Advances in Pediatric Lung Function Testing Techniques.

For decades spirometry has been the benchmark test for capturing lung function in children but its recognized limitations required the development of other techniques. This article introduces novel techniques in lung function assessment for pediatric patients, including multiple breath washout, impulse oscillometry, structured light plethysmography, and electrical impedance tomography, and common themes in interpreting the results. Challenges include standardization, reference data, and clinical integration of these innovative tools. Further research is ongoing to optimize these tests for clinical use, especially in diverse populations and pediatric settings.

A randomised trial of oral prednisone for cystic fibrosis pulmonary exacerbation treatment.

BACKGROUND: Elevated markers of systemic and pulmonary inflammation are associated with failure to recover lung function following pulmonary exacerbations in people with cystic fibrosis (pwCF). Our aim was to determine whether adjuvant oral prednisone treatment would improve recovery of forced expiratory volume in 1 s (FEV1) % pred in CF pulmonary exacerbations not responding to antibiotic therapy. METHODS: This was a randomised, double-blind, placebo-controlled trial in pwCF treated with intravenous antibiotics for a pulmonary exacerbation. At day 7, those who had not returned to >90% baseline FEV1 % pred were randomised to adjuvant prednisone 1 mg·kg-1 twice daily (maximum 60 mg·day-1) or placebo for 7 days. The primary outcome was the difference in proportion of subjects who recovered >90% baseline FEV1 % pred at day 14 of i.v. antibiotic therapy. RESULTS: 173 subjects were enrolled, with 76 randomised. 50% of subjects in the prednisone group recovered baseline FEV1 on day 14 compared with 39% of subjects in the placebo group (difference of 11%, 95% CI -11-34%; p=0.34). The mean±sd change in FEV1 % pred from day 7 to day 14 was 6.8±8.8% predicted in the prednisone group and 4.6±6.9% predicted in the placebo group (mean difference 2.2% predicted, 95% CI -1.5-5.9%; p=0.24). Time to subsequent exacerbation was not prolonged in prednisone-treated subjects (hazard ratio 0.83, 95% CI 0.45-1.53; p=0.54). CONCLUSIONS: This study failed to detect a difference in FEV1 % pred recovery between adjuvant oral prednisone and placebo treatment in pwCF not responding at day 7 of i.v. antibiotic therapy for pulmonary exacerbations.

Standards for the care of people with cystic fibrosis (CF); recognising and addressing CF health issues.

This is the third in a series of four papers updating the European Cystic Fibrosis Society (ECFS) standards for the care of people with CF. This paper focuses on recognising and addressing CF health issues. The guidance was produced with wide stakeholder engagement, including people from the CF community, using an evidence-based framework. Authors contributed sections, and summary statements which were reviewed by a Delphi consultation. Monitoring and treating airway infection, inflammation and pulmonary exacerbations remains important, despite the widespread availability of CFTR modulators and their accompanying health improvements. Extrapulmonary CF-specific health issues persist, such as diabetes, liver disease, bone disease, stones and other renal issues, and intestinal obstruction. These health issues require multidisciplinary care with input from the relevant specialists. Cancer is more common in people with CF compared to the general population, and requires regular screening. The CF life journey requires mental and emotional adaptation to psychosocial and physical challenges, with support from the CF team and the CF psychologist. This is particularly important when life gets challenging, with disease progression requiring increased treatments, breathing support and potentially transplantation. Planning for end of life remains a necessary aspect of care and should be discussed openly, honestly, with sensitivity and compassion for the person with CF and their family. CF teams should proactively recognise and address CF-specific health issues, and support mental and emotional wellbeing while accompanying people with CF and their families on their life journey.

Long-term outcomes of pulmonary embolism in children and adolescents.

