized. We identified patients with complete control of vomiting, defined as no vomiting and no additional antiemetics needed., Results: Among 136 patients, 29% received guideline-inconsistent care, 37% received guideline-consistent care, and 34% received guideline-consistent PLUS care. Overall, 48% of patients achieved complete control of vomiting. Older patients (p < 0.0001) and those receiving higher emetogenicity chemotherapy (p = 0.0003) were more likely to receive guideline-consistent or guideline-consistent PLUS therapy. With guideline-consistent and -consistent PLUS grouped together, the diagnosis was also associated with improved adherence to CPGs (p = 0.022). Multivariate analysis showed that patients more likely to receive guideline-consistent prophylaxis were of older age (OR 1.11, p = 0.016) and solid tumor patients (OR 5.59, p = 0.028)., Conclusions: Despite high rates of CPG adherence, complete control of vomiting remains suboptimal, which highlights the need for novel and/or risk-adapted therapies., (© 2024 Wiley Periodicals LLC.)

Background: Respiratory viruses are a common cause of infection in immunosuppressed children undergoing cancer therapy. Pulmonary sequelae have been documented following respiratory viral infections (RVIs) in hematopoietic stem cell transplant (HSCT) recipients; however potential late effects in children undergoing nonmyeloablative chemotherapy have not been investigated., Aim: To evaluate the long-term pulmonary morbidity of respiratory viral infections during chemotherapy in children with acute lymphoblastic leukemia (ALL)., Methods: Childhood ALL survivors, aged 7 to 18 years, greater than 6 months posttreatment were recruited. Exclusion criteria included HSCT or proven bacterial/fungal respiratory infection during treatment. Subjects were classified into "viral" or "control" groups according to retrospective medical records that documented the presence of laboratory-proven RVIs during chemotherapy. Symptom questionnaires (Liverpool, ISAAC) and lung function testing (spirometry, plethysmography, diffusing capacity, forced oscillation technique to ATS/ERS standards) were then performed cross-sectionally at the time of recruitment., Results: Fifty-four patients (31 viral, 23 control) were recruited: median (range) age 11.2 (7.2-18.1) years, and at 4.9 (0.5-13) years posttherapy. Abnormalities were detected in 17 (31%) individuals (8 viral, 9 control), with the most common being DLCO impairment (3 viral, 4 control) and reduced respiratory reactance at 5 Hz (5 viral, 6 control). Children with RVIs during chemotherapy reported more current respiratory symptoms, particularly wheeze (odds ratio [OR], 3.0; 95% confidence interval [CI]: 0.9-10.0; P = .09) and cough (OR, 2.7; 95% CI: 0.8-9.5; P = .11). No differences in lung function tests were observed between the two groups., Conclusions: Our study found children with RVIs during chemotherapy developed more long-term respiratory symptoms than controls; however, differences did not reach statistical significance. No differences in static lung function were found between the two groups. Overall, pulmonary abnormalities and/or significant ongoing respiratory symptoms were detected in nearly a third of ALL survivors treated without HSCT. Larger, prospective studies are warranted to evaluate the etiology and clinical significance of these findings., (© 2019 Wiley Periodicals, Inc.)

There is growing recognition of the degree to which symptoms negatively impact on children receiving cancer treatments. A recent study described that almost all inpatient pediatric oncology patients are experiencing at least one bothersome symptom and almost 60% are experiencing at least one severely bothersome symptom. Poor symptom control occurs because of challenges with communication of bothersome symptoms to clinicians, lack of clinical practice guidelines (CPGs) for most of these symptoms, and failure to administer preventative and therapeutic interventions known to be effective for symptom control. This article reviews approaches used to improve symptom control for children receiving cancer treatments. Areas addressed include systematic symptom screening and creation of CPGs for symptom management. Challenges with electronic health integration are also addressed. Several multi-symptom assessment scales have been developed but none have yet been used to directly influence patient management. The number of CPGs applicable to symptom control in pediatric oncology is increasing but remains small. Improving the creation of and adherence to CPGs for symptom management is an important priority. Finally, identifying ways that symptom management systems can be integrated into clinical work flows is essential; these will likely need to focus on electronic health records.

