Surfactant Dysfunction Disorders Research Articles

Imaging of pulmonary fibrosis in children: A review, with proposed diagnostic criteria.

Computed tomography (CT) imaging findings of pulmonary fibrosis are well established for adults and have been shown to correlate with prognosis and outcome. Recognition of fibrotic CT findings in children is more limited. With approved treatments for adult pulmonary fibrosis, it has become critical to define CT criteria for fibrosis in children, to identify patients in need of treatment and those eligible for clinical trials. Understanding how pediatric fibrosis compares with idiopathic pulmonary fibrosis and other causes of fibrosis in adults is increasingly important as these patients transition to adult care teams. Here, we review what is known regarding the features of pulmonary fibrosis in children compared with adults. Pulmonary fibrosis in children may be associated with genetic surfactant dysfunction disorders, autoimmune systemic disorders, and complications after radiation, chemotherapy, transplantation, and other exposures. Rather than a basal-predominant usual interstitial pneumonia pattern with honeycombing, pediatric fibrosis is primarily characterized by reticulation, traction bronchiectasis, architectural distortion, or cystic lucencies/abnormalities. Ground-glass opacities are more frequent in children with fibrotic interstitial lung disease than adults, and disease distribution appears more diffuse, without clearly defined axial or craniocaudal predominance. Following discussion and consensus amongst a panel of expert radiologists, pathologists and physicians, distinctive disease features were integrated to develop criteria for the first global Phase III trial in children with pulmonary fibrosis.

Severe Neonatal Interstitial Lung Disease Caused by a Rare Surfactant Protein C Mutation.

Childhood interstitial lung disease (chILD) is a collective term for a group of rare lung disorders of heterogeneous origin. Surfactant dysfunction disorders are a cause of chILD with onset during the neonatal period and infancy. Clinical signs of tachypnea and hypoxemia are nonspecific and usually caused by common conditions like lower respiratory tract infections. We report on a full-term male newborn who was readmitted to the hospital at 7 days of age with marked tachypnea and poor feeding during the respiratory syncytial virus season. After exclusion of infection and other, more common congenital disorders, chILD was diagnosed using chest computed tomography and genetic analysis. A likely pathogenic heterozygous variant of SFTPC (c.163C>T, L55F) was detected by whole exome sequencing. The patient received supplemental oxygen and noninvasive respiratory support and was treated with intravenous methylprednisolone pulses and hydroxychloroquine. Despite the treatment, his respiratory situation deteriorated continuously, leading to several hospitalizations and continuous escalation of noninvasive ventilatory support. At 6 months of age, the patient was listed for lung transplant and transplanted successfully aged 7 months.

Gene Therapeutics for Surfactant Dysfunction Disorders: Targeting the Alveolar Type 2 Epithelial Cell.

Genetic disorders of surfactant dysfunction result in significant morbidity and mortality, among infants, children, and adults. Available medical interventions are limited, nonspecific, and generally ineffective. As such, the need for effective therapies remains. Pathogenic variants in the SFTPB, SFTPC, and ABCA3 genes, each of which encode proteins essential for proper pulmonary surfactant production and function, result in interstitial lung disease in infants, children, and adults, and lead to morbidity and early mortality. Expression of these genes is predominantly limited to the alveolar type 2 (AT2) epithelial cells present in the distal airspaces of the lungs, thus providing an unequivocal cellular origin of disease pathogenesis. While several treatment strategies are under development, a gene-based therapeutic holds great promise as a definitive therapy. Importantly for clinical translation, the genes associated with surfactant dysfunction are both well characterized and amenable to a gene-therapeutic-based strategy. This review focuses on the pathophysiology associated with these genetic disorders of surfactant dysfunction, and also provides an overview of the current state of gene-based therapeutics designed to target and transduce the AT2 cells.

Correlating SFTPC gene variants to interstitial lung disease in Egyptian children

BackgroundInterstitial lung disease (ILD) is a broad heterogeneous group of lung disorders that is characterized by inflammation of the lungs. Surfactant dysfunction disorders are a rare form of ILD diseases that result from mutations in surfactant protein C gene (SFTPC) with prevalence of approximately 1/1.7 million births. SFTPC patients are presented with clinical manifestations of ILD ranging from fatal respiratory failure of newborn to chronic respiratory problems in children. In the current study, we aimed to investigate the spectrum of SFTPC genetic variants as well as the correlation of the SFTPC gene mutations with ILD disease in twenty unrelated Egyptian children with diffuse lung disease and suspected surfactant dysfunction using Sanger sequencing. ResultsSequencing of SFTPC gene revealed five variants: c.42+35G>A (IVS1+35G>A) (rs8192340) and c.43-21T>C (IVS1-21T>C) (rs13248346) in intron 1, c.436-8C>G (IVS4-8C>G) (rs2070687) in intron 4, c.413C>A p.T138N (rs4715) in exon 4, and c.557G>Ap.S186N (rs1124) in exon 5. ConclusionThe present study confirms the association of detecting variants of SFTPC with surfactant dysfunction disorders.

Cryo-EM structures of the human surfactant lipid transporter ABCA3.

The adenosine 5′-triphosphate (ATP)–binding cassette (ABC) transporter ABCA3 plays a critical role in pulmonary surfactant biogenesis. Mutations in human ABCA3 have been recognized as the most frequent causes of inherited surfactant dysfunction disorders. Despite two decades of research, in vitro biochemical and structural studies of ABCA3 are still lacking. Here, we report the cryo-EM structures of human ABCA3 in two distinct conformations, both at resolution of 3.3 Å. In the absence of ATP, ABCA3 adopts a “lateral-opening” conformation with the lateral surfaces of transmembrane domains (TMDs) exposed to the membrane and features two positively charged cavities within the TMDs as potential substrate binding sites. ATP binding induces pronounced conformational changes, resulting in the collapse of the potential substrate binding cavities. Our results help to rationalize the disease-causing mutations in human ABCA3 and suggest a conserved “lateral access and extrusion” mechanism for both lipid export and import mediated by ABCA transporters.

Etiologic spectrum of interstitial lung diseases in Chinese children older than 2\u2009years of age

BackgroundChildhood interstitial lung diseases (ILD) (chILD) refer to a rare heterogeneous group of disorders. Global collaborations have been working on the etiologies and classification scheme of chILD. With the development of medical technologies, some new diseases were identified to be associated with chILD and its etiologic spectrum is expanding. The aim of this study is to describe the etiologic spectrum of chILD in children older than 2 years of age and summarize the approaches to diagnosis of chILD.MethodsWe made a retrospective analysis of children older than 2 years of age with chILD who referred to Beijing Children’s Hospital from 21 provinces all over China from 2013 to 2018. After excluding pulmonary infection, congenital heart disease, bronchopulmonary dysplasia, bronchiolitis obliterans and bronchiectasis, 133 patients were included and categorized by etiology. Clinical manifestations, high-resolution computed tomography, laboratory data, genetic data and pathologic findings were all collected and reviewed.ResultsSystemic disease associated ILD were the most common causes, accounting for 49.6% of the patients, followed by alveolar structure disorder-associated ILD (27%), exposure related ILD (13.5%), and disorders masquerading as ILD (3.8%). In systemic disease associated ILD, in addition to common etiologies such as vasculitis (10.5%) and connective tissue diseases (9.0%), primary immunodeficiency diseases (PID) associated ILD (9.8%), interstitial pneumonia with autoimmune features (6.8%), and metabolic diseases (6.8%) were not rarely found. Some newly reported etiologies such as STING–associated vasculopathy with onset in infancy, COPA syndrome and STAT3 mutation were included in PID associated ILD. Genetic tests contributed to 15% of the diagnoses which mainly distributed in PID associated ILD, metabolic diseases and surfactant dysfunction disorders, and contributed to the final diagnoses more than lung biopsies (13.5%) and biopsies of rashes or other tissues (12%).ConclusionsThis study first demonstrated an etiologic spectrum of chILD in Chinese children older than 2 years of age and summarized the approaches to diagnosis. The etiologic spectrum of chILD is expanding with more genetic etiologies being recognized.

ABCA3 missense mutations causing surfactant dysfunction disorders have distinct cellular phenotypes.

Mutations in the ATP-binding cassette subfamily A member 3 (ABCA3) gene are the most common monogenetic cause of surfactant dysfunction disorders in newborns and interstitial lung diseases in children and young adults. Although the effect of mutations resulting in truncated or incomplete proteins can be predicted, the consequences of missense variants cannot be as easily. Our aim was to investigate the intracellular handling and disturbance of the cellular surfactant system in a stable cell model with several different clinically relevant ABCA3 missense mutations. We found that the investigated missense mutations within the ABCA3 gene affect surfactant homeostasis in different ways: first by disrupting intracellular ABCA3 protein localization (c.643C>A, p.Q215K; c.2279T>G, p.M760R), second by impairing the lipid transport of ABCA3 protein (c.875A>T, p.E292V; c.4164G>C, p.K1388N), and third by yet undetermined mechanisms predisposing for the development of interstitial lung diseases despite correct localization and normal lipid transport of the variant ABCA3 protein (c.622C>T, p.R208W; c.863G>A, p.R288K; c.2891G>A, p.G964D). In conclusion, we classified cellular consequences of missense ABCA3 sequence variations leading to pulmonary disease of variable severity. The corresponding molecular pathomechanisms of such ABCA3 variants may specifically be addressed by targeted treatments.

CT features of diffuse lung disease in infancy.

Diffuse lung disease in infancy includes a wide range of very rare and peculiar pulmonary conditions usually not seen in older children, in whom diffuse lung disease has much greater overlap with adult disorders. The acronym chILD (childhood Interstitial Lung Disease) commonly defines these disorders, although air spaces, airways, alveolar epithelium, vasculature, pleura, and pleural spaces can also be involved, besides the pulmonary interstitium. chILD can be caused by diffuse developmental disorders, alveolar growth abnormalities, surfactant dysfunction disorders, and other specific conditions of poorly understood etiology. Chest CT imaging studies play a pivotal role in the evaluation of chILD. In some conditions CT findings can be specific, and thus make it possible avoiding further testing. In other disorders, findings are nonspecific, although they may suggest a diagnostic pattern and guide further testing. Nevertheless, chILD disorders often remain unrecognized on imaging studies, as they are very rare. The aim of this article is to review the CT patterns of lung involvement in a series of infants with chILD.

Chronic interstitial lung disease in children.

Children's interstitial lung diseases (chILD) are increasingly recognised and contain many lung developmental and genetic disorders not yet identified in adult pneumology. Worldwide, several registers have been established. The Australasian Registry Network for Orphan Lung Disease (ARNOLD) has identified problems in estimating rare disease prevalence; focusing on chILD in immunocompetent patients, a period prevalence of 1.5 cases per million children and a mortality rate of 7% were determined. The chILD-EU register highlighted the workload to be covered per patient included and provided protocols for diagnosis and initial treatment, similar to the United States chILD network. Whereas case reports may be useful for young physicians to practise writing articles, cohorts of patients can catapult progress, as demonstrated by recent studies on persistent tachypnoea of infancy, hypersensitivity pneumonitis in children and interstitial lung disease related to interferonopathies from mutations in transmembrane protein 173. Translational research has linked heterozygous mutations in the ABCA3 transporter to an increased risk of interstitial lung diseases, not only in neonates, but also in older children and adults. For surfactant dysfunction disorders in infancy and early childhood, lung transplantation was reported to be as successful as in adult patients. Mutual potentiation of paediatric and adult pneumologists is mandatory in this rapidly extending field for successful future development.This brief review highlights publications in the field of paediatric interstitial lung disease as reviewed during the Clinical Year in Review session presented at the 2017 European Respiratory Society (ERS) Annual Congress in Milan, Italy. It was commissioned by the ERS and critically presents progress made as well as drawbacks.

Structure, function and deficiency diseases of lung surfactant protein-c

Pulmonary surfactant is a mixture of lipids and hydrophobic surfactant proteins B (SP-B) and SP-C and hydrophilic proteins SP-A and SP-D. Pulmonary surfactant reduces the surface tension at the air-water interface of the lung alveoli by forming a surface active film. In this way, it prevents alveoli from collapsing and facilitates the process of breathing. SP-C cooperates with SP-B to enhance the surface active properties of surfactant phospholipids. Reports on the association of lung disease with SP-C deficiency have led to new insights into the importance of SP-C for proper surfactant homeostasis. In most animal species the major form of SP-C is a 35-residue peptide chain which contains two thioester-linked palmitoyl groups, giving a total molecular mass of 4.2 kDa. Though t he function of SP-C in vivo remains unclear, but effects of SP-C on the adsorption, spreading, and stability of lipid films at an air ⁄ water interface have been documented in a number of in vitro studies. Genetic disorders disrupting normal surfactant metabolism (surfactant dysfunction disorders) have been recognized in the neonatal and pediatric populations. Although rare, these disorders cause significant mortality and morbidity, including acute respiratory distress and failure in full-term neonates, and interstitial lung disease (ILD) in older infants, children, and adults. The genes involved in these disorders are critical for surfactant production and function in the lung and include SP-C gene ( SFTPC ) besides others . More than 40 mutations in the SFTPC gene have been identified in people with dysfunction of lung surfactant. Mutations in the SFTPC gene result in the reduction or absence of mature SP-C and accumulation of abnormal forms of SP-C, resulting into breathing problems in newborns and onset of breathing difficulties in children and adults. SFTPC gene mutations associated with surfactant dysfunction affect the processing of the SP-C protein. Many of these mutations occur in a region of gene called the BRICHOS domain, which appears to be involved in the processing of SP-C protein. It is not known which of these outcomes causes the symptoms of SP-C dysfunction. Recent reports suggest that abnormally processed SP-C proteins form altered three-dimensional shape and accumulate inside lung cells. These misfolded proteins may trigger a cellular response that results in cell damage and death. Mutations in BRICHOS domain of SP-C have been associated to ER stress, proteasome dysfunction, and apoptosis. This article reviews information on structure and function of SP-C and the associated mutations in SFTPC gene in relation to SP-C deficiency diseases.

The Expanded Spectrum of Genetic Surfactant Dysfunction Disorders

The Expanded Spectrum of Genetic Surfactant Dysfunction Disorders

Large ABCA3 and SFTPC Deletions Resulting in Lung Disease

Mutations in genes encoding proteins important in the function and metabolism of pulmonary surfactant are recognized causes of lung disease. Clinical genetic testing is available for these disorders, but children with phenotypes consistent with surfactant dysfunction and no identifiable mutations in the known causative genes have been reported. To identify the mechanism(s) for lung disease in two children with the phenotype of surfactant dysfunction who had negative testing in clinical laboratories for gene mutations causing surfactant dysfunction. Amplicons spanning multiple exons of candidate genes were generated by polymerase chain reaction and sequenced. A 4,335-base deletion that included all of exon 12 of the gene encoding member A3 of the adenosine triphosphate-binding cassette transporter was identified in a full-term infant with respiratory failure. A 333-base deletion involving part of exon 4 and the adjacent intron of the gene encoding surfactant protein C was identified in a child with interstitial lung disease. Large deletions are a cause of surfactant dysfunction disorders and may need to be sought for specifically in children whose phenotypes suggest these syndromes but in whom clinical genetic testing is unrevealