Interstitial Lung Disease In Children Research Articles

Pediatric interstitial lung disease

Interstitial lung disease in children (chILD) is rare and encompasses more than 200 entities, with new especially genetic causes being discovered. Several classifications have been proposed, and there is considerable overlap with entities which present in adult life. Presentation may be shortly after birth with acute respiratory distress and in infancy and childhood either with a primary respiratory presentation or with systemic symptoms such as poor feeding and failure to thrive. Newborn acute presentations are usually due either to a mutation in one of the surfactant protein (Sp) genes or the alveolar capillary dysplasia (ACD)-congenital alveolar dysplasia (CAD) spectrum. The latter usually progress rapidly to extracorporeal membrane oxygenation, and early lung biopsy is advisable to prevent prolonged futile treatment being offered. Outside the newborn period, a staged protocol for investigation is proposed. This starts with a computed tomography scan, which confirms or otherwise the presence of chILD, and occasionally can lead to a specific diagnosis. In particular in settings where there is a high burden of infection, infective mimics of chILD need to be excluded. The next investigations aim to try to move from pattern recognition to specific diagnoses, both genetic and environmental. The speed of progression to lung biopsy will depend on the clinical state of the child, and the biopsy itself may suggest a hunt for a new underlying cause, such as immunodeficiency. Specific genetic causing chILD includes mutations in SpB and SpC and processing genes (thyroid transcription factor-1 [TTF-1] and adenosine triphosphate-binding cassette subfamily A) (the last three can present at any time in the life course); genes involved in Sp catabolism (granulocyte-macrophage colony factor receptor A and B genes), an increasing number implicated in the ACD-CAD spectrum, and other non-Sp related genes such as Filamin-A and integrin genes. Environmental causes are also important and vary across the world. Vaping has been implicated as causing a large number of chILDs, and a vaping history is essential in any young person with an unusual respiratory illness. Medications, both prescribed and over-the-counter such as oily laxatives, are also causes of chILD. There are important conditions of unknown cause presenting in early childhood. Neuroendocrine cell hyperplasia of infancy (NEHI) and pulmonary interstitial glycogenosis generally have a good prognosis, and are probably best considered as part of a spectrum of pulmonary dysmaturity syndromes, in some of which underlying gene mutations have been detected, for example, TTF-1 for NEHI. Pulmonary alveolar proteinosis is an example of an umbrella description, which may present at any age, and has a number of underlying causes with different specific treatments, underscoring the need to move from pattern recognition to specific diagnoses. chILDs have important implications for adult physicians; there may be late as yet poorly described sequelae of the disease or its treatment in adult life; there may be genetic implications for the wider family; and there may be late chILD relapses. Smooth transition to adult services is essential for all chILD survivors, with pediatric and adult chest physicians working closely together.

Sleep in children and young adults with interstitial and diffuse lung disease

ObjectiveObstructive sleep apnea (OSA) is common in adult patients with interstitial lung disease (ILD). The aim of the study was to evaluate the prevalence of OSA and sleep quality in children and young adults with children's interstitial and diffuse lung disease (chILD). MethodsA polysomnography (PSG) was performed in room air in all consecutive patients followed at a national reference centre between June 2018 and September 2019. Clinical and PSG data were collected. ResultsThe PSG data of 20 patients (12 girls, median age 9 (range 0.5–20) years), were analyzed. Seven (35%) patients had pulmonary alveolar proteinosis (PAP), 5 (25%) a disorder of surfactant metabolism, 3 (15%) diffuse pulmonary hemorrhage, 4 (20%) chILD of unknown etiology and one patient had laryngeal and pulmonary sarcoidosis. The median obstructive apnea-hypnea index (OAHI) was normal at 0 events/hour, with a value > 4 events/hour being observed in 2 young adults: an 18-year-old male with PAP and a vital capacity of 27% predicted who had an OAHI of 10.7 events/hour, and a 20-year-old male with laryngeal and pulmonary sarcoidosis who had positional OSA with an OAHI of 19.5 events/hour. The median total sleep time, sleep efficiency, % of wake after sleep onset, and sleep stages were moderately disturbed. ConclusionsModerate or severe OSA was not observed in children <18 years with chILD. Mild or moderate OSA was observed in 2 young adults with PAP and sarcoidosis. As opposed to adults, OSA seems uncommon in children with chILD.