Background: Clinical and prognostic value of preschool Multiple Breath Washout (MBW) remains unclear., Methods: Initial MBW results (Exhalyzer® D, EcoMedics AG) in preschool Cystic Fibrosis (CF) subjects (age 2-6 years) at a time of clinical stability were compared to (1) concurrent clinical status measures and (2) later spirometry outcomes. Abnormal Lung Clearance Index (LCI) was defined using published reference data (ULN for LCI 8.0)., Results: LCI was abnormal in 56% (28/50), with mean (SD) LCI 8.61(1.85) at age 4.71(1.3) years. Abnormal LCI was associated with higher dornase alfa use, previous positive bacterial cultures and pF508.del homozygous genotype. Later spirometry (n = 44; mean (SD) 2.3(0.5) years after MBW) demonstrated that abnormal initial preschool LCI was a strong predictor of lower later spirometry outcomes., Conclusion: Abnormal preschool LCI was associated with concurrent measures of clinical status and later spirometry deficits, suggesting early prognostic utility of MBW testing in this age range., (Copyright © 2019. Published by Elsevier B.V.)

The identification of preventive interventions that are safe and effective for cisplatin-induced ototoxicity is important, especially in children because hearing loss can impair speech-language acquisition development. Previous randomised trials assessed systemic drugs such as amifostine, sodium diethyldithiocarbamate or disulfiram, and sodium thiosulfate. Amifostine, sodium diethyldithiocarbamate, and disulfiram did not show hearing preservation. Paediatric trials assessing sodium thiosulfate showed efficacy in terms of hearing protection. The SIOPEL 6 trial consisted solely of patients with localised hepatoblastoma and no effects on survival were shown. In the ACCL0431 trial, which included heterogeneous patients, a post-hoc analysis showed significantly worse overall survival among patients who had disseminated disease receiving sodium thiosulfate than among controls, but not among those with localised disease. Intratympanically administered drugs have mainly been assessed in adults and include N-acetylcysteine and dexamethasone. Inconsistent effects of these drugs were identified but these studies were limited by design, small sample size, and statistical approach. Future studies of systemic drugs will need to consider the measurement of disease outcomes through study design and sample size, and ototoxicity endpoints should be harmonised to enhance comparability between trials., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Purpose: To determine the efficacy and safety of different prophylactic systemic antibiotics in adult and pediatric patients receiving chemotherapy or undergoing hematopoietic stem cell transplantation (HSCT)., Methods: We conducted a systematic review and performed searches of Ovid MEDLINE, MEDLINE in-process and Embase; and Cochrane Central Register of Controlled Trials. Studies were included if patients had cancer or were HSCT recipients with anticipated neutropenia, and the intervention was systemic antibacterial prophylaxis. Strategies synthesized included fluoroquinolone vs no antibiotic/nonabsorbable antibiotic; fluoroquinolone vs trimethoprim-sulfamethoxazole; trimethoprim-sulfamethoxazole vs no antibiotic; and cephalosporin vs. no antibiotic. Fluoroquinolone vs cephalosporin and levofloxacin vs ciprofloxacin were compared by network meta-analysis. Primary outcome was bacteremia., Results: Of 20 984 citations screened, 113 studies comparing prophylactic antibiotic to control were included. The following were effective in reducing bacteremia: fluoroquinolone vs no antibiotic/nonabsorbable antibiotic (risk ratio (RR) 0.56, 95% confidence interval (CI) 0.41-0.76), trimethoprim-sulfamethoxazole vs no antibiotic (RR 0.59, 95% CI 0.41-0.85) and cephalosporin vs no antibiotic (RR 0.30, 95% CI 0.16-0.58). Fluoroquinolone was not significantly associated with increased Clostridium difficile infection (RR 0.62, 95% CI 0.31-1.24) or invasive fungal disease (RR 1.28, 95% CI 0.79-2.08) but did increase resistance to fluoroquinolone among bacteremia isolates (RR 3.35, 95% CI 1.12 to 10.03). Heterogeneity in fluoroquinolone effect on bacteremia was not explained by evaluated study, population, or methodological factors. Network meta-analysis revealed no direct comparisons for pre-specified analyses; superior regimens were not identified., Conclusions: Fluoroquinolone, trimethoprim-sulfamethoxazole, and cephalosporin prophylaxis reduced bacteremia. A clinical practice guideline to facilitate prophylactic antibiotic decision-making is required., (© 2019 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

This clinical practice guideline (CPG) provides clinicians with recommendations regarding chemotherapy emetogenicity classification in pediatric oncology patients. This information is critically important for the appropriate selection of antiemetic prophylaxis. Recommendations are based on a systematic review limited to pediatric patients and a framework for classification when antiemetic prophylaxis is provided. Findings of 87 publications informed the emetogenicity classification of 49 single-agent and 13 combination-agent regimens. Information required for the classification of many chemotherapies commonly administered to pediatric patients is lacking. In the absence of pediatric data, consultation of methodologically sound CPGs aimed at adult oncology patients may be appropriate., (© 2019 Wiley Periodicals, Inc.)

