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.

Situs Ambiguus Is Associated With Adverse Clinical Outcomes in Children With Primary Ciliary Dyskinesia.

BACKGROUND: Primary ciliary dyskinesia (PCD) is a rare disorder of motile cilia associated with situs abnormalities. At least 12% of patients with PCD have situs ambiguus (SA), including organ laterality defects falling outside normal arrangement (situs solitus [SS]) or mirror image inversion (situs inversus totalis [SIT]). RESEARCH QUESTION: Do patients with PCD and SA achieve worse clinical outcomes compared with those with SS or SIT? STUDY DESIGN AND METHODS: This cross-sectional, multicenter study evaluated participants aged 21 years or younger with PCD. Participants were classified as having SA, including heterotaxy, or not having SA (SS or SIT). Markers of disease severity were compared between situs groups, adjusting for age at enrollment and severe CCDC39 or CCDC40 genotype, using generalized linear models and logistic and Poisson regression. RESULTS: In 397 participants with PCD (mean age, 8.4 years; range, 0.1-21), 42 patients were classified as having SA, including 16 patients (38%) with complex cardiovascular malformations or atrial isomerism, 13 patients (31%) with simple CVM, and 13 patients (31%) without cardiovascular malformations. Of these, 15 patients (36%) underwent cardiac surgery, 24 patients (57%) showed an anatomic spleen abnormality, and seven patients (17%) showed both. The remaining 355 participants did not have SA, including 152 with SIT and 203 with SS. Overall, 70 participants (17%) harbored the severe CCDC39 or CCDC40 genotype. Compared with participants without SA, those with SA showed lower median BMI z scores (P = .03), lower FVC z scores (P = .01), and more hospitalizations and IV antibiotic courses for acute respiratory infections during the 5 years before enrollment (P < .01). Participants with cardiovascular malformations requiring surgery or with anatomic spleen abnormalities showed lower median BMI z scores and more hospitalizations and IV therapies for respiratory illnesses compared with participants without SA. INTERPRETATION: Children with PCD and SA achieve worse nutritional and pulmonary outcomes with more hospitalizations for acute respiratory illnesses than those with SS or SIT combined. Poor nutrition and increased hospitalizations for respiratory infections in participants with SA and PCD are associated with cardiovascular malformations requiring cardiac surgery, splenic anomalies, or both. TRIAL REGISTRY: ClinicalTrials.gov; Nos.: NCT02389049 and NCT00323167; URL: www. CLINICALTRIALS: gov.

Pediatric Pulmonology 2022 year in review: Rare and diffuse lung disease.

The field of rare and diffuse pediatric lung disease continues to evolve and expand rapidly as clinicians and researchers make advancements in the diagnosis and treatment of children's interstitial and diffuse lung disease, non-cystic fibrosis bronchiectasis, and primary ciliary dyskinesia. Papers published on these topics in Pediatric Pulmonology and other journals in 2022 describe newly recognized disorders, elucidate disease mechanisms and courses, explore potential biomarkers, and assess novel treatments. In this review, we will discuss these important advancements and place them in the context of existing literature.

Laterality Defects in Primary Ciliary Dyskinesia: Relationship to Ultrastructural Defect or Genotype.

Rationale: The association between organ laterality abnormalities and ciliary ultrastructural defect or genotype in primary ciliary dyskinesia is poorly understood. Objectives: To determine if there is an association between presence and/or type of laterality abnormality and ciliary ultrastructural defect or genotype. Methods: Participants with primary ciliary dyskinesia in a multicenter, prospective study were grouped based on ciliary ultrastructural defect or genotype. In a retrospective analysis of these data, the association of ciliary ultrastructural defect or genotype and likelihood of a laterality abnormality was evaluated by logistic regression adjusted for presence of two loss-of-function versus one or more not-loss-of-function variants. Results: Of 559 participants, 286 (51.2%), 215 (38.5%), and 58 (10.4%) were identified as having situs solitus, situs inversustotalis, and situs ambiguus, respectively; heterotaxy, defined as situs ambiguus with complex cardiovascular defects, was present in 14 (2.5%). Compared with the group with inner dynein arm defects with microtubular disorganization, laterality defects were more likely in the outer dynein arm defects group (odds ratio [OR], 2.07; 95% confidence interval [CI], 1.21-3.54; P < 0.01) and less likely in the normal/near normal ultrastructure group (OR, 0.04; 95% CI, 0.013-0.151; P < 0.01). Heterotaxy was present in 11 of 242 (4.5%) in the outer dynein arm defects group but 0 of 96 in the inner dynein arm defects with microtubular disorganization group (P = 0.038). Conclusion: In primary ciliary dyskinesia, risk of a laterality abnormality differs by ciliary ultrastructural defect. Pathophysiologic mechanisms underlying these differences require further exploration.

A multi-disciplinary, comprehensive approach to management of children with heterotaxy.

