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Primary ciliary dyskinesia (PCD) is characterized by impaired mucociliary clearance, recurrent respiratory infections, and progressive airway damage and obstructive lung disease. While the association of ciliary ultrastructure defect/genotype with severity of airflow obstruction has been well characterized, their association with airway abnormalities on chest computed tomography (CT) has been minimally evaluated.We sought to delineate the association of ciliary defect class/genotype with chest CT scores in children with PCD.Cross-sectional analysis of children with PCD (N=146) enrolled in a prospective multicenter observational study, stratified by defect type: ODA (outer dynein arm), ODA/IDA (outer and inner dynein arm), IDA/MTD (inner dynein arm and microtubular disorganization), and Normal/Near Normal ultrastructure with associated genotypes. CTs were scored utilizing the Melbourne-Rotterdam Annotated Grid Morphometric Analysis for PCD (MERAGMA-PCD), evaluating airway abnormalities in a hierarchical order: atelectasis, bronchiectasis, bronchial wall thickening, mucus plugging/tree in bud opacities. Volume fraction of each component was expressed as % of total lung volume. %Disease was computed as the sum of all components. Regression analyses were utilized to describe the association between clinical predictors and CT scores.Acceptable chest CTs were obtained in 141 children (71 male): 57 ODA, 20 ODA/IDA, 40 IDA/MTD, 24 Normal/Near Normal. Mean (SD) age was 8.5 (4.6) years, forced expiratory volume in 1 second (FEV1) % predicted was 82.4 (19.5), and %Disease was 4.6 (3.5). Children with IDA/MTD defects had higher %Disease compared to children with ODA defects (2.71% higher (95%CI: 1.37-4.06, p0.001)), driven by higher %Mucus plugging (2.35% higher (1.43-3.26, p0.001)). Increasing age, lower BMI, and lower FEV1 were associated with higher %Disease (0.23%, 95%CI: 0.11-0.35, p0.001; 0.03%, 95%CI: 0.01-0.04, p=0.008; and 0.05%, 95%CI: 0.01-0.08, p=0.011, respectively).Children with IDA/MTD defects had significantly greater airway disease on CT, primarily mucus plugging, compared to children with ODA defects.

Elexacaftor/tezacaftor/ivacaftor (ETI) improves pulmonary disease in people with cystic fibrosis (PwCF), but its effect on gastrointestinal symptoms, which also affect quality of life, is not clear.PROMISE is a 56-center prospective, observational study of ETI in PwCF12 years and at least one F508del allele. Gastrointestinal symptoms, evaluated by validated questionnaires: Patient Assessment of Upper Gastrointestinal Disorders-Symptom (PAGI-SYM), Patient Assessment of Constipation-Symptom (PAC-SYM), Patient Assessment of Constipation-Quality of Life (PAC-QOL)), fecal calprotectin, steatocrit and elastase-1 were measured before and 6 months after ETI initiation. Mean difference and 95% confidence intervals were obtained from linear regression with adjustment for age and sex.438 participants fully completed at least 1 questionnaire. Mean (SD) for baseline PAGI-SYM, PAC-SYM, and PAC-QOL total scores were 0.56 (0.59), 0.47 (0.45), and 0.69 (0.53) out of maximum 5, 4, and 5, respectively (higher score indicates greater severity). Corresponding age- and sex-adjusted 6 months mean changes (95% CI) in total scores were -0.15 (-0.21, -0.09) for PAGI-SYM, -0.14 (-0.19, -0.09) for PAC-SYM, and -0.15 (-0.21, -0.10) for PAC-QOL. While statistically significant, changes were small and unlikely to be of clinical importance. Fecal calprotectin showed a change (95% CI) from baseline of -66.2 µg/g (-86.1, -46.2) at 6 months, while fecal elastase and steatocrit did not meaningfully change.After 6 months of ETI, fecal markers of inflammation decreased. Gastrointestinal symptoms improved, but the effect size was small. Pancreatic insufficiency did not improve.

Chronic azithromycin improves outcomes in cystic fibrosis (CF), but its mechanism of action is unclear. The OPTIMIZE trial demonstrated improvement in time to first pulmonary exacerbation in children with new Pseudomonas treated with azithromycin. Azithromycin effect on systemic markers of inflammation over 18 months was assessed by change from baseline for high-sensitivity C-reactive protein, myeloperoxidase, calprotectin and absolute neutrophil count in the OPTIMIZE population. Subjects treated with chronic azithromycin or placebo had samples collected at baseline, 39 and 78 weeks of treatment. In 129 subjects, a significant decrease in high-sensitivity C-reactive protein was present at 39 weeks in the azithromycin group compared to placebo, but no significant difference between the groups at 78 weeks. No differences in change from baseline in myeloperoxidase, calprotectin or absolute neutrophil count were present at either time point. This supports the concept of a transient immunomodulatory effect for chronic azithromycin therapy in children with CF.