Environmental hazards and demographic and clinical data of childhood interstitial lung diseases in a tertiary institute in Egypt

BackgroundThe incidence of childhood interstitial lung diseases increased in the last years in Egypt. Changes in environmental and climatic conditions may be contributing factors. Also, raising birds at home increased in the past years due to financial issues. Other environmental factors include increased industries, traffic, and pollution. Our study aimed to assess the environmental hazards and the severity of childhood interstitial lung diseases.ResultsSixty-five percent of patients with childhood interstitial lung diseases (chILD) were exposed to cigarette smoke; 45% were exposed to birds, 30% to industrial wastes, 20% to grass and pesticides, and 10% to animals.ConclusionsExposure to cigarette smoke and birds increases the risk of development of chILD.

Childhood interstitial lung disease: A case-based review of the imaging findings.

Childhood interstitial lung disease (chILD) consists of a large, heterogeneous group of individually rare disorders. chILD demonstrates major differences in disease etiology, natural history, and management when compared with the adult group. It occurs primarily secondary to an underlying developmental or genetic abnormality affecting the growth and maturity of the pediatric lung. They present with different clinical, radiologic, and pathologic features. In this pictorial review article, we will divide chILD into those more prevalent in infancy and those not specific to infancy. We will use a case based approach to discuss relevant imaging findings including modalities such as radiograph and computed tomography in a wide variety of pathologies.

Lung involvement in monogenic interferonopathies.

Monogenic type I interferonopathies are inherited heterogeneous disorders characterised by early onset of systemic and organ specific inflammation, associated with constitutive activation of type I interferons (IFNs). In the last few years, several clinical reports identified the lung as one of the key target organs of IFN-mediated inflammation. The major pulmonary patterns described comprise children's interstitial lung diseases (including diffuse alveolar haemorrhages) and pulmonary arterial hypertension but diagnosis may be challenging. Respiratory symptoms may be either mild or absent at disease onset and variably associated with systemic or organ specific inflammation. In addition, associated extrapulmonary clinical features may precede lung function impairment by years, and patients may display severe/endstage lung involvement, although this may be clinically hidden during the long-term disease course. Conversely, a few cases of atypical severe lung involvement at onset have been reported without clinically manifested extrapulmonary signs. Hence, a multidisciplinary approach involving pulmonologists, paediatricians and rheumatologists should always be considered when a monogenic interferonopathy is suspected. Pulmonologists should also be aware of the main pattern of presentation to allow prompt diagnosis and a targeted therapeutic strategy. In this regard, promising therapeutic strategies rely on Janus kinase-1/2 (JAK-1/2) inhibitors blocking the type I IFN-mediated intracellular cascade.

ТРАНСПЛАНТАЦИЯ ЛЕГКИХ У ПОДРОСТКА С ЛЕГОЧНЫМ ФИБРОЗОМ В ИСХОДЕ ИНТЕРСТИЦИАЛЬНОЙ БОЛЕЗНИ ЛЕГКИХ (ГИПЕРСЕНСИТИВНОГО ПНЕВМОНИТА)

Interstitial lung disease (ILD) is a large group of diseases with a severe course and, as a rule, an unfavorable prognosis, since irreversible pulmonary fibrosis forms in the outcome of most ILD. Among ILD in children and adolescents, hypersensitivity pneumonitis (HP) is of significant clinical importance. The clinical observation presented in the article demonstrates the first successful experience in our country (2018) of transplanting both lungs to an adolescent with pulmonary fibrosis resulting from the HP chronic course. Lung transplantation has become the only way to prolong the patient's life.

Children's Interstitial and Diffuse Lung Diseases (ChILD) in 2020.

The term children interstitial lung diseases (chILD) refers to a heterogeneous group of rare diseases that diffusely affect the lung. ChILD specific to children younger than 2 years of age include diffuse developmental disorders, growth abnormalities, specific conditions of undefined etiology (neuroendocrine cell hyperplasia of infancy and pulmonary interstitial glycogenosis) and surfactant protein disorders. Clinical manifestations are highly variable, ranging from the absence of relevant symptoms to a severe onset. Most commonly, chILD presents with nonspecific respiratory signs and symptoms, such as dyspnea, polypnea, dry cough, wheezing, recurrent respiratory infections and exercise intolerance. In the diagnostic approach to a child with suspected ILD, chest high resolution computed tomography and genetic tests play a central role. Then, if the diagnosis remains uncertain, laryngotracheal-bronchoscopy and lung biopsy are needed. Pharmacological treatment is mostly empiric and based on anti-inflammatory and immunomodulatory drugs including corticosteroids, hydroxychloroquine and azithromycin. Despite chILD overall rarity, pediatric pulmonologists must be familiar with these diseases in order to carry out a timely diagnosis and patient treatment.

Rare health conditions 41: Childhood interstitial lung disease or ChILD, Neuroblastoma and Ehlers-Danlos syndromes

The purpose of this series is to highlight a range of rare health conditions. Rare health conditions are those that affect no more and usually less than 1 person in every 2000 and many healthcare assistants and nurses will encounter some of these conditions, given the high number of them. This 41st article will explore three of these conditions: childhood interstitial lung disease or ChILD, neuroblastoma and Ehlers-Danlos syndromes.

Clinical characteristics of connective tissue disease associated interstitial lung disease in children

Objective: To elucidate the clinical features of connective tissue disease associated interstitial lung disease (CTD-ILD) in children. Methods: A total of 24 children diagnosed with CTD-ILD and treated in Department of Rheumatology and Immunology, Shanghai Children's Medical Center from January 2010 to December 2019 were included in the study. Their medical data including clinical features, lab test, imaging, pulmonary function test, treatment and outcome were analyzed statistically. Results: In these 24 patients, 4 were males and 20 females. Their main clinical presentations were cough (10/24, 42%), shortness of breath (10/24, 42%), tachycardia in quiet state (8/24, 33%), fatigue with activity (7/24, 29%), and fever (6/24, 25%). The main abnormal physical examination findings were moist rales (4/24, 17%) and acropachy (2/24, 8%). There were various abnormal findings in the patients' lab test. All the patients (100%) had pulmonary interstitial changes on chest CT. Eight patients had spirometry test, and all (100%) showed decreased diffusion capacity. After immunosuppressive treatment, 15 cases (63%) improved, 4 cases (17%) gave up or died, while 5 cases (21%) had no significant improvement on the imaging examination. Conclusions: The onset of pediatric CTD-ILD could be insidious. Early diagnosis and aggressive treatment may change the prognosis, but are both difficult and need further studies.