ABSTRACT: Knowledge regarding the long-term consequences of pulmonary embolism (PE) in children is limited. This cohort study describes the long-term outcomes of PE in children who were followed-up at a single-center institution using a local protocol that included clinical evaluation, chest imaging, echocardiography, pulmonary function tests, and cardiopulmonary exercise tests at follow-up, starting 3 to 6 months after acute PE. Children objectively diagnosed with PE at age 0 to 18 years, who had ≥6 months of follow-up were included. Study outcomes consisted of PE resolution, PE recurrence, death, and functional outcomes (dyspnea, impaired pulmonary or cardiac function, impaired aerobic capacity, and post-PE syndrome). The frequency of outcomes was compared between patients with/without underlying conditions. In total, 150 patients were included; median age at PE was 16 years (25th-75th percentile, 14-17 years); 61% had underlying conditions. PE did not resolve in 29%, recurrence happened in 9%, and death in 5%. One-third of patients had at least 1 documented abnormal functional finding at follow-up (ventilatory impairments, 31%; impaired aerobic capacity, 31%; dyspnea, 26%; and abnormal diffusing capacity of the lungs to carbon monoxide, 22%). Most abnormalities were transient. When alternative explanations for the impairments were considered, the frequency of post-PE syndrome was lower, ranging between 0.7% and 8.5%. Patients with underlying conditions had significantly higher recurrence, more pulmonary function and ventilatory impairments, and poorer exercise capacity. Exercise intolerance was, in turn, most frequently because of deconditioning than to respiratory or cardiac limitation, highlighting the importance of physical activity promotion in children with PE.

Outpatient management of pulmonary exacerbations in children with cystic fibrosis.

INTRODUCTION: Pulmonary exacerbations are common events in children with cystic fibrosis (CF) and are usually treated with oral antibiotics on an outpatient basis. Even these mild clinical events are clinically meaningful and contribute to the progression of lung disease. AREAS COVERED: This review discusses the challenges in diagnosing pulmonary exacerbations in children in the absence of a standardized definition. It describes an approach to the management of these events and emphasizes knowledge gaps and areas of future research directions. Information to write this narrative review was collected from 1) a PubMed search [keywords: exacerbation, children, cystic fibrosis] that was not limited by date 2) a hand search of references of retrieved literature 3) personal expertise of the literature and the management of cystic fibrosis. EXPERT OPINION: Pulmonary exacerbations require prompt diagnosis and management to preserve lung function. More work is needed to understand the impact of CFTR modulators on the frequency and severity of these events and how they influence approaches to management. In a new era of CF care, there is a need to incorporate sensitive outcome measures into clinical care to inform treatment decisions and track treatment response.

Comparative analysis of respiratory symptom scores to detect acute respiratory events in children with cystic fibrosis.

BACKGROUND: Patient-reported outcomes (PROs) are important outcome measures in research and clinical practice. This study describes the longitudinal variability the Cystic Fibrosis Questionnaire-Revised (CFQ-R) Respiratory score and the Chronic Respiratory Infection Symptom Score (CRISS), as well as their ability to identify acute respiratory events in children with CF. METHODS: In this prospective observational study, the parent-proxy (6 -13 years) and self-reported (6-18 years) CFQ-R Respiratory score and CRISS (6-18 years) were measured every 3 months over 2 years. The lung clearance index (LCI) and FEV1 were also measured. We compared the diagnostic accuracy of the PROs in distinguishing acute respiratory events and clinically stable visits, using the minimal important difference of each PRO as the threshold. RESULTS: A total of 98 children with CF were included. On average, the symptom scores did not change between clinically stable visits. The positive predictive value (PPV) and negative predictive value (NPV) of a ≥8.5-point worsening in the parent-proxy CFQ-R score to identify acute respiratory events (n=119) (PPV 70.2% and NPV 87.0%) were higher than for the self-reported CFQ-R score (PPV 58.9% and NPV 72.2%). The PPV and NPV of an ≥11-point change in the CRISS for acute respiratory events (n=137) was 56.5% and 79.6%, respectively. The PPV and NPV of all PROs were increased when combined with the LCI and/or FEV1pp. CONCLUSION: Symptoms scores differ in their ability to identify acute respiratory events in children with CF; PPV and NPV of all PROs were improved when combined with lung function outcomes.

Evaluation of clinically relevant changes in the lung clearance index in children with cystic fibrosis and healthy controls.