Spirometry is an important tool in the diagnosis and management of pediatric pulmonary diseases. Reference equations enable the comparison of an individual's lung function to that of a healthy reference population of the same age, sex, height, and race/ethnicity. This comparison is important both in distinguishing health from disease and in monitoring the lung function of a growing child over time. A range of reference equations exist, and no single equation is ideal for all situations. However, there are important considerations to understand when choosing an equation. This article reviews how reference equations are created, how to use them to interpret lung function measurements, and how to choose appropriate reference equations, highlights current limitations, and suggests areas for future research and collaboration.

Highly effective CFTR modulator drug therapy is increasingly available to those with cystic fibrosis. Multiple observational research studies are now being conducted to better understand the impacts of this important therapeutic milestone on long-term outcomes, patient care needs, and future research priorities. PROMISE is a large, multi-disciplinary academic study focused on the broad impacts of starting elexacaftor/tezacaftor/ivacaftor in the US population age 6 years and older. The many areas of investigation and rationale for each are discussed by organ systems, along with recognition of remaining important questions that will not be addressed by this study alone. Knowledge gained through this and multiple complementary studies around the world will help to understand important health outcomes, clinical care priorities, and research needs for a large majority of people treated with these or similarly effective medications targeting the primary cellular impairment in cystic fibrosis.

Rationale: In cystic fibrosis (CF), the lung clearance index (LCI), derived from multiple breath washout (MBW), is more sensitive in detecting early lung disease than FEV(1); MBW has been less thoroughly evaluated in young patients with primary ciliary dyskinesia (PCD). Objectives: Our objectives were 1) to evaluate the sensitivity of MBW and spirometry for the detection of mild lung disease in young children with PCD and CF compared with healthy control (HC) subjects and 2) to compare patterns of airway obstruction between disease populations. Methods: We used a multicenter, single-visit, observational study in children with PCD and CF with a forced expiratory volume in 1 second (FEV(1)) greater than 60% predicted and HC subjects, ages 3–12 years. Nitrogen MBW and spirometry were performed and overread for acceptability. χ(2) and Kruskall-Wallis tests compared demographics and lung function measures between groups, linear regression evaluated the effect of disease state, and Spearman’s rank correlation coefficient compared the LCI and spirometric measurements. Results: Twenty-five children with PCD, 49 children with CF, and 80 HC children were enrolled, among whom 17 children with PCD (68%), 36 children with CF (73%), and 53 (66%) HC children performed both acceptable spirometry and MBW; these children made up the analytic cohort. The median age was 9.0 years (interquartile range [IQR], 6.8–11.1). The LCI was abnormal (more than 7.8) in 10 of 17 (59%) patients with PCD and 21 of 36 (58%) patients with CF, whereas FEV(1) was abnormal in three of 17 (18%) patients with PCD and six of 36 (17%) patients with CF. The LCI was significantly elevated in patients with PCD and CF compared with HC subjects (ratio of geometric mean vs. HC: PCD 1.27; 95% confidence interval [CI], 1.15–1.39; and CF 1.24; 95% CI, 1.15–1.33]). Children with PCD had lower midexpiratory-phase forced expiratory flow % predicted compared with children with CF (62% [IQR, 50–78%] vs. 85% [IQR, 68–99%]; P = 0.05). LCI did not correlate with FEV(1). Conclusions: The LCI is more sensitive than FEV(1) in detecting lung disease in young patients with PCD, similar to CF. LCI holds promise as a sensitive endpoint for the assessment of early PCD lung disease.

Background Cystic fibrosis (CF) is an autosomal recessive disease characterized by chronic sinopulmonary symptoms and chronic gastrointestinal symptoms that begins in infancy. Children with CF are increasingly being included in clinical trials. In order to fully evaluate the impact of new therapies in future clinical trials, an understanding of baseline adverse event (AE) rates in children with CF is needed. To address this, we determined the rates of common AEs in pediatric patients with CF who participated in two clinical trials. Methods We reviewed AEs for placebo recipients in the AZ0004 study and inhaled tobramycin recipients in the Early Pseudomonas Infection Control (EPIC) clinical trial. AEs were categorized based on Medical Dictionary for Regulatory Activities (MedDRA) coding classifications and pooled into common, batched AE descriptors. AE rates were estimated from negative binomial models according to age groups, severity of lung disease, and season. Results A total of 433 children had 8,266 total AEs reported, or 18.1 (95% CI 17.0, 19.2) AEs per person per year. Respiratory AEs were the most commonly reported AEs, with a rate of 7.6 events per person-year. The total SAE rate was 0.33 per person per-year. Cough was the most commonly reported respiratory AE, with 61% of subjects reporting at least one episode of cough within 4 months. The rate ratio of any AE was higher in Spring, Fall, and Winter, compared with Summer. Conclusions AEs occur commonly in pediatric CF clinical trial participants. Season of enrollment could affect AE rates.