Non-tuberculous mycobacterial (NTM) (especially M. abscessus complex) infections pose a considerable challenge in the management of lung disease in patients with cystic fibrosis (CF). The apparent increase in prevalence is likely multifactorial. Emergent evidence of patient-to-patient transmission and isolation of highly resistant strains is a concern for all CF centers around the world. Treatment is often long and burdensome with multiple agents. Treatment side effects are frequent and can cause significant morbidity. Although consensus guidelines provide some direction, many units are faced with the challenges of: finding drug combinations for highly resistant strains; dealing with interruptions of treatment; discussing additional facilitating procedures in the form of gastrostomy and long-term vascular access devices; as well as supporting families emotionally and psychologically through the process., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Providing evidence-based supportive care for children with cancer has the potential to optimize treatment outcomes and improve quality of life. The Children's Oncology Group (COG) Supportive Care Guidelines Subcommittee conducted a systematic review to identify current supportive care clinical practice guidelines (CPGs) relevant to childhood cancer or pediatric hematopoietic stem cell transplant. Only 22 papers met the 2011 Institute of Medicine criteria to be considered a CPG. The results highlight the paucity of CPGs available to pediatric oncology healthcare professionals and the pressing need to create CPGs using current methodological standards., (© 2018 Wiley Periodicals, Inc.)

Background: The single-center double-blind, randomized controlled Managing Asthma in Pregnancy (MAP) trial in Newcastle, Australia, compared a treatment algorithm using the fraction of exhaled nitric oxide (FENO) in combination with asthma symptoms (FENO group) against a treatment algorithm using clinical symptoms only (clinical group) in pregnant asthmatic women (Australian New Zealand Clinical Trials Registry, no. 12607000561482). The primary outcome was a 50% reduction in asthma exacerbations during pregnancy in the FENO group. However, the effect of FENO-guided management on the development of asthma in the offspring is unknown., Objective: We sought to investigate the effect of FENO-guided asthma management during pregnancy on asthma incidence in childhood., Methods: A total of 179 mothers consented to participate in the Growing into Asthma (GIA) double-blind follow-up study with the primary aim to determine the effect of FENO-guided asthma management on childhood asthma incidence., Results: A total of 140 children (78%) were followed up at 4 to 6 years of age. FENO-guided as compared to symptoms-only approach significantly reduced doctor-diagnosed asthma (25.9% vs 43.2%; odds ratio [OR], 0.46, 95% CI, 0.22-0.96; P = .04). Furthermore, frequent wheeze (OR, 0.27; 95% CI, 0.09-0.87; P = .03), use of short-acting β-agonists (OR, 0.49; 95% CI, 0.25-0.97; P = .04), and emergency department visits for asthma (OR, 0.17; 95% CI, 0.04-0.76; P = .02) in the past 12 months were less common in children born to mothers from the FENO group. Doctor-diagnosed asthma was associated with common risk alleles for early onset asthma at gene locus 17q21 (P = .01 for rs8069176; P = .03 for rs8076131), and higher airways resistance (P = .02) and FENO levels (P = .03). A causal mediation analysis suggested natural indirect effects of FENO-guided asthma management on childhood asthma through "any use" and "time to first change in dose" of inhaled corticosteroids during the MAP trial (OR: 0.83; 95% CI: 0.59-0.99, and OR: 0.90; 95% CI: 0.70-1.03, respectively)., Conclusions: FENO-guided asthma management during pregnancy prevented doctor-diagnosed asthma in the offspring at preschool age, in part mediated through changes in use and dosing of inhaled corticosteroids during the MAP trial., (Copyright © 2018 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

We report a 2-year-old, previously healthy boy, who presented with chronic pneumonia. He was diagnosed with culture-confirmed pulmonary tuberculosis. Complications included spontaneous pneumothorax presumed to be secondary to cavity formation and complete subsegmental airway obstruction that did not resolve with prolonged oral corticosteroid treatment.

Dexamethasone use during hematopoietic cell transplant (HCT) conditioning varies between pediatric centers. This study aimed to estimate the difference in 1-year treatment-related mortality (TRM) between patients who did or did not receive dexamethasone during HCT conditioning. Secondary objectives were to estimate the difference between dexamethasone-exposed and dexamethasone-unexposed groups in 1-year event-free survival (EFS), time to neutrophil engraftment, acute graft-versus-host disease (aGVHD), and invasive fungal disease (IFD) at day + 100. This was a seven-site, international, retrospective cohort study. Patients < 18 years old undergoing their first allogeneic or autologous myeloablative HCT for hematologic malignancy or aplastic anemia between January 1, 2012, and July 31, 2017, were included. To control for potential confounders, propensity score weighting was used to calculate the standardized mean difference for all endpoints. Among 242 patients, 140 received dexamethasone during HCT conditioning and 102 did not. TRM was unaffected by dexamethasone exposure (1.7%; 95% CI - 7.4, 10.2%). Between-group differences in secondary outcomes were small. However, dexamethasone exposure significantly increased possible, probable, and proven IFD incidence (9.0%, 95% CI 0.8, 17.3%). TRM is not increased in pediatric patients who receive dexamethasone during HCT conditioning. Clinicians should consider potential IFD risk when selecting chemotherapy-induced vomiting prophylaxis for pediatric HCT patients., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