BACKGROUND: The limits of reproducibility of the lung clearance index (LCI) are higher in children with cystic fibrosis (CF) compared with healthy children, and it is currently unclear what defines a clinically meaningful change. METHODS: In a prospective multisite observational study of children with CF and healthy controls (HCs), we measured LCI, FEV1% predicted and symptom scores at quarterly visits over 2 years. Two reviewers performed a detailed review of visits to evaluate the frequency that between visit LCI changes outside ±10%, ±15%, ±20% represented a clinically relevant signal. In the setting of acute respiratory symptoms, we used a generalised estimating equation model, with a logit link function to determine the ability of LCI worsening at different thresholds to predict failure of lung function recovery at follow-up. RESULTS: Clinically relevant LCI changes outside ±10%, ±15% and ±20% were observed at 25.7%, 15.0% and 8.3% of CF visits (n=744), respectively. The proportions of LCI changes categorised as noise, reflecting biological variability, were comparable between CF and HC at the 10% (CF 9.9% vs HC 13.0%), 15% (CF 4.3% vs HC 3.1%) and 20% (CF 2.4% vs HC 1.0%) thresholds. Compared with symptomatic CF visits without a worsening in LCI, events with ≥10% LCI increase were more likely to fail to recover baseline LCI at follow-up. CONCLUSION: The limits of reproducibility of the LCI in healthy children can be used to detect clinically relevant changes and thus inform clinical care in children with CF.

Development and Validation of an Algorithm for Quality Grading of Pediatric Spirometry: A Quality Improvement Initiative.

Rationale: Current spirometry quality grading for individuals 7 years and older include within-test repeatability thresholds up to 250 ml, which may be inappropriately wide for children. Objectives:1) To develop, internally validate, and implement a quality grading algorithm for forced expiratory volume in 1 second (FEV1) and forced vital capacity (FVC) for school-aged children and 2) to compare the algorithm with the one proposed by the American Thoracic Society (ATS). Methods: We conducted a review of existing algorithms and obtained expert input. A pediatric quality grading algorithm was drafted and modified in an iterative process until consensus was achieved, with the main difference from current criteria being tighter volume repeatability for the pediatric quality grading. Four pulmonary function technicians evaluated the interrater agreement of the algorithm in a blinded fashion on an unselected consecutive sample of 87 prebronchodilator spirometry tests, and the grades were compared with those from the ATS algorithm in the same sample of spirometry tests. The algorithm was then implemented into the workflow of the pulmonary function laboratory. Results: For FEV1 and FVC, the interrater agreement values for the pediatric algorithm were 92% and 83%, respectively. When the ATS algorithm was used, 75.9% (n = 66) and 63.2% (n = 55) of subjects achieved a grade of A for FEV1 and FVC; when the pediatric algorithm was used, 69.0% (n = 60) and 58.6% (n = 51) met grade A criteria. There was a more uniform distribution of tests for the pediatric algorithm across grades B through F for FEV1 and FVC, and no grade C tests were observed for the ATS grading algorithm. A total of 2,464 tests graded prospectively by using the pediatric algorithm showed a median (interquartile range) FEV1 and FVC repeatability within 29 ml (13-57 ml) and 34 ml (15-66 ml), respectively. Most subjects received a grade of A for FEV1 (81.1%) and FVC (71.6%), performing a repeatable spirometry test to within 100 ml. Conclusions: A quality grading algorithm that uses smaller ranges of expired volumes to define repeatability is feasible and may be more appropriate in a pediatric pulmonary function laboratory.

Determinants of lung disease progression measured by lung clearance index in children with cystic fibrosis.