CHILDHOOD-ONSET INTERSTITIAL LUNG DISEASE: A RARE CASE OF IDIOPATHIC, NONSPECIFIC INTERSTITIAL PNEUMONIA IN A TEENAGER

SESSION TITLE: Fellows Diffuse Lung Disease SESSION TYPE: Fellow Case Reports PRESENTED ON: October 18-21, 2020 INTRODUCTION: Childhood interstitial lung disease (chILD) is remarkably rare with a reported prevalence from 0.13 per 100,000 children under 17 years to 16.2 per 100,000 children under 15 years of age (1). Here we present a case of a teenager with idiopathic nonspecific interstitial pneumonia (NSIP). CASE PRESENTATION: A 15-year old previously healthy female presented with a three-week history of dry cough, fever, malaise and shortness of breath which progressed to dyspnea on exertion despite a course of outpatient antibiotics. She had no environmental exposures, history of smoking or vaping nor family history of pulmonary pathology. Initial vital signs were significant for hypoxemia to 80% and a chest x-ray and CT scan with bilateral consolidations and ground glass opacities. Initial laboratory tests showed elevated inflammatory markers, other tests including SARS-CoV-2 PCR were negative . Bronchoscopy, bronchoalveolar lavage, and transbronchial biopsies yielded no definitive diagnosis. Following bronchoalveolar lavage, she developed rapid clinical deterioration necessitating mechanical ventilation, paralytics, and inhaled nitric oxide. Given elevated inflammatory markers and after infection was excluded, intravenous steroids were initiated with partial improvement. After extubation, a protracted inability to wean off oxygen support, and spirometry showing ongoing, severe restrictive lung disease, lung biopsy via video-assisted thorascopic surgery was performed lending to the ultimate diagnosis NSIP. Hypersensitivity pneumonitis panel, ILD panel and genetic testing were unrevealing, as such her case was classified as idiopathic NSIP. DISCUSSION: NSIP in adolescents is very rare. A meta-analysis (2) reports the average age of patients with NSIP to be 54.8 years. In the pediatric population, NSIP can be associated with systemic disease processes such as collagen vascular disease, including systemic lupus erythematosus, juvenile rheumatoid arthritis, and dermatomyositis associated with antibodies to melanoma differentiation-associated gene 5 (anti-MDA5), as well as a complication of blood stem cell transplants and surfactant dysfunction mutations, although most cases are idiopathic (3). Given that the etiology of NSIP is broad and in most cases idiopathic, response to corticosteroids is also variable. Our patient had a partial response to corticosteroids early on in her treatment, manifested by augmented gas exchange and improved symptomatology. The relatively slow response to treatment in the first several weeks is likely consistent with her biopsy findings which showed fibroblast proliferation and fibrosis. CONCLUSIONS: ILD and particularly NSIP are rare conditions in adolescents but should be suspected in patients with hypoxemia and abnormal imaging in the absence of infectious or autoimmune etiologies. An extensive workup is recommended to determine association with systemic conditions, treatment and prognosis. Reference #1: (1) Griese M, Haug M, Brasch F, et al. Incidence and classification of pediatric diffuse parenchymal lung diseases in Germany. Orphanet J Rare Dis. 2009;4:26. Published 2009 Dec 12. doi:10.1186/1750-1172-4-26 Reference #2: (2) Ebner L, Christodoulidis S, Stathopoulou T, et al. Meta-analysis of the radiological and clinical features of Usual Interstitial Pneumonia (UIP) and Nonspecific Interstitial Pneumonia (NSIP). PLoS One. 2020;15(1):e0226084. Published 2020 Jan 13. doi:10.1371/journal.pone.0226084 Reference #3: (3) Vece TJ, Fan LL. Interstitial Lung Disease in Children Older Than 2 Years. Pediatr Allergy Immunol Pulmonol. 2010;23(1):33-41. doi:10.1089/ped.2010.0008 DISCLOSURES: No relevant relationships by Giuliana Cerro, source=Web Response No relevant relationships by Gary Goulin, source=Web Response No relevant relationships by Jack Green, source=Web Response No relevant relationships by Michael Lewis, source=Web Response No relevant relationships by Tim Shen, source=Web Response

Interstitial Lung Disease in Children With Selected Primary Immunodeficiency Disorders-A Multicenter Observational Study.

Primary immunodeficiencies (PIDs) are rare disorders of the immune system encompassing inborn errors of immunity. Primary antibody deficiencies constitute the largest group of PID with common variable immunodeficiency (CVID) being the most common symptomatic form. Combined immunodeficiencies (CID) accompanied by antibody deficiency can mimic CVID and these patients need the verification of the final diagnosis. Respiratory involvement, especially interstitial lung disease (ILD), poses a relevant cause of morbidity and mortality among patients with PID and in some cases is the first manifestation of immunodeficiency. In this study we present a retrospective analysis of a group of children with primary immunodeficiency and ILD - the clinical, radiological, histological characteristics, treatment strategies and outcomes. Eleven children with PID-related ILD were described. The majority of them presented CVID, in three patients CID was recognized. All patients underwent detailed pulmonary diagnostics. In eight of them histological analysis of lung biopsy was performed. We noted that in two out of 11 patients acute onset of ILD with respiratory failure was the first manifestation of the disease and preceded PID diagnosis. The most common histopathological diagnosis was GLILD. Among the analyzed patients three did not require any immunosuppressive therapy. All eight treated children received corticosteroids as initial treatment, but in some of them second-line therapy was introduced. The relevant side effects in some patients were observed. The study demonstrated that the response to corticosteroids is usually prompt. However, the resolution of pulmonary changes may be incomplete and second-line treatment may be necessary.

Pulmonary function testing in children's interstitial lung disease.

The use of pulmonary function tests (PFTs) has been widely described in airway diseases like asthma and cystic fibrosis, but for children's interstitial lung disease (chILD), which encompasses a broad spectrum of pathologies, the usefulness of PFTs is still undetermined, despite widespread use in adult interstitial lung disease. A literature review was initiated by the COST/Enter chILD working group aiming to describe published studies, to identify gaps in knowledge and to propose future research goals in regard to spirometry, whole-body plethysmography, infant and pre-school PFTs, measurement of diffusing capacity, multiple breath washout and cardiopulmonary exercise tests in chILD. The search revealed a limited number of papers published in the past three decades, of which the majority were descriptive and did not report pulmonary function as the main outcome.PFTs may be useful in different stages of management of children with suspected or confirmed chILD, but the chILD spectrum is diverse and includes a heterogeneous patient group in all ages. Research studies in well-defined patient cohorts are needed to establish which PFT and outcomes are most relevant for diagnosis, evaluation of disease severity and course, and monitoring individual conditions both for improvement in clinical care and as end-points in future randomised controlled trials.