In primary ciliary dyskinesia, factors leading to disease heterogeneity are poorly understood.To describe early lung disease progression in primary ciliary dyskinesia and identify associations between ultrastructural defects and genotypes with clinical phenotype.This was a prospective, longitudinal (5 yr), multicenter, observational study. Inclusion criteria were less than 19 years at enrollment and greater than or equal to two annual study visits. Linear mixed effects models including random slope and random intercept were used to evaluate longitudinal associations between the ciliary defect group (or genotype group) and clinical features (percent predicted FEVA total of 137 participants completed 732 visits. The group with absent inner dynein arm, central apparatus defects, and microtubular disorganization (IDA/CA/MTD) (n = 41) were significantly younger at diagnosis and in mixed effects models had significantly lower percent predicted FEVParticipants with IDA/MTD/CA defects, which included individuals with CCDC39 or CCDC40 mutations, had worse lung function and growth indices compared with those with outer dynein arm defects and DNAH5 mutations, respectively. The only group with a significant lung function decline over time were participants with IDA/MTD/CA defects.

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: This document presents the American Thoracic Society clinical practice guidelines for the diagnosis of primary ciliary dyskinesia (PCD). Target Audience: Clinicians investigating adult and pediatric patients for possible PCD. Methods: Systematic reviews and, when appropriate, meta-Analyses were conducted to summarize all available evidence pertinent to our clinical questions. Evidence was assessed using the GRADE (Grading of Recommendations, Assessment, Development and Evaluation) approach for diagnosis and discussed by amultidisciplinary panelwith expertise in PCD. Predetermined conflict-of-interest management strategies were applied, and recommendations were formulated, written, and graded exclusively by the nonconflicted panelists. Three conflicted individuals were also prohibited from writing, editing, or providing feedback on the relevant sections of the manuscript. Results: After considering diagnostic test accuracy, confidence in the estimates for each diagnostic test, relative importance of test results studied, desirable and undesirable direct consequences of each diagnostic test, downstream consequences of each diagnostic test result, patient values and preferences, costs, feasibility, acceptability, and implications for health equity, the panel made recommendations for or against the use of specific diagnostic tests as compared with using the current reference standard (transmission electron microscopy and/or genetic testing) for the diagnosis of PCD. Conclusions: The panel formulated and provided a rationale for the direction as well as for the strength of each recommendation to establish the diagnosis of PCD.

Cystic fibrosis (CF) is the most common life-limiting inherited illness of whites. Most of the morbidity and mortality in CF stems from impaired mucociliary clearance leading to chronic, progressive airways obstruction and damage. Significant progress has been made in the care of patients with CF, with advances focused on improving mucociliary clearance, minimizing inflammatory damage, and managing infections; these advances include new antimicrobial therapies, mucolytic and osmotic agents, and antiinflammatory treatments. More recently, researchers have targeted disease-causing mutations using therapies to promote gene transcription and improve channel function, which has led to impressive physiologic changes in some patients. As we develop more advanced, allele-directed therapies for the management of CF, it will become increasingly important to understand the specific genetic and environmental interactions that cause the significant heterogeneity of lung disease seen in the CF population. This understanding of CF endotypes will allow for more targeted, personalized therapies for future patients. This article reviews the genetic and molecular basis of CF lung disease, the treatments currently available, and novel therapies that are in development.

Pulmonary hypertension (PH) is a rare disease in newborns, infants, and children that is associated with significant morbidity and mortality. In the majority of pediatric patients, PH is idiopathic or associated with congenital heart disease and rarely is associated with other conditions such as connective tissue or thromboembolic disease. Incidence data from the Netherlands has revealed an annual incidence and point prevalence of 0.7 and 4.4 for idiopathic pulmonary arterial hypertension and 2.2 and 15.6 for pulmonary arterial hypertension, respectively, associated with congenital heart disease (CHD) cases per million children. The updated Nice classification for PH has been enhanced to include a greater depth of CHD and emphasizes persistent PH of the newborn and developmental lung diseases, such as bronchopulmonary dysplasia and congenital diaphragmatic hernia. The management of pediatric PH remains challenging because treatment decisions continue to depend largely on results from evidence-based adult studies and the clinical experience of pediatric experts. (J Am Coll Cardiol 2013;62:D117–26) a 2013 by the American College of Cardiology Foundation Pulmonary hypertension (PH) can present at any age from infancy to adulthood. The distribution of etiologies in children is quite different than that of adults, with a predominance of idiopathic pulmonary arterial hypertension (IPAH) and PAH associated with congenital heart disease (APAH-CHD) (1–5). In pediatric populations, IPAH is usually diagnosed in its later stages due to nonspecific symptoms. Without appropriate treatments, median survival rate after diagnosis of children with IPAH appears worse when compared with that of adults (6). Therapeutic strategies for adult PAH have not been sufficiently studied in children, especially regarding potential toxicities, formulation, or optimal dosing, and appropriate treatment targets for goal-oriented therapy in children are lacking. Nevertheless, children with PAH are currently treated with targeted PAH drugs and may benefit from these new therapies. This review provides an overview of recent information regarding the current approach and diagnostic classification of PAH in children as based on discussions and recommendations from the Pediatric Task Force of the 5th World Symposium on Pulmonary Hypertension (WSPH) in Nice, France (2013).