The multiple breath washout (MBW) test is widely reported in the context of Lung Clearance Index (LCI). LCI reflects global ventilation inhomogeneity but does not provide information regarding the localization of disease along the respiratory tree. The MBW-derived normalized phase III slope (S nIII ) indices (S cond and S acin ), instead, can distinguish between convective-dependent and diffusion-convection-dependent ventilation inhomogeneity considered to occur within the conductive and acinar airways, respectively. In cystic fibrosis, S cond tends to become abnormal even earlier than LCI and spirometry. The value of S cond and S acin in clinical practice has been recently explored in other respiratory conditions, including asthma, primary ciliary dyskinesia, bronchopulmonary dysplasia, bronchiolitis obliterans, and sickle cell disease. In this narrative review we offer an overview on the theoretical background, potentialities, and limitations of S nIII analysis in children, including challenges and feasibility aspects. Moreover, we summarize current evidence on the use of S nIII -derived indices across different groups of pediatric chronic respiratory disease and we highlight the gaps in knowledge that need to be addressed in future studies., (© 2024 The Author(s). Pediatric Pulmonology published by Wiley Periodicals LLC.)

Introduction: Major methodological issues with the existing algorithm (WBreath) used for the analysis of speed-of-sound-based infant sulfur hexafluoride (SF 6 ) multiple-breath washout (MBW) measurements lead to implausible results and complicate the comparison between different age groups and centers., Methods: We developed OASIS-a novel algorithm to analyze speed-of-sound-based infant SF 6 MBW measurements. This algorithm uses known context of the measurements to replace the dependence of WBreath on model input parameters. We validated the functional residual capacity (FRC) measurement accuracy of this new algorithm in vitro, and investigated its use in existing infant MBW data sets from different infant cohorts from Switzerland and South Africa., Results: In vitro, OASIS managed to outperform WBreath at FRC measurement accuracy, lowering mean (SD) absolute error from 5.1 (3.2) % to 2.1 (1.6) % across volumes relevant for the infant age range, in variable temperature, respiratory rate, tidal volume and ventilation inhomogeneity conditions. We showed that changes in the input parameters to WBreath had a major impact on MBW results, a methodological drawback which does not exist in the new algorithm. OASIS produced more plausible results than WBreath in longitudinal tracking of lung clearance index (LCI), provided improved measurement stability in LCI over time, and improved comparability between centers., Discussion: This new algorithm represents a meaningful advance in obtaining results from a legacy system of lung function measurement by allowing a single method to analyze measurements from different age groups and centers., (© 2024 The Author(s). Pediatric Pulmonology published by Wiley Periodicals LLC.)

Background: The performance of serum galactomannan (GM) for the diagnosis of invasive aspergillosis (IA) has been studied mainly in adults. Paediatric data are scarce and based on small and heterogeneous cohorts., Objective: To evaluate the performance of serum GM for the diagnosis of IA in a paediatric oncologic population at high risk of IA and to clarify the impact of antifungal prophylaxis on this test., Methods: We performed a retrospective study from January 2014 to December 2020 in the paediatric oncologic haematologic department of the University Hospital of Bordeaux. The diagnosis of IA was made using the recommendations of the EORTC and the MSGERC., Results: Among the 329 periods at high risk of IA in 222 patients, the prevalence of IA was 1.8% (3 proven and 3 probable IA). In the total population, the sensitivity, and the positive predictive value (PPV) were respectively 50% and 17.6%. Under antifungal prophylaxis, the sensitivity and PPV dropped, respectively, to 33.3% and 14.3%. In this group, the post-test probability of IA was 2% for a negative serum GM and only 14%., Conclusion: In this large cohort of children at high risk of IA, the incidence of IA is low and the diagnostic performance of GM is poor, especially in the case of mould-active prophylaxis. Screening should be targeted rather than systematic and should be reserved for patients at highest risk for IA without mould-active prophylaxis. Combination with other tests such as Aspergillus PCR would increase the accuracy of GM in screening setting., (© 2024 The Author(s). Mycoses published by Wiley‐VCH GmbH.)