The lung clearance index (LCI) measured by the multiple breath washout (MBW) test is sensitive to early lung disease in children with cystic fibrosis. While LCI worsens during the preschool years in cystic fibrosis, there is limited evidence to clarify whether this continues during the early school age years, and whether the trajectory of disease progression as measured by LCI is modifiable.A cohort of children (healthy and cystic fibrosis) previously studied for 12 months as preschoolers were followed during school age (5-10 years). LCI was measured every 3 months for a period of 24 months using the Exhalyzer D MBW nitrogen washout device. Linear mixed effects regression was used to model changes in LCI over time.A total of 582 MBW measurements in 48 healthy subjects and 845 measurements in 64 cystic fibrosis subjects were available. The majority of children with cystic fibrosis had elevated LCI at the first preschool and first school age visits (57.8% (37 out of 64)), whereas all but six had normal forced expiratory volume in 1 s (FEV1) values at the first school age visit. During school age years, the course of disease was stable (-0.02 units·year-1 (95% CI -0.14-0.10). LCI measured during preschool years, as well as the rate of LCI change during this time period, were important determinants of LCI and FEV1, at school age.Preschool LCI was a major determinant of school age LCI; these findings further support that the preschool years are critical for early intervention strategies.

Lung Clearance Index to Track Acute Respiratory Events in School-Age Children with Cystic Fibrosis.

Rationale: The lung clearance index (LCI) is responsive to acute respiratory events in preschool children with cystic fibrosis (CF), but its utility to identify and manage these events in school-age children with CF is not well defined.Objectives: To describe changes in LCI with acute respiratory events in school-age children with CF.Methods: In a multisite prospective observational study, the LCI and FEV1 were measured quarterly and during acute respiratory events. Linear regression was used to compare relative changes in LCI and FEV1% predicted at acute respiratory events. Logistic regression was used to compare the odds of a significant worsening in LCI and FEV1% predicted at acute respiratory events. Generalized estimating equation models were used to account for repeated events in the same subject.Measurements and Main Results: A total of 98 children with CF were followed for 2 years. There were 265 acute respiratory events. Relative to a stable baseline measure, LCI (+8.9%; 95% confidence interval, 6.5 to 11.3) and FEV1% predicted (-6.6%; 95% confidence interval, -8.3 to -5.0) worsened with acute respiratory events. A greater proportion of events had a worsening in LCI compared with a decline in FEV1% predicted (41.7% vs. 30.0%; P = 0.012); 53.9% of events were associated with worsening in LCI or FEV1. Neither LCI nor FEV1 recovered to baseline values at the next follow-up visit.Conclusions: In school-age children with CF, the LCI is a sensitive measure to assess lung function worsening with acute respiratory events and incomplete recovery at follow-up. In combination, the LCI and FEV1 capture a higher proportion of events with functional impairment.

The remaining barriers to normalcy in CF: Advances in assessment of CF lung disease.

Despite early diagnosis of cystic fibrosis (CF) through newborn screening, a substantial proportion of infants and young children with CF still demonstrate physiologic and structural evidence of lung disease progression, such as obstructive airway disease and bronchiectasis. The growing availability of highly effective CF transmembrane conductance regulatory modulator therapy to the vast majority of people with CF has led to the potential to alter the natural history of CF lung disease, but to assess the full impact of these therapies on CF lung disease and to help guide treatment, sensitive measures of early and mild disease are needed. Chest imaging using computed tomography or magnetic resonance imaging is one approach, but technologic barriers and/or concern about exposure to ionizing radiation may limit its use. However, advances in physiologic measurement techniques and exhaled breath analysis offer another option for assessment of CF lung disease.

Designing Clinical Trials for Anti-Inflammatory Therapies in Cystic Fibrosis.

The inflammatory response in the CF airway begins early in the disease process and becomes persistent through life in most patients. Inflammation, which is predominantly neutrophilic, worsens airway obstruction and plays a critical role in the development of structural lung damage. While cystic fibrosis transmembrane regulator modulators will likely have a dramatic impact on the trajectory of CF lung disease over the coming years, addressing other important aspects of lung disease such as inflammation will nevertheless remain a priority. Considering the central role of neutrophils and their products in the inflammatory response, potential therapies should ultimately affect neutrophils and their products. The ideal anti-inflammatory therapy would exert a dual effect on the pro-inflammatory and pro-resolution arms of the inflammatory cascade, both of which contribute to dysregulated inflammation in CF. This review outlines the key factors to be considered in the design of clinical trials evaluating anti-inflammatory therapies in CF. Important lessons have been learned from previous clinical trials in this area and choosing the right efficacy endpoints is key to the success of any anti-inflammatory drug development program. Identifying and validating non-invasive biomarkers, novel imaging techniques and sensitive lung function tests capable of monitoring disease activity and therapeutic response are important areas of research and will be useful for the design of future anti-inflammatory drug trials.