The underlying defect in the cystic fibrosis (CF) airway leads to defective mucociliary clearance and impaired bacterial killing, resulting in endobronchial infection and inflammation that contributes to progressive lung disease. Little is known about the respiratory microbiota in the early CF airway and its relationship to inflammation.To examine the bacterial microbiota and inflammatory profiles in bronchoalveolar lavage fluid and oropharyngeal secretions in infants with CF.Infants with CF from U.S. and Australian centers were enrolled in a prospective, observational study examining the bacterial microbiota and inflammatory profiles of the respiratory tract. Bacterial diversity and density (load) were measured. Lavage samples were analyzed for inflammatory markers (interleukin 8, unbound neutrophil elastase, and absolute neutrophil count) in the epithelial lining fluid.Thirty-two infants (mean age, 4.7 months) underwent bronchoalveolar lavage and oropharyngeal sampling. Shannon diversity strongly correlated between upper and lower airway samples from a given subject, although community compositions differed. Microbial diversity was lower in younger subjects and in those receiving daily antistaphylococcal antibiotic prophylaxis. In lavage samples, reduced diversity correlated with lower interleukin 8 concentration and absolute neutrophil count.In infants with CF, reduced bacterial diversity in the upper and lower airways was strongly associated with the use of prophylactic antibiotics and younger age at the time of sampling; less diversity in the lower airway correlated with lower inflammation on bronchoalveolar lavage. Our findings suggest modification of the respiratory microbiome in infants with CF may influence airway inflammation.

Objective Pseudomonas aeruginosa has been suggested as a major determinant of poor pulmonary outcomes in cystic fibrosis (CF), although other factors play a role. Our objective was to investigate the association of early childhood Pseudomonas infection on differences in lung function in adolescence with CF. Methods Two populations of subjects with CF were studied: from the Gene Modifier Study (GMS), 346 F508del homozygotes with severe vs. mild adolescent lung disease, and from the Colorado Newborn Screen Study (NBS) 172 subjects diagnosed with CF by newborn screening. Associations of Pseudomonas infection and lung function in early childhood with lung function in adolescence were investigated using multivariate linear regression analyses. Results Among GMS subjects, those with severe adolescent lung disease had worse lung function in childhood (FEV1 25 percentage points lower) compared to subjects with mild adolescent lung disease, regardless of early childhood Pseudomonas status. Among NBS subjects, those with lowest adolescent lung function had significantly lower early childhood lung function and faster rate of decline in FEV1 than subjects with highest adolescent lung function; early Pseudomonas infection was not associated with rate of FEV1 decline. The strongest predictor of adolescent lung function was early childhood lung function. Subjects with a higher percentage of cultures positive for Pseudomonas before age 6 or a lower BMI at 2–4 years old also had lower adolescent lung function, though these associations were not as strong as with early childhood lung function. Conclusions In separate analyses of two distinct populations of subjects with CF, we found a strong correlation between lower lung function in early childhood and adolescence, regardless of early childhood Pseudomonas status. Factors in addition to early Pseudomonas infection have a strong impact on lung function in early childhood in CF. Further exploration may identify novel underlying genetic or environmental factors that predispose children with CF to early loss of lung function.

Primary ciliary dyskinesia (PCD), a genetically heterogeneous, recessive disorder of motile cilia, is associated with distinct clinical features. Diagnostic tests, including ultrastructural analysis of cilia, nasal nitric oxide measurements, and molecular testing for mutations in PCD genes, have inherent limitations.To define a statistically valid combination of systematically defined clinical features that strongly associates with PCD in children and adolescents.Investigators at seven North American sites in the Genetic Disorders of Mucociliary Clearance Consortium prospectively and systematically assessed individuals (aged 0-18 yr) referred due to high suspicion for PCD. The investigators defined specific clinical questions for the clinical report form based on expert opinion. Diagnostic testing was performed using standardized protocols and included nasal nitric oxide measurement, ciliary biopsy for ultrastructural analysis of cilia, and molecular genetic testing for PCD-associated genes. Final diagnoses were assigned as "definite PCD" (hallmark ultrastructural defects and/or two mutations in a PCD-associated gene), "probable/possible PCD" (no ultrastructural defect or genetic diagnosis, but compatible clinical features and nasal nitric oxide level in PCD range), and "other diagnosis or undefined." Criteria were developed to define early childhood clinical features on the basis of responses to multiple specific queries. Each defined feature was tested by logistic regression. Sensitivity and specificity analyses were conducted to define the most robust set of clinical features associated with PCD.From 534 participants 18 years of age and younger, 205 were identified as having "definite PCD" (including 164 with two mutations in a PCD-associated gene), 187 were categorized as "other diagnosis or undefined," and 142 were defined as having "probable/possible PCD." Participants with "definite PCD" were compared with the "other diagnosis or undefined" group. Four criteria-defined clinical features were statistically predictive of PCD: laterality defect; unexplained neonatal respiratory distress; early-onset, year-round nasal congestion; and early-onset, year-round wet cough (adjusted odds ratios of 7.7, 6.6, 3.4, and 3.1, respectively). The sensitivity and specificity based on the number of criteria-defined clinical features were four features, 0.21 and 0.99, respectively; three features, 0.50 and 0.96, respectively; and two features, 0.80 and 0.72, respectively.Systematically defined early clinical features could help identify children, including infants, likely to have PCD. Clinical trial registered with ClinicalTrials.gov (NCT00323167).