Purpose: The aim of this work was to develop a clinical practice guideline for the prevention and treatment of Clostridium difficile infection (CDI) in children and adolescents with cancer and pediatric hematopoietic stem-cell transplantation (HSCT) patients., Methods: An international multidisciplinary panel of experts in pediatric oncology and infectious diseases with patient advocate representation was convened. We performed systematic reviews of randomized controlled trials for the prevention or treatment of CDI in any population and considered the directness of the evidence to children with cancer and pediatric HSCT patients. We used the Grading of Recommendations Assessment, Development, and Evaluation approach to generate recommendations., Results: The panel made strong recommendations to administer either oral metronidazole or oral vancomycin for the initial treatment of nonsevere CDI and oral vancomycin for the initial treatment of severe CDI. Fidaxomicin may be considered in the setting of recurrent CDI. The panel suggested that probiotics not be routinely used for the prevention of CDI, and that monoclonal antibodies and probiotics not be routinely used for the treatment of CDI. A strong recommendation to not use fecal microbiota transplantation was made in this population. We identified key knowledge gaps and suggested directions for future research., Conclusion: We present a guideline for the prevention and treatment of CDI in children and adolescents with cancer and pediatric HSCT patients. Future research should include randomized controlled trials that involve children with cancer and pediatric HSCT patients to improve the management of CDI in this population.

Multiple breath nitrogen washout (MBNW) indices provide insight into ventilation heterogeneity globally [lung clearance index (LCI)] and within acinar (S acin ) and conducting (S cond ) airways. Normal aging leads to an accelerated deterioration of S acin in older adults, but little is known about the contribution of peripheral airway function to changes in pulmonary function indices reflecting expiratory airflow [forced expiratory volume in one second (FEV 1 )/forced vital capacity (FVC)] and gas trapping [residual volume (RV)/total lung capacity (TLC)] with aging. We aimed to examine associations between MBNW and FEV 1 /FVC as well as RV/TLC in healthy adults, and to determine if these relationships differ in older (≥50 yr) versus younger subjects (<50 yr). Seventy-nine healthy adult volunteers aged 23-89 yr with no cardiac or respiratory disease and a smoking history of <5 pack-years underwent spirometry, plethysmography, and MBNW. After adjustment for sex, height, and body mass index, the following relationships were present across the entire cohort: S acin was inversely related to FEV 1 /FVC (R 2  = 0.22, P < 0.001); S acin and S cond were positively related to RV/TLC (R 2  = 0.53, P < 0.001); on separate analyses, the relationship between S acin and FEV 1 /FVC was strongest in the older group (R 2  = 0.20, P = 0.003) but markedly weaker in the younger group (R 2  = 0.09, P = 0.04); and S acin and S cond were related to RV/TLC in older (R 2  = 0.20, P = 0.003) but not younger subgroups. No relationships were observed between LCI and FEV 1 /FVC or RV/TLC. Changes in FEV 1 /FVC and RV/TLC are at least in part due to changes in peripheral airway function with aging. Further studies of the relationships between MBNW and standard pulmonary function indices may prove useful for their combined application and interpretation in obstructive airways disease. NEW & NOTEWORTHY This study explores associations between multiple breath nitrogen washout (MBNW) and standard pulmonary function indices reflecting expiratory airflow [forced expiratory volume in one second (FEV 1 )/forced vital capacity (FVC)] and gas trapping [residual volume (RV)/total lung capacity (TLC)] in healthy adults across a wide range of ages. We have demonstrated statistically significant relationships between MBNW and FEV 1 /FVC as well as RV/TLC. These findings provide novel evidence of the contribution of peripheral airway function to changes in standard pulmonary function indices with aging.

Background: Although a number of risk factors have been associated with invasive fungal disease (IFD), a systematic review of the literature to document pediatric-specific factors has not been performed., Methods: We used the Ovid SP platform to search Medline, Medline In-Process, and Embase for studies that identified risk factors for IFD in children with cancer or those who undergo hematopoietic stem cell transplantation (HSCT). We included studies if they consisted of children or adolescents (<25 years) who were receiving treatment for cancer or undergoing HSCT and if the study evaluated risk factors among patients with and those without IFD., Results: Among the 3566 studies screened, 22 studies were included. A number of pediatric factors commonly associated with an increased risk for IFD were confirmed, including prolonged neutropenia, high-dose steroid exposure, intensive-timing chemotherapy for acute myeloid leukemia, and acute and chronic graft-versus-host disease. Increasing age, a factor not commonly associated with IFD risk, was identified as a risk factor in multiple published cohorts., Conclusions: With this systematic review, we have confirmed IFD risk factors that are considered routinely in daily clinical practice. Increasing age should also be considered when assessing patient risk for IFD. Future efforts should focus on defining more precise thresholds for a particular risk factor (ie, age, neutropenia duration) and on development of prediction rules inclusive of individual factors to further refine the risk prediction.