Changes in the parent cystic fibrosis questionnaire-revised (CFQ-R) with respiratory symptoms in preschool children with cystic fibrosis.

INTRODUCTION: The Cystic Fibrosis Questionnaire-Revised (CFQ-R) Respiratory score is a validated and widely used patient-reported outcome. This study aimed to establish changes in the score with acute respiratory events in preschool children with CF and to investigate its' relationship with physiological outcomes. METHODS: The Parent CFQ-R, multiple breath washout test and spirometry were performed at six study visits over one year. The clinical status of participants, stable or symptomatic, was defined by the patient's physician. Linear regression and distribution-based statistical methods were used to examine the changes in the CFQ-R from the last stable visit and to investigate its relationship with physiological outcomes. RESULTS: There were 272 stable and 115 symptomatic visits from 78 participants. The mean CFQ-R Respiratory score did not change between consecutive stable visits (-0.73, SD 20.4). The mean (SD) score deteriorated by 15.5 (20.7) points between stable and symptomatic visits and improved by 14.8 (20.1) points between symptomatic and stable follow-up visits. When a clinically important change is defined as 0.5SD change (10-points), the positive predictive value (PPV) was 45% and the negative predictive value (NPV) was 84%. For visits with a 10-point worsening in the CFQ-R Respiratory score and a 15% increase in LCI, the PPV was better (81%) than using either measure alone. CONCLUSION: The CFQ-R Respiratory score is responsive to acute respiratory events in preschool children with CF and its utility to monitor individual patients is improved when combined with LCI.

How to use noninvasive positive airway pressure device data reports to guide clinical care.

There has been a significant increase in the past few decades in the number of children receiving noninvasive positive airway pressure (PAP) therapy at home. At present, PAP therapy can be successfully used in children of all ages, for a variety of indications. Data acquired from PAP devices is clinically useful, providing objective information regarding adherence, leak, and efficacy of PAP therapy. However, guidelines outlining a standardized approach to interpretation of PAP device data in pediatrics is currently lacking. Given the rapidly expanding use of PAP therapy in pediatric practice, we aim to provide an overview of the interpretation of data reports, otherwise called "data downloads," from PAP devices and illustrate how they can be used to guide clinical care.

Anti-inflammatories and mucociliary clearance therapies in the age of CFTR modulators.

Cystic fibrosis (CF) is a genetic and life-limiting disease caused by mutations in the CF transmembrane conductance regulator (CFTR) gene. This multi-system disease is characterized by progressive lung disease and pancreatic insufficiency amongst other manifestations. CFTR primarily functions as a chloride channel that transports ions across the apical membrane of epithelial cells but has other functions, including bicarbonate secretion and inhibition of sodium transport. Defective CFTR disrupts these functions, causing viscous and dehydrated mucus to accumulate, compromising the airway lumen and contributing to obstructive pulmonary disease. The combination of CFTR dysfunction, mucus obstruction, and infection drive an exaggerated and dysfunctional inflammatory response, which contributes to irreversible airway destruction and fibrosis. CFTR modulators, an exciting new class of drugs, increase the expression and/or function of CFTR variant protein and improve multiple clinical endpoints, such as lung function, pulmonary exacerbation rates, and nutritional status. However, these genotype-specific drugs are not universally available, the clinical response is variable, and lung function still declines over time when bronchiectasis is established. Consequently, even in the age of CFTR modulators, we must target other important aspects of the CF airway disease, such as inflammation and mucociliary clearance. This review highlights the mechanisms of inflammation and mucus accumulation in the CF lung and discusses anti-inflammatory and mucociliary clearance agents that are currently in development focusing on compounds for which clinical trial data have recently become available.