Objective The multiple breath wash-out technique (MBW) that measures lung clearance index (LCI) and functional residual capacity (FRC) may be more sensitive than spirometry for identification of early obstructive airways disease. The open MBW setup using mass spectrometry referenced in previous publications is not readily available in the U.S. Our objective was to assess validity and sensitivity of a commercially available device that uses a closed (rebreathing) setup with photoacoustic spectroscopy for MBW testing. Study Design and Methods Subjects aged 5–21 who were either healthy or had a history of cystic fibrosis were enrolled. Subjects completed MBW (Innocor device; Innovision, Denmark) and spirometry; measures obtained included LCI, FRC, and forced expiratory volume in 1 sec, as well as changes in end-tidal carbon dioxide levels (CO2) and tidal volume during MBW testing. Results Seventeen subjects attempted a total of 76 MBW maneuvers; 80% were completed and 60% met criteria for acceptability; most were unacceptable due to errors in the tracer gas curve. Substantial intra-subject variability for LCI and FRC were noted (mean 26% ± 55 and 36% ± 63, respectively). Subjects were also noted to have significant increases in exhaled CO2 and tidal volume during MBW testing. Conclusions In our initial experience using a commercially available closed setup for MBW testing, we found a significant degree of intra-subject variability leading us to suspend testing. Variability could be due to hypercapnea and instability of tidal breathing secondary to the rebreathing setup. Further studies are needed to better understand the closed system MBW setup. Pediatr Pulmonol. 2012; 47:1242–1250. © 2012 Wiley Periodicals, Inc.

Rationale: Implementation of intervention strategies to prevent lung damage in early cystic fibrosis (CF) requires objective outcome measures that capture and track lung disease.

Background Recent studies have shown the presence of lung disease in even asymptomatic infants with cystic fibrosis (CF). While pulmonary function testing (PFT) is often used to follow progression of lung disease and guide treatment in older children with CF, little data is available on change in infant PFTs in young children with CF. Objective To determine change in infant PFTs before and after antibiotic therapy for pulmonary exacerbation in infants with CF. Methods Retrospective cohort study of infants with CF who underwent clinically indicated infant PFTs before and after antibiotic therapy for CF pulmonary exacerbation at the University of North Carolina at Chapel Hill. Results Pre- and post-antibiotics PFT data was available on 11 infants with CF, with a mean age of 102 weeks at time of first PFT. The majority of infants were symptomatic prior to antibiotics, and showed statistically significant improvement in clinical parameters following treatment. Prior to antibiotics, PFTs showed evidence of substantial obstructive disease (mean z-scores for FVC, FEV0.5, and FEF25-75 of −1.81, −3.06, and −4.5, respectively) and air-trapping/hyperinflation (mean z-scores for FRCpleth, RV, and RV/TLC of 8.86, 7.1, and 3.31, respectively). Following antibiotics, all of the above parameters showed statistically significant improvement. Discussion We have shown a statistically significant improvement in infant PFT measures following antibiotic therapy in a cohort of 11 infants with CF, which paralleled improvement in clinical parameters. Though infant PFTs showed improvement, they remained abnormal in the majority of subjects, with persistent air-trapping and hyperinflation after antibiotic therapy. Our findings suggest that infant PFTs are sensitive to acute clinical changes in children with CF, and may be a useful tool in managing infants with CF. Pediatr Pulmonol. 2012; 47:441–446. © 2011 Wiley Periodicals, Inc.

Rationale Pseudomonas aeruginosa (Pa) is associated with poor pulmonary outcomes in cystic fibrosis (CF), but the association between age of Pa infection and severity of subsequent lung disease has not been thoroughly investigated. Objective Our goal was to determine the association between age of Pa acquisition and subsequent severity of CF lung disease. Methods Case-control study using CF Foundation Registry data of 629 ΔF508 homozygotes with severe and mild lung disease (FEV1 in the lowest and highest quartile of birth cohort, respectively). Multivariate logistic regression was performed to determine the association between age of Pa acquisition and lung disease severity. Results Earlier age of Pa infection was strongly associated with increased odds of severe lung disease. For first and persistent Pa, adjusted odds ratios for severe lung disease were 6.5 (95% CI 3.1, 13.7; P Conclusions Earlier Pa infection, particularly before 5 years of age, is strongly associated with severe CF lung disease later in life. This study is not designed to determine causality; Pa infection may be causing lung injury, or may be a marker of ongoing inflammation and lung damage in young children with CF.

The lung clearance index (LCI) is a lung function parameter derived from the multiple-breath washout (MBW) test. Although first developed 60 years ago, the technique was not widely used for many years. Recent technological advances in equipment design have produced gains in popularity for this test among cystic fibrosis (CF) researchers and clinicians, particularly for testing preschool-aged children. LCI has been shown to be feasible and sensitive to early CF lung disease in patients of all ages from infancy to adulthood. A workshop was convened in January 2014 by the North American Cystic Fibrosis Foundation to determine the readiness of the LCI for use in multicenter clinical trials as well as clinical care. The workshop concluded that the MBW text is a valuable potential outcome measure for CF clinical trials in preschool-aged patients and in older patients with FEV1 in the normal range. However, gaps in knowledge about the choice of device, gas, and standardization across systems are key issues precluding its use as a clinical trial end point in infants. Based on the current evidence, there are insufficient data to support the use of LCI or MBW parameters in the routine clinical management of patients with CF.