Heterotaxy (HTX) is a rare condition of abnormal thoraco-abdominal organ arrangement across the left-right axis of the body. The pathogenesis of HTX includes a derangement of the complex signaling at the left-right organizer early in embryogenesis involving motile and non-motile cilia. It can be inherited as a single-gene disorder, a phenotypic feature of a known genetic syndrome or without any clear genetic etiology. Most patients with HTX have complex cardiovascular malformations requiring surgical intervention. Surgical risks are relatively high due to several serious comorbidities often seen in patients with HTX. Asplenia or functional hyposplenism significantly increase the risk for sepsis and therefore require antimicrobial prophylaxis and immediate medical attention with fever. Intestinal rotation abnormalities are common among patients with HTX, although volvulus is rare and surgical correction carries substantial risk. While routine screening for intestinal malrotation is not recommended, providers and families should promptly address symptoms concerning for volvulus and biliary atresia, another serious morbidity more common among patients with HTX. Many patients with HTX have chronic lung disease and should be screened for primary ciliary dyskinesia, a condition of respiratory cilia impairment leading to bronchiectasis. Mental health and neurodevelopmental conditions need to be carefully considered among this population of patients living with a substantial medical burden. Optimal care of children with HTX requires a cohesive team of primary care providers and experienced subspecialists collaborating to provide compassionate, standardized and evidence-based care. In this statement, subspecialty experts experienced in HTX care and research collaborated to provide expert- and evidence-based suggestions addressing the numerous medical issues affecting children living with HTX.

Pediatric Pulmonology 2020 year in review: Asthma.

Pediatric asthma is a heterogeneous and common chronic condition with significant morbidity and burden on the healthcare system. Despite advances in the field, the disease has proven to be increasingly complex to diagnose and management strategies are constantly evolving. Studies from 2020 have advanced the field even further, particularly with regard to new methods of diagnosis and monitoring, treatment of severe asthma, modifiable risk factors like exercise and obesity, aerosol delivery, and viral respiratory infections contributing to the development of asthma. Continued studies are needed to improve our care for children with asthma and we look forward to future advances. This article is part of our 2020 "Year in Review" series, in which we summarize publications in major topic areas, in the context of selected literature from other journals relevant to our discipline.

ATS Core Curriculum 2020. Pediatric Pulmonary Medicine.

The American Thoracic Society Core Curriculum updates clinicians annually in adult and pediatric pulmonary disease, medical critical care, and sleep medicine, in a 3- to 4-year recurring cycle of topics. These topics will be presented at the 2020 International Conference. Below is the pediatric pulmonary medicine core, including pediatric hypoxemic respiratory failure; modalities in noninvasive management of chronic respiratory failure in childhood; surgical and nonsurgical management of congenital lung malformations; an update on smoke inhalation lung injury; an update on vaporizers, e-cigarettes, and other electronic delivery systems; pulmonary complications of sarcoidosis; pulmonary complications of congenital heart disease; and updates on the management of congenital diaphragmatic hernia.

Notch regulates BMP responsiveness and lateral branching in vessel networks via SMAD6.

Functional blood vessel growth depends on generation of distinct but coordinated responses from endothelial cells. Bone morphogenetic proteins (BMP), part of the TGFß superfamily, bind receptors to induce phosphorylation and nuclear translocation of SMAD transcription factors (R-SMAD1/5/8) and regulate vessel growth. However, SMAD1/5/8 signalling results in both pro- and anti-angiogenic outputs, highlighting a poor understanding of the complexities of BMP signalling in the vasculature. Here we show that BMP6 and BMP2 ligands are pro-angiogenic in vitro and in vivo, and that lateral vessel branching requires threshold levels of R-SMAD phosphorylation. Endothelial cell responsiveness to these pro-angiogenic BMP ligands is regulated by Notch status and Notch sets responsiveness by regulating a cell-intrinsic BMP inhibitor, SMAD6, which affects BMP responses upstream of target gene expression. Thus, we reveal a paradigm for Notch-dependent regulation of angiogenesis: Notch regulates SMAD6 expression to affect BMP responsiveness of endothelial cells and new vessel branch formation.

The Ras activator RasGRP3 mediates diabetes-induced embryonic defects and affects endothelial cell migration.

RATIONALE: Fetuses that develop in diabetic mothers have a higher incidence of birth defects that include cardiovascular defects, but the signaling pathways that mediate these developmental effects are poorly understood. It is reasonable to hypothesize that diabetic maternal effects are mediated by 1 or more pathways activated downstream of aberrant glucose metabolism, because poorly controlled maternal glucose levels correlate with the frequency and severity of the defects. OBJECTIVE: We investigated whether RasGRP3 (Ras guanyl-releasing protein 3), a Ras activator expressed in developing blood vessels, mediates diabetes-induced vascular developmental defects. RasGRP3 is activated by diacylglycerol, and diacylglycerol is overproduced by aberrant glucose metabolism in diabetic individuals. We also investigated the effects of overactivation and loss of function for RasGRP3 in primary endothelial cells and developing vessels. METHODS AND RESULTS: Analysis of mouse embryos from diabetic mothers showed that diabetes-induced developmental defects were dramatically attenuated in embryos that lacked Rasgrp3 function. Endothelial cells that expressed activated RasGRP3 had elevated Ras-ERK signaling and perturbed migration, whereas endothelial cells that lacked Rasgrp3 function had attenuated Ras-ERK signaling and did not migrate in response to endothelin-1. Developing blood vessels exhibited endothelin-stimulated vessel dysmorphogenesis that required Rasgrp3 function. CONCLUSIONS: These findings provide the first evidence that RasGRP3 contributes to developmental defects found in embryos that develop in a diabetic environment. The results also elucidate RasGRP3-mediated signaling in endothelial cells and identify endothelin-1 as an upstream input and Ras/MEK/ERK as a downstream effector pathway. RasGRP3 may be a novel therapeutic target for the fetal complications of diabetes.