Background: Different interfaces (mouthpiece/nose clip vs. facemask) are used during multiple breath washout (MBW) tests in young children., Methods: We investigated the effect of interface choice and breathing modalities on MBW outcomes in healthy adults and preschool children., Results: In adults (n = 26) facemask breathing significantly increased LCI, compared to mouthpiece use (mean difference (95% CI) 0.4 (0.2; 0.6)), with results generalizable across sites and different equipment. Exclusively nasal breathing within the facemask increased LCI, as compared to oral breathing. In preschoolers (2-6 years, n = 46), no significant inter-test difference was observed across interfaces for LCI or FRC. Feasibility and breathing stability were significantly greater with facemask (incorporating dead space volume minimization), vs. mouthpiece. This was more pronounced in subjects <4 years of age., Conclusion: Both nasal vs. oral breathing and mouthpiece vs. facemask affect LCI measurements in adults. This effect was minimal in preschool children, where switching between interfaces is most likely to occur., (Copyright © 2018 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.)

Aim: Ex-premature school children show mild-to-moderate airway obstruction and decreased CO diffusing capacity. Multiple breath nitrogen washout (N2MBW) and NO diffusing capacity (DLNO) measurements may provide new insight into long-term pulmonary and vascular impairment in bronchopulmonary dysplasia (BPD)., Methods: We examined a randomly selected group of 70 ex-premature children (gestational age <28 weeks or birth weight <1500 g; 42 with and 28 without BPD) and 38 term-born healthy controls of 8-13 years of age. Subjects performed N2MBW (lung clearance index, LCI; Sacin, and Scond), DLNO (membrane related diffusing capacity, Dm and pulmonary capillary volume, Vc), Fractional exhaled NO, CO diffusing capacity, conventional spirometry (FEV1, FVC, FEF25-75) and plethysmography (RV, TLC). Respiratory symptoms were assessed by questionnaire., Results: Compared to healthy controls, the BPD group had higher z-scores for lung clearance index (P = 0.003), Sacin (P = 0.005), lower CO diffusing capacity (P = 0.025), DLNO (P = 0.022), DLNO/VA z-scores (P = 0.025) and a significant larger proportion had respiratory complaints. Amongst ex-premature children, the BPD group did not differ from the non-BPD group except for a decreased Dm (P = 0.023). Ex-premature with BPD showed predominantly airway obstruction (FEV1/FVC; P < 0.0001), signs of hyperinflation (RV/TLC-ratio; P = 0.028), and 25% had a positive bronchodilator response (>12% in FEV1)., Conclusion: Ex-premature school children exhibited relatively mild but significant long-term respiratory symptoms and pulmonary peripheral impairment judged by N2MBW and DLNO measurements along with well-known airway obstruction. Larger longitudinal studies are needed to assess the clinical use of these advanced methods of assessing ventilation inhomogeneity and DLNO., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Fatigue is a prevalent and distressing symptom in children and adolescents with cancer and in those who have undergone haemopoietic stem-cell transplantation. A multidisciplinary and multinational group of experts in paediatric oncology and fatigue, together with patient advocates, developed a clinical practice guideline for management of fatigue on the basis of systematic reviews that included six paediatric and 456 adult randomised studies. We used the Grading of Recommendations Assessment, Development and Evaluation approach to generate recommendations, and made strong recommendations, supported by evidence of moderate quality, for use of physical activity, relaxation, and mindfulness to reduce fatigue. When these approaches are unsuccessful or not feasible, cognitive or cognitive behavioural therapies may be offered (weak recommendation supported by evidence of moderate quality). Maturity and cognitive ability of individual patients will affect the feasibility of interventions. Systemic pharmacological approaches should not be routinely used to manage fatigue in children. Apart from identification of optimal approaches to implement recommended interventions in clinical practice, future research should also address knowledge gaps, including establishment of minimum age thresholds for interventions and inclusion of paediatric patients in randomised trials of fatigue management., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Suspensions of plasmonic nanoparticles can diffract optical beams due to the combination of thermal lensing and self-phase modulation. Here, we demonstrate extremely efficient optical continuous wave (CW) beam switching across the visible range in optimized suspensions of 5-nm Au and Ag nanoparticles in non-polar solvents, such as hexane and decane. On-axis modulation of greater than 30 dB is achieved at incident beam intensities as low as 100 W/cm 2 with response times under 200 μs, at initial solution transparency above 70%. No evidence of laser-induced degradation is observed for the highest intensities used. Numerical modeling of experimental data reveals thermo-optic coefficients of up to -1.3 × 10 -3 /K, which, to our knowledge, is the highest observed to date in such nanoparticle suspensions.