Functional Genomics of ABCA3 Variants.

Rare or private, biallelic variants in the ABCA3 (ATP-binding cassette transporter A3) gene are the most common monogenic cause of lethal neonatal respiratory failure and childhood interstitial lung disease. Functional characterization of fewer than 10% of over 200 disease-associated ABCA3 variants (majority missense) suggests either disruption of ABCA3 protein trafficking (type I) or of ATPase-mediated phospholipid transport (type II). Therapies remain limited and nonspecific. A scalable platform is required for functional characterization of ABCA3 variants and discovery of pharmacologic correctors. To address this need, we first silenced the endogenous ABCA3 locus in A549 cells with CRISPR/Cas9 genome editing. Next, to generate a parent cell line (A549/ABCA3-/-) with a single recombination target site for genomic integration and stable expression of individual ABCA3 missense variant cDNAs, we used lentiviral-mediated integration of a LoxFAS cassette, FACS, and dilutional cloning. To assess the fidelity of this cell-based model, we compared functional characterization (ABCA3 protein processing, ABCA3 immunofluorescence colocalization with intracellular markers, ultrastructural vesicle phenotype) of two individual ABCA3 mutants (type I mutant, p.L101P; type II mutant, p.E292V) in A549/ABCA3-/- cells and in both A549 cells and primary, human alveolar type II cells that transiently express each cDNA after adenoviral-mediated transduction. We also confirmed pharmacologic rescue of ABCA3 variant-encoded mistrafficking and vesicle diameter in A549/ABCA3-/- cells that express p.G1421R (type I mutant). A549/ABCA3-/- cells provide a scalable, genetically versatile, physiologically relevant functional genomics platform for discovery of variant-specific mechanisms that disrupt ABCA3 function and for screening of potential ABCA3 pharmacologic correctors.

Antineutrophil Cytoplasmic Antibodies Negative Microscopic Polyangiitis With Initial Pulmonary Manifestation

Microscopic polyangiitis (MPA) is a small vessel vasculitides mostly associated with anti-neutrophil cytoplasmic antibodies (ANCA). The kidney is the most commonly affected organ in MPA. We report the case of a 9-year-old girl with ANCA-negative MPA who initially presented with respiratory symptoms, including cough, sputum, and dyspnea. Based on her symptoms, atypical pneumonia was suspected. Also, childhood interstitial lung disease was considered based on findings seen on chest CT. Despite initial improvement of symptoms with oral corticosteroid therapy, dyspnea with initiation of corticosteroid tapering was noted. A final diagnosis of MPA was made after lung biopsy. ANCA was negative in both the initial and repeat blood tests. Oral cyclophosphamide and prednisolone treatments led to full remission. Since then, the patient has been treated with low dose prednisolone and azathioprine for maintenance. A good treatment response was achieved and her clinical symptoms, pulmonary functions, and radiologic findings have since improved. Thus, early and precise diagnosis of MPA is crucial for remission induction and prevention of symptom relapse. (J Rheum Dis 2020;27:203-208)

Variation in the bombesin staining of pulmonary neuroendocrine cells in pediatric pulmonary disorders-A useful marker for airway maturity.

Pulmonary neuroendocrine cells (NEC) increase with age due to pulmonary maturity. The aim of this study was to determine whether open lung biopsies from patients with interstitial lung diseases have increased pulmonary NEC compared with neuroendocrine cell hyperplasia of infancy (NEHI). Our second aim was to assess pulmonary NECs in the lung autopsy of children without lung disease who died from different causes. Lung tissue of 5 infants with NEHI; 21 patients with pediatric interstitial lung disease (chILD); 17 lung autopsies of infants at varying age without lung disease were included. The percentage of the airways containing neuroendocrine cells, the average percentage of neuroendocrine cells (NECs) per airway, and the number of neuroendocrine bodies (NEBs) in each case were analyzed. The mean percentage of the airways containing neuroendocrine cells were 95% in the NEHI group, 30% in the chILD group, 89% under Intrauterine 37 weeks, 70% between intrauterine 37 to 40 weeks, 52% at postnatal 4 days to 6 months of autopsy ages. In theNEHI group, diffuse NE cell distribution and large NEBs were noticed in the lung biopsy. In thechILD group, neuroendocrine cells were dispersed, did not form clusters and NE cells showed solitary distribution. In thelung autopsy group, linear NE cells were detected at younger aged fetuses and solitary distribution of NE cells was detected with the older increasing age. Our findings confirm that NECs are seen in many other childhood interstitial lung diseases; NE cell hyperplasia may be a marker of decreased pulmonary development and NE cells decrease with the increasing age of the fetus during Intrauterine life.

Overview of the ChILD Research Network: A roadmap for progress and success in defining rare diseases.

Children's interstitial and diffuse lung diseases are a diverse group of rare lung disorders that present in childhood with diffuse pulmonary infiltrates and respiratory signs and symptoms. Children with these disorders face high morbidity and mortality and their families must cope with overwhelming uncertainty. Physicians caring for these patients are challenged by a paucity of directed therapies, or even understanding of natural history. Through the establishment of the Children's Interstitial Lung Disease Foundation Research Network and the Children's Interstitial Lung Disease Foundation significant progress has been made through collaboration and research. This review outlines the past and current successes in the new and rapidly growing field of Children's Interstitial and Diffuse Lung Disease.

Interstitial lung diseases in children

Interstitial lung disease (ILD) in children (chILD) is a heterogeneous group of rare respiratory disorders that are mostly chronic and associated with high morbidity and mortality. The pathogenesis of the various chILD is complex and the diseases share common features of inflammatory and fibrotic changes of the lung parenchyma that impair gas exchanges. The etiologies of chILD are numerous. In this review, we chose to classify them as ILD related to exposure/environment insults, ILD related to systemic and immunological diseases, ILD related to primary lung parenchyma dysfunctions and ILD specific to infancy. A growing part of the etiologic spectrum of chILD is being attributed to molecular defects. Currently, the main genetic mutations associated with chILD are identified in the surfactant genes SFTPA1, SFTPA2, SFTPB, SFTPC, ABCA3 and NKX2-1. Other genetic contributors include mutations in MARS, CSF2RA and CSF2RB in pulmonary alveolar proteinosis, and mutations in TMEM173 and COPA in specific auto-inflammatory forms of chILD. However, only few genotype-phenotype correlations could be identified so far. Herein, information is provided about the clinical presentation and the diagnosis approach of chILD. Despite improvements in patient management, the therapeutic strategies are still relying mostly on corticosteroids although specific therapies are emerging. Larger longitudinal cohorts of patients are being gathered through ongoing international collaborations to improve disease knowledge and targeted therapies. Thus, it is expected that children with ILD will be able to reach the adulthood transition in a better condition.

Neuroendocrine Cell Hyperplasia of Infancy. Clinical Score and Comorbidities.

Rationale: Neuroendocrine cell hyperplasia of infancy (NEHI) is an important form of children's interstitial and diffuse lung disease for which the diagnostic strategy has evolved. The prevalence of comorbidities in NEHI that may influence treatment has not been previously assessed.Objectives: To evaluate a previously unpublished NEHI clinical score for assistance in diagnosis of NEHI and to assess comorbidities in NEHI.Methods: We performed a retrospective chart review of 199 deidentified patients with NEHI from 11 centers. Data were collected in a centralized Research Electronic Data Capture registry and we performed descriptive statistics.Results: The majority of patients with NEHI were male (66%). The sensitivity of the NEHI Clinical Score was 87% (95% confidence interval [CI], 0.82-0.91) for all patients from included centers and 93% (95% CI, 0.86-0.97) for those with complete scores (e.g., no missing data). Findings were similar when we limited the population to the 75 patients diagnosed by lung biopsy (87%; 95% CI, 0.77-0.93). Of those patients evaluated for comorbidities, 51% had gastroesophageal reflux, 35% had aspiration or were at risk for aspiration, and 17% had evidence of immune system abnormalities.Conclusions: The NEHI Clinical Score is a sensitive tool for clinically evaluating NEHI; however, its specificity has not yet been addressed. Clinicians should consider evaluating patients with NEHI for comorbidities, including gastroesophageal reflux, aspiration, and immune system abnormalities, because these can contribute to the child's clinical picture and may influence clinical course and treatment.

Functional characterization of four ATP-binding cassette transporter A3 gene (ABCA3) variants.