Rationale: Although infection contributes to morbidity in patients with cystic fibrosis (CF), the host inflammatory response is also an important cause of progressive pulmonary function deterioration. Quantifying the inflammatory burden in these patients is challenging and often requires invasive procedures. Positron emission tomographic imaging with [18F]fluorodeoxyglucose ([18FDG]) could be used as a noninvasive alternative to quantify lung inflammation. Objective: To determine the relationships among lung [18F]FDG uptake, bronchoalveolar lavage (BAL) neutrophil concentrations, and pulmonary function in patients with CF. Methods: Twenty patients and seven healthy volunteers were studied. A subset of seven patients also consented to undergo BAL. The uptake of [18F]FDG by the lungs was measured as the net influx rate constant Ki. Patients were stratified by rate of decline in pulmonary function into stable, intermediate, and rapidly declining groups. Ki was compared among groups and was correlated against neutrophil concentrations in BAL fluid. Results: Ki was significantly elevated (p < 0.05) among patients with CF as a whole compared with healthy control subjects (0.0015 ± 0.0009 versus 0.0007 ± 0.0002 ml blood/ml lung/min) but especially in patients with rapidly declining pulmonary function (0.0022 ± 0.0011 ml blood/ml lung/min). Ki correlated positively with the number of neutrophils present in BAL fluid. Conclusion: Imaging with [18F]fluorodeoxyglucose and positron emission tomography can be used to assess inflammatory burden in patients with CF. Elevations in Ki may be able to identify patients with more aggressive disease and may be useful in monitoring changes in inflammatory burden in response to novel treatments.

The relationship between clinical phenotype of childhood primary ciliary dyskinesia (PCD) and ultrastructural defects and genotype is poorly defined.To delineate clinical features of childhood PCD and their associations with ultrastructural defects and genotype.A total of 118 participants younger than 19 years old with PCD were evaluated prospectively at six centers in North America using standardized procedures for diagnostic testing, spirometry, chest computed tomography, respiratory cultures, and clinical phenotyping.Clinical features included neonatal respiratory distress (82%), chronic cough (99%), and chronic nasal congestion (97%). There were no differences in clinical features or respiratory pathogens in subjects with outer dynein arm (ODA) defects (ODA alone; n = 54) and ODA plus inner dynein arm (IDA) defects (ODA + IDA; n = 18) versus subjects with IDA and central apparatus defects with microtubular disorganization (IDA/CA/MTD; n = 40). Median FEV1 was worse in the IDA/CA/MTD group (72% predicted) versus the combined ODA groups (92% predicted; P = 0.003). Median body mass index was lower in the IDA/CA/MTD group (46th percentile) versus the ODA groups (70th percentile; P = 0.003). For all 118 subjects, median number of lobes with bronchiectasis was three and alveolar consolidation was two. However, the 5- to 11-year-old IDA/CA/MTD group had more lobes of bronchiectasis (median, 5; P = 0.0008) and consolidation (median, 3; P = 0.0001) compared with the ODA groups (median, 3 and 2, respectively). Similar findings were observed when limited to participants with biallelic mutations.Lung disease was heterogeneous across all ultrastructural and genotype groups, but worse in those with IDA/CA/MTD ultrastructural defects, most of whom had biallelic mutations in CCDC39 or CCDC40.

Cystic fibrosis (CF) is a life-limiting, monogenic disorder characterized by chronic sinopulmonary and gastrointestinal involvement. Progressive pulmonary disease leads to death in the majority of patients. Despite its well-defined molecular basis related to defects in the cystic fibrosis transmembrane conductance regulator anion transport channel, there are large gaps in our understanding of the origin of CF lung disease. Disease has been shown to be present in infancy, and there is mounting evidence that abnormalities begin in utero. Heterogeneity of clinical presentations and severity suggest that many factors involved in lung disease have yet to be fully elucidated. Although new advances in therapeutic treatments have shown promise in delaying disease progression, the prevention of pulmonary disease at its origin (primary prevention) should be a key goal of CF care. The objective of this workshop was to (1) review our understanding of the origins of CF lung disease, (2) determine gaps in the knowledge base that are most significant and most likely to enable prevention of CF lung disease, and (3) prioritize new research questions that will promote pulmonary health in both CF and other childhood lung diseases. The goal of this report is to provide recommendations for future research that will improve our understanding of pulmonary development in health and disease, improve outcome measures and biomarkers for early lung disease, and determine therapeutic targets and strategies to prevent the development of lung disease in children with CF.

