Pediatric Pulmonology 2023 year in review: Rare and diffuse lung disease.

The field of pediatric rare and diffuse lung disease continues its maturation as research advances the understanding of diagnosis and treatment of children's interstitial lung disease, noncystic fibrosis bronchiectasis, and primary ciliary dyskinesia. The rarity and breadth of these conditions make them challenging to study, yet we continue to make progress in our understanding of pathophysiology, genotype/phenotype relationships, and treatment. Papers published on these topics in Pediatric Pulmonology and other journals in 2023 describe the power of multicenter cooperation and patient registries, enhance our understanding of pathophysiology and genotype/phenotype relationships, and report progress in treatments. In this review, we hope to increase awareness and knowledge of these conditions and to inspire future research.

The US national registry for childhood interstitial and diffuse lung disease: Report of study design and initial enrollment cohort.

INTRODUCTION: Childhood interstitial and diffuse lung disease (chILD) encompasses a broad spectrum of rare disorders. The Children's Interstitial and Diffuse Lung Disease Research Network (chILDRN) established a prospective registry to advance knowledge regarding etiology, phenotype, natural history, and management of these disorders. METHODS: This longitudinal, observational, multicenter registry utilizes single-IRB reliance agreements, with participation from 25 chILDRN centers across the U.S. Clinical data are collected and managed using the Research Electronic Data Capture (REDCap) electronic data platform. RESULTS: We report the study design and selected elements of the initial Registry enrollment cohort, which includes 683 subjects with a broad range of chILD diagnoses. The most common diagnosis reported was neuroendocrine cell hyperplasia of infancy, with 155 (23%) subjects. Components of underlying disease biology were identified by enrolling sites, with cohorts of interstitial fibrosis, immune dysregulation, and airway disease being most commonly reported. Prominent morbidities affecting enrolled children included home supplemental oxygen use (63%) and failure to thrive (46%). CONCLUSION: This Registry is the largest longitudinal chILD cohort in the United States to date, providing a powerful framework for collaborating centers committed to improving the understanding and treatment of these rare disorders.

Effect of Hypertonic Saline on Lung Function as Add-on Treatment in People With Cystic Fibrosis Receiving Dornase Alfa: A Cystic Fibrosis Foundation Patient Registry Analysis.

BACKGROUND: Introduction of novel therapies for cystic fibrosis (CF) raises the question of whether traditional treatments can be withdrawn. Nebulized hypertonic saline (HS) potentially could be discontinued in patients receiving dornase alfa (DA). RESEARCH QUESTION: In the era before modulators, did people with CF who are F508del homozygous (CFF508del) and who received DA and HS have better preserved lung function than those treated with DA only? STUDY DESIGN AND METHODS: Retrospective analysis of the Cystic Fibrosis Foundation Patient Registry data (2006-2014). Among 13,406 CFF508del with data for at least 2 consecutive years, 1,241 CFF508del had spirometry results and were treated with DA for 1 to 5 years without DA or HS during the preceding (baseline) year. Absolute FEV1 % predicted change while receiving DA and HS, relative to treatment with DA only, was the main outcome. A marginal structural model was applied to assess the effect of 1 to 5 years of HS treatment while controlling for time-dependent confounding. RESULTS: Of 1,241 CFF508del, 619 patients (median baseline age, 14.6 years; interquartile range, 6-53 years) received DA only and 622 patients (median baseline age, 14.55 years; interquartile range, 6-48.1 years) were treated with DA and HS for 1 to 5 years. After 1 year, patients receiving DA and HS showed FEV1 % predicted that averaged 6.60% lower than that in patients treated with DA only (95% CI, -8.54% to -4.66%; P < .001). Lower lung function in the former relative to the latter persisted throughout follow-up, highlighting confounding by indication. After accounting for baseline age, sex, race, DA use duration, baseline and previous year's FEV1 % predicted, and time-varying clinical characteristics, patients treated with DA and HS for 1 to 5 years were similar to those treated with DA only regarding FEV1 % predicted (year 1: mean FEV1 % predicted change, +0.53% [95% CI, -0.66% to +1.71%; P = .38]; year 5: mean FEV1 % predicted change, -1.82% [95% CI, -4.01% to +0.36%; P = .10]). INTERPRETATION: In the era before modulators, CFF508del showed no significant difference in lung function when nebulized HS was added to DA for 1 to 5 years.

Growth trajectories and oxygen use in neuroendocrine cell hyperplasia of infancy.