Background: Our objective was to determine whether, compared with control interventions, pharmacologic interventions reduce the severity of fatigue in patients with cancer or recipients of hematopoietic stem-cell transplantation (hsct)., Methods: For a systematic review, we searched medline, embase, the Cochrane Central Register of Controlled Trials, cinahl, and Psychinfo for randomized trials of systemic pharmacologic interventions for the management of fatigue in patients with cancer or recipients of hsct. Two authors independently identified studies and abstracted data. Methodologic quality was assessed using the Cochrane Risk of Bias tool. The primary outcome was fatigue severity measured using various fatigue scales. Data were synthesized using random-effects models., Results: In the 117 included trials (19,819 patients), the pharmacologic agents used were erythropoietins ( n = 31), stimulants ( n = 19), l-carnitine ( n = 6), corticosteroids ( n = 5), antidepressants ( n = 5), appetite stimulants ( n = 3), and other agents ( n = 48). Fatigue was significantly reduced with erythropoietin [standardized mean difference (smd): -0.52; 95% confidence interval (ci): -0.89 to -0.14] and with methylphenidate (smd: -0.36; 95% ci: -0.56 to -0.15); modafinil (or armodafinil) and corticosteroids were not effective., Conclusions: Erythropoietin and methylphenidate significantly reduced fatigue severity in patients with cancer and in recipients of hsct. Concerns about the safety of those agents might limit their usefulness. Future research should identify effective interventions for fatigue that have minimal adverse effects.

Background: Obstructive airway disease is nonuniformly distributed throughout the bronchial tree, although the extent to which this occurs can vary among conditions. The multiple-breath washout (MBW) test offers important insights into pediatric lung disease, not available through spirometry or resistance measurements. The European Respiratory Society/American Thoracic Society inert gas washout consensus statement led to the emergence of validated commercial equipment for the age group 6 years and above; specific recommendations for preschool children were beyond the scope of the document. Subsequently, the focus has shifted to MBW applications within preschool subjects (aged 2-6 yr), where a "window of opportunity" exists for early diagnosis of obstructive lung disease and intervention., Methods: This preschool-specific technical standards document was developed by an international group of experts, with expertise in both custom-built and commercial MBW equipment. A comprehensive review of published evidence was performed., Results: Recommendations were devised across areas that place specific age-related demands on MBW systems. Citing evidence where available in the literature, recommendations are made regarding procedures that should be used to achieve robust MBW results in the preschool age range. The present work also highlights the important unanswered questions that need to be addressed in future work., Conclusions: Consensus recommendations are outlined to direct interested groups of manufacturers, researchers, and clinicians in preschool device design, test performance, and data analysis for the MBW technique.

Background: Data on long term variability of Lung Clearance Index (LCI) in Cystic Fibrosis (CF) is urgently needed to guide test result interpretation. Our aim was to evaluate LCI variability in clinically stable CF lung disease in school age children., Methods: Paediatric patients, aged 6 to 17years, attending the outpatient CF clinic performed Multiple Breath Nitrogen Washout (Exhalyzer® D) and spirometry every third month over a period of one year. Clinical stability was assessed by the Cystic Fibrosis Clinical Score (CFCS) at each visit., Results: Twentyfive children were recruited: baseline median (range) FEV 1 % pred. 91 (55-122)%, LCI 9.1 (6.4-18.6), CFCS 15 (12-23). A total of 107 visits were included in the study, of which 93% were defined as clinically stable. In clinically stable visits, within-subject variability of LCI and FEV 1 % pred. were 10% and 16%, respectively. The upper limit of normal (ULN, 95% percentile) of LCI variability during clinical stability was 17%., Conclusions: LCI within-subject variability was low and comparable to FEV 1 % pred. which strengthen the use of LCI to monitor lung disease progression in CF patients. An increase in LCI >17% compared to previous LCI-measurement in clinically stable CF patients may therefore indicate early lung disease progression., (Copyright © 2017 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.)

Purpose: Objective was to determine whether physical activity reduces the severity of fatigue in patients with cancer or hematopoietic stem cell transplant (HSCT) recipients., Methods: We conducted a meta-analysis of randomized trials comparing physical activity with control interventions for the management of fatigue in patients with cancer or HSCT recipients., Results: There were 170 trials included. Physical activity reduced the severity of fatigue when compared to all control groups (standardized mean difference -0.49, 95% confidence interval -0.60 to -0.37; P < 0.00001). Aerobic, neuromotor, resistance and combination exercises were all effective in reducing fatigue although smaller effects were observed with resistance exercises (P interaction = 0.01). Other intervention and patient characteristics did not influence the effect of physical activity on the severity of fatigue., Conclusions: Physical activity was effective at reducing fatigue in patients with cancer and HSCT recipients across patient sub-groups. Determining the best approaches for safe implementation should be a priority., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Nitrogen multiple breath washout (N 2 MBW) is a sensitive method to identify peripheral airway involvement in asthma, but is a time-consuming test. The N 2 vital capacity single breath (VC SBW) test offers greater time efficiency, but concordance with N 2 MBW is poorly understood. The prevalence of peripheral airway abnormality was determined by N 2 MBW and N 2 SBW tests in 194 asthmatic subjects aged 18-1 years. N 2 MBW data were related to findings in 400 healthy controls, aged 17-71 years, while N 2 SBW data were compared to findings in 224 healthy controls, aged 15-65 years, to derive equipment-specific reference values. Amongst asthmatic subjects, relationships between N 2 SBW and N 2 MBW outcomes were studied. N 2 SBW relationship with clinical history, spirometry, blood eosinophils and fraction exhaled nitric oxide (FENO) data was also explored. The prevalence of peripheral airway involvement (i.e. abnormal ventilation distribution) determined by N 2 SBW-derived phase III slope (N 2 S III ) was 24·7%, compared to 44% determined by N 2 MBW-derived lung clearance index (LCI) (P<0·001). Predictors of abnormal N 2 S III were older age, smoking history and lower FEV 1. N 2 SBW offers lower sensitivity than N 2 MBW to detect small airway dysfunction in adult asthma, but may be a marker of more severe disease., (© 2018 Scandinavian Society of Clinical Physiology and Nuclear Medicine. Published by John Wiley & Sons Ltd.)

Purpose: To determine whether non-physical activity mind and body practices reduce the severity of fatigue in patients with cancer or hematopoietic stem cell transplant (HSCT) recipients compared to control interventions., Methods: We included randomized trials which compared non-physical activity mind and body practices compared with control interventions for the management of fatigue in cancer and HSCT patients., Results: Among 55 trials (4975 patients), interventions were acupuncture or acupressure (n=12), mindfulness (n=11), relaxation techniques (n=10), massage (n=6), energy therapy (n=5), energizing yogic breathing (n=3) and others (n=8). When combined, all interventions significantly reduced fatigue severity compared to all controls (standardized mean difference -0.51, 95% confidence interval -0.73 to -0.29). More specifically, mindfulness and relaxation significantly reduced fatigue severity., Conclusions: Mindfulness and relaxation were effective at reducing fatigue severity in patients with cancer and HSCT recipients. Future studies should evaluate how to translate these findings into clinical practice across different patient groups., (Copyright © 2017 Elsevier B.V. All rights reserved.)

The detrimental effects on breathing pattern during multiple breath inert gas washout (MBW) have been described with different inhaled gases [100% oxygen (O 2 ) and sulfur hexafluoride (SF 6 )] but detailed comparisons are lacking. N 2 - and SF 6 -based tests were performed during spontaneous quiet sleep in 10 healthy infants aged 0.7-1.3 yr using identical hardware. Differences in breathing pattern pre and post 100% O 2 and 4% SF 6 exposure were investigated, and the results obtained were compared [functional residual capacity (FRC) and lung clearance index (LCI)]. During 100% O 2 exposure. mean inspiratory flow ("respiratory drive") decreased transiently by mean (SD) 28 (9)% ( P < 0.001), and end-tidal CO 2 (carbon dioxide) increased by mean (SD) 0.3 (0.4)% units ( P < 0.05) vs. air breathing prephase. During subsequent N 2 washin (i.e., recovery phase), the pattern of change reversed. No significant effect on breathing pattern was observed during SF 6 testing. In vitro testing confirmed that technical artifacts did not explain these changes. Mean (SD) FRC and LCI in vivo were significantly higher with N 2 vs. SF 6 washout: 216 (33) vs. 186 (22) ml ( P < 0.001) and 8.25 (0.85) vs. 7.55 (0.57) turnovers ( P = 0.021). Based on these results, SF 6 based MBW is the preferred methodology for tests in this age range. NEW & NOTEWORTHY Inert gas choice for multiple breath inert gas washout (MBW) in infants has important consequences on both breathing pattern during test performance and the functional residual capacity and lung clearance index values obtained. Data suggest the detrimental effect of breathing pattern of 100% O 2 and movement of O 2 across the alveolar capillary membrane, with direct effects on MBW outcomes. SF 6 MBW during infancy avoids this and can be further optimized by addressing the sources of technical artifact identified in this work.