ABCA3 transports phospholipids across lamellar body membranes in pulmonary alveolar type II cells and is required for surfactant assembly. Rare, biallelic, pathogenic ABCA3 variants result in lethal neonatal respiratory distress syndrome and childhood interstitial lung disease. Qualitative functional characterization of ABCA3 missense variants suggests two pathogenic classes: disrupted intracellular trafficking (type I mutant) or impaired ATPase-mediated phospholipid transport into the lamellar bodies (type II mutant). We qualitatively compared wild-type (WT-ABCA3) with four uncharacterized ABCA3 variants (c.418A>C;p.Asn140His, c.3609_3611delCTT;p.Phe1203del, c.3784A>G;p.Ser1262Gly, and c.4195G>A;p.Val1399Met) in A549 cells using protein processing, colocalization with intracellular organelles, lamellar body ultrastructure, and ATPase activity. We quantitatively measured lamellar body-like vesicle diameter and intracellular ABCA3 trafficking using fluorescence-based colocalization. Three ABCA3 variants (p.Asn140His, p.Ser1262Gly, and p.Val1399Met) were processed and trafficked normally and demonstrated well-organized lamellar body-like vesicles, but had reduced ATPase activity consistent with type II mutants. P.Phe1203del was processed normally, had reduced ATPase activity, and well-organized lamellar body-like vesicles, but quantitatively colocalized with both endoplasmic reticulum and lysosomal markers, an intermediate phenotype suggesting disruption of both intracellular trafficking and phospholipid transport. All ABCA3 mutants demonstrated mean vesicle diameters smaller than WT-ABCA3. Qualitative and quantitative functional characterization of ABCA3 variants informs mechanisms of pathogenicity.

Impaired Mitochondrial Respiration in Hermansky‐Pudlak Syndrome 1‐Defective Alveolar Type 2 Cells is Associated with Enhanced Mitochondrial Fission

Alveolar epithelial injury is central to the pathogenesis of pulmonary fibrosis in lung diseases across the lifespan, from bronchopulmonary dysplasia and childhood interstitial lung disease to idiopathic pulmonary fibrosis. Disturbances in mitochondrial structure that alter function have been associated with lung epithelial cell injury, yet molecular mechanisms regulating mitochondrial dynamics in the setting of pulmonary fibrosis remain unclear. Hermansky‐Pudlak Syndrome (HPS) patients, especially those with mutations in HPS1 and HPS4, develop fibrosis in earlier age than patients with idiopathic pulmonary fibrosis (IPF), suggesting that loss of HPS gene function drives alveolar epithelial injury. Here we show enhanced mitochondrial fragmentation in HPS1‐defective alveolar type 2 (AT2) cells associated with impaired phosphorylation of Dynamin‐related protein 1 (DRP1) at Serine (Ser)637 (inactivating phosphorylation). Ectopic expression of constitutively active GTPase Rab32, Rab32(Q85L), designed to bypass the guanine nucleotide exchange factor (GEF) function of HPS1‐HPS4 complex (BLOC‐3), in MLE15/DHPS1 cells restores mitochondrial architecture and increases p‐Ser637‐Drp1. In addition, MLE15/DHPS1 cells exhibit markedly reduced mitochondrial respiration, signified by reduced oxygen consumption (OCR), and robust glycolysis, indicated by a brisk increase in extracellular acidification rate (ECAR) after addition of glucose and accumulation of lactate in culture media. Despite robust glycolysis, MLE15/DHPS1 cells have lower total cellular ATP than MLE15/WT cells. Moreover, MLE15/DHPS1 cells demonstrate dependency on glucose as a nutrient source, reflected in activation of the energy sensor 5’ AMP‐activated protein kinase (AMPK) and cell death upon decreasing glucose in culture media. Taken together, our results suggest that HPS1, functioning in a heterodimer with HPS4 as an activator of Rab32, plays a central role in balancing mitochondrial fission/fusion in AT2 cells, while loss of HPS1 disrupts oxidative phosphorylation and drives metabolic reprogramming in AT2 cells.Support or Funding InformationNIH (GM108807/SG). SG is the Julia Carell Stadler Professor of Pediatrics. NIH/NIGMS 1R35GM128915‐01 (to VG); NIH/NCI 1R21 CA227483‐01A1 (to VG). NIH/R01 DK106348 and U01 CA235508 (to JY)