RATIONALE: Neuroendocrine cell hyperplasia of infancy (NEHI) typically presents in infancy with tachypnea, retractions, and hypoxemia. Some infants have failure to thrive, yet the frequency of this and other non-respiratory phenotypic features have not been delineated. While gradual improvement occurs, the clinical course is variable and the duration of supplemental oxygen requirement has not been defined. OBJECTIVES: Our objective was to identify factors in NEHI that may drive differences in clinical course. We hypothesized that failure to thrive would be associated with greater duration of supplemental oxygen use. METHODS: Children with NEHI were identified as a nested retrospective cohort within an ongoing observational prospective study. An electronic questionnaire evaluating health status was distributed to the parents/guardians. Clinical data were obtained via chart review and parent interview. RESULTS: Of 42 children, 74% had a diagnosis of failure to thrive during their clinical course. Time to event analysis demonstrated that 50% discontinued daytime and nighttime oxygen at 32 and 87.5 months after initiation, respectively. Diagnosis of failure to thrive was associated with longer continuous oxygen supplementation, P = 0.03. Additional parental concerns identified through the electronic questionnaire included developmental delays, multiple hospitalizations, and delays in diagnosis. CONCLUSIONS: NEHI is associated with substantial respiratory and extra-pulmonary morbidity. Failure to thrive may be associated with greater respiratory morbidity, though further studies are required to define this interaction. Determining the association of these comorbidities and respiratory course in NEHI may enable development of strategies to improve these modifiable factors and potentially pulmonary outcomes.

Teaming Up for Asthma Control: EPR-3 Compliant School Program in Missouri Is Effective and Cost-Efficient.

INTRODUCTION: Teaming Up for Asthma Control (TUAC) is a work force development intervention to improve asthma control among children by increasing the competency of school nurses and delivering guideline-based education. We hypothesized that the knowledge and skills of participating school nurses would improve and that this change would positively affect students' asthma health and reduce health care utilization cost. METHODS: Asthma education for school nurses was provided online in a pretest/posttest format or in instructor-led groups. Students with persistent asthma were identified by using a checklist. Expert evaluators obtained student participants' preassessments/postassessments before and after the 3 asthma checkups by the school nurse, and the assessments were compared. Health care costs were assessed using Medicaid administrative claims data. RESULTS: A total of 54 school nurses and 178 students in Missouri participated in the TUAC evaluation from 2011 through 2014. Among school nurses who completed the online education (n = 42, 77.8%), knowledge scores significantly increased from pretest (49.1%) to posttest (90.7%, P < .001). Of school nurses who completed assessments on 3 children (n = 34), 91.2% met the ±6% equivalence for 1 or more assessments on forced expiratory volume in 1 second (FEV1) compared with the expert evaluator. At enrollment, 69.7% of students had "not well-controlled" or "very poorly controlled" asthma. Postintervention, FEV1 significantly improved (82.9% to 92.1% predicted), and self-reported impairment and tobacco smoke exposure significantly declined (P < .001). For TUAC students enrolled in Medicaid, there was an average 12-month health care cost difference (-$1,431) compared with controls. CONCLUSION: School nurses effectively assessed asthma status, students' outcomes improved, and health care utilization costs declined. This evaluation contributed to program improvements to further improve health outcomes among students with asthma.

Persistent Lung Disease in Adults with NKX2.1 Mutation and Familial Neuroendocrine Cell Hyperplasia of Infancy.

RATIONALE: Neuroendocrine cell hyperplasia of infancy (NEHI) is a diffuse lung disease that presents in infancy and improves during childhood. Long-term outcomes have not previously been described. In one familial cohort, we have reported that NEHI is associated with a heterozygous variant of NKX2.1/TTF1. OBJECTIVES: Our objective was to determine whether pulmonary abnormalities persist in adults with NEHI, to aid in elucidating the natural history of this disease. METHODS: Four adult relatives with heterozygous NKX2.1 mutation and with clinical histories compatible with NEHI enrolled in a prospective study that included questionnaires, pulmonary function tests, and chest computed tomography scans. MEASUREMENTS AND MAIN RESULTS: Mild radiologic abnormalities including mosaicism were seen in all four cases. Three individuals had obstruction on pulmonary function tests, two had marked air trapping, and three had symptomatic impairments with exercise intolerance. CONCLUSIONS: Although clinical improvement occurs over time, NEHI may result in lifelong pulmonary abnormalities in some cases. Further studies are required to better describe the natural history of this disease and would be facilitated by additional delineation of genetic mechanisms to enable improved case identification.