Primary ciliary dyskinesia (PCD) is caused when defects of motile cilia lead to chronic airway infections, male infertility, and situs abnormalities. Multiple causative PCD mutations account for only 65% of cases, suggesting that many genes essential for cilia function remain to be discovered. By using zebrafish morpholino knockdown of PCD candidate genes as an in vivo screening platform, we identified c21orf59, ccdc65, and c15orf26 as critical for cilia motility. c21orf59 and c15orf26 knockdown in zebrafish and planaria blocked outer dynein arm assembly, and ccdc65 knockdown altered cilia beat pattern. Biochemical analysis in Chlamydomonas revealed that the C21orf59 ortholog FBB18 is a flagellar matrix protein that accumulates specifically when cilia motility is impaired. The Chlamydomonas ida6 mutant identifies CCDC65/FAP250 as an essential component of the nexin-dynein regulatory complex. Analysis of 295 individuals with PCD identified recessive truncating mutations of C21orf59 in four families and CCDC65 in two families. Similar to findings in zebrafish and planaria, mutations in C21orf59 caused loss of both outer and inner dynein arm components. Our results characterize two genes associated with PCD-causing mutations and elucidate two distinct mechanisms critical for motile cilia function: dynein arm assembly for C21orf59 and assembly of the nexin-dynein regulatory complex for CCDC65.

Defects of motile cilia cause primary ciliary dyskinesia (PCD), characterized by recurrent respiratory infections and male infertility. Using whole-exome resequencing and high-throughput mutation analysis, we identified recessive biallelic mutations in ZMYND10 in 14 families and mutations in the recently identified LRRC6 in 13 families. We show that ZMYND10 and LRRC6 interact and that certain ZMYND10 and LRRC6 mutations abrogate the interaction between the LRRC6 CS domain and the ZMYND10 C-terminal domain. Additionally, ZMYND10 and LRRC6 colocalize with the centriole markers SAS6 and PCM1. Mutations in ZMYND10 result in the absence of the axonemal protein components DNAH5 and DNALI1 from respiratory cilia. Animal models support the association between ZMYND10 and human PCD, given that zmynd10 knockdown in zebrafish caused ciliary paralysis leading to cystic kidneys and otolith defects and that knockdown in Xenopus interfered with ciliogenesis. Our findings suggest that a cytoplasmic protein complex containing ZMYND10 and LRRC6 is necessary for motile ciliary function. © 2013 The American Society of Human Genetics.

RATIONALE: Primary Ciliary Dyskinesia (PCD), a genetic disorder of motile cilia, is associated with a range of clinical features including neonatal respiratory distress, chronic sino-oto-pulmonary disease, and laterality defects. The present “gold standard” diagnostic test, electron microscopic (EM) analysis of cilia, requires specialized technical expertise, is expensive and is not readily available. Genetic testing for PCD is evolving, but detects 0.05 for addition. Odds ratio estimate for each diagnostic criterion was 4.8 (95% confidence limits 2.6-8.6) with #1; 2.8 (1.6-4.9) with #2; 4.4 (2-6-7.3 with #3 and 5.2(3-1-8.8) with #5. Sensitivity and specificity were 0.47 and 0.96 for criteria and 0.92 and 0.61 for criterion. >3 >1 CONCLUSION: Clinical criteria may be useful for defining a PCD diagnosis (if for criteria out of 4 selected are met) and/or directing >3 which individuals warrant further diagnostic testing (if 1 or 2 criteria are met). Validation and cost analysis assessment are needed before utilization in the clinical setting.

The multiple breath wash-out technique (MBW) that measures lung clearance index (LCI) and functional residual capacity (FRC) may be more sensitive than spirometry for identification of early obstructive airways disease. The open MBW setup using mass spectrometry referenced in previous publications is not readily available in the U.S. Our objective was to assess validity and sensitivity of a commercially available device that uses a closed (rebreathing) setup with photoacoustic spectroscopy for MBW testing.Subjects aged 5-21 who were either healthy or had a history of cystic fibrosis were enrolled. Subjects completed MBW (Innocor device; Innovision, Denmark) and spirometry; measures obtained included LCI, FRC, and forced expiratory volume in 1 sec, as well as changes in end-tidal carbon dioxide levels (CO(2) ) and tidal volume during MBW testing.Seventeen subjects attempted a total of 76 MBW maneuvers; 80% were completed and 60% met criteria for acceptability; most were unacceptable due to errors in the tracer gas curve. Substantial intra-subject variability for LCI and FRC were noted (mean 26% ± 55 and 36% ± 63, respectively). Subjects were also noted to have significant increases in exhaled CO(2) and tidal volume during MBW testing.In our initial experience using a commercially available closed setup for MBW testing, we found a significant degree of intra-subject variability leading us to suspend testing. Variability could be due to hypercapnea and instability of tidal breathing secondary to the rebreathing setup. Further studies are needed to better understand the closed system MBW setup.

Recent studies have shown the presence of lung disease in even asymptomatic infants with cystic fibrosis (CF). While pulmonary function testing (PFT) is often used to follow progression of lung disease and guide treatment in older children with CF, little data is available on change in infant PFTs in young children with CF.To determine change in infant PFTs before and after antibiotic therapy for pulmonary exacerbation in infants with CF.Retrospective cohort study of infants with CF who underwent clinically indicated infant PFTs before and after antibiotic therapy for CF pulmonary exacerbation at the University of North Carolina at Chapel Hill.Pre- and post-antibiotics PFT data was available on 11 infants with CF, with a mean age of 102 weeks at time of first PFT. The majority of infants were symptomatic prior to antibiotics, and showed statistically significant improvement in clinical parameters following treatment. Prior to antibiotics, PFTs showed evidence of substantial obstructive disease (mean z-scores for FVC, FEV(0.5) , and FEF(25-75) of -1.81, -3.06, and -4.5, respectively) and air-trapping/hyperinflation (mean z-scores for FRCpleth, RV, and RV/TLC of 8.86, 7.1, and 3.31, respectively). Following antibiotics, all of the above parameters showed statistically significant improvement.We have shown a statistically significant improvement in infant PFT measures following antibiotic therapy in a cohort of 11 infants with CF, which paralleled improvement in clinical parameters. Though infant PFTs showed improvement, they remained abnormal in the majority of subjects, with persistent air-trapping and hyperinflation after antibiotic therapy. Our findings suggest that infant PFTs are sensitive to acute clinical changes in children with CF, and may be a useful tool in managing infants with CF.

Rationale: Pseudomonas aeruginosa (Pa) is associated with poor pulmonary outcomes in cystic fibrosis (CF), but the association between age of Pa infection and severity of subsequent lung disease has not been thoroughly investigated. Objective: Our goal was to determine the association between age of Pa acquisition and subsequent severity of CF lung disease. Methods: Case–control study using CF Foundation Registry data of 629 ΔF508 homozygotes with severe and mild lung disease (FEV1 in the lowest and highest quartile of birth cohort, respectively). Multivariate logistic regression was performed to determine the association between age of Pa acquisition and lung disease severity. Results: Earlier age of Pa infection was strongly associated with increased odds of severe lung disease. For first and persistent Pa, adjusted odds ratios for severe lung disease were 6.5 (95% CI 3.1, 13.7; P < 0.0001) and 11.2 (5.4, 23.1; P < 0.0001), respectively, for subjects with infection before age 5 versus at ≥10 years; the association was stronger in females than males. Conclusions: Earlier Pa infection, particularly before 5 years of age, is strongly associated with severe CF lung disease later in life. This study is not designed to determine causality; Pa infection may be causing lung injury, or may be a marker of ongoing inflammation and lung damage in young children with CF.

Primary ciliary dyskinesia is a genetically heterogeneous disorder of motile cilia. Most of the disease-causing mutations identified to date involve the heavy (dynein axonemal heavy chain 5) or intermediate(dynein axonemal intermediate chain 1) chain dynein genes in ciliary outer dynein arms, although a few mutations have been noted in other genes. Clinical molecular genetic testing for primary ciliary dyskinesia is available for the most common mutations. The respiratory manifestations of primary ciliary dyskinesia (chronic bronchitis leading to bronchiectasis, chronic rhino-sinusitis, and chronic otitis media)reflect impaired mucociliary clearance owing to defective axonemal structure. Ciliary ultrastructural analysis in most patients (>80%) reveals defective dynein arms, although defects in other axonemal components have also been observed. Approximately 50% of patients with primary ciliary dyskinesia have laterality defects (including situs inversus totalis and, less commonly, heterotaxy, and congenital heart disease),reflecting dysfunction of embryological nodal cilia. Male infertility is common and reflects defects in sperm tail axonemes. Most patients with primary ciliary dyskinesia have a history of neonatal respiratory distress, suggesting that motile cilia play a role in fluid clearance during the transition from a fetal to neonatal lung. Ciliopathies involving sensory cilia, including autosomal dominant or recessive polycystic kidney disease, Bardet-Biedl syndrome, and Alstrom syndrome, may have chronic respiratory symptoms and even bronchiectasis suggesting clinical overlap with primary ciliary dyskinesia.

Rationale: Nasal nitric oxide (nNO) is a promising non−invasive screening test for Primary Ciliary Dyskinesia (PCD) in people over 6 years of age. Little is known about how nNO production changes between birth and 6 years. Methods: Using an IRB approved protocol, a chemiluminescence analyzer was used to measure nNO in 162 children less than 6 years (101 healthy controls, 22 with PCD, 24 with asthma, and 15 with cystic fibrosis (CF)). In addition, nNO was measured in 19 healthy normal newborn infants. All patients were tested during tidal breathing with mouth open. Results: Normal newborn infants have very low nNO production at 9.2 ± 3.3 nl/min (mean ± SD) which overlaps with previously reported values for PCD. There is an age−associated increase in nNO in healthy controls (solid circles) and in PCD (open circles) under 6 years of age. After 1 year of age, nNO in PCD children (19.7 ± 13.8 nl/min, range 4.5 − 45) is significantly different from healthy controls (121.1 ± 61.1 nl/min, range 49 − 488.7) (p

Primary ciliary dyskinesia (PCD) is an autosomal recessive disease in which ciliary dysfunction leads to chronic lung, sinus, and middle ear disease. PCD is often not diagnosed until late childhood due to its presumed rarity and the technical expertise necessary for diagnosis; as such, little is known about lung disease in young children with PCD. We report on 3 young children with PCD who had evidence of lung disease on infant pulmonary function testing, bronchoscopy, and/or computed tomography (CT) of the chest before 3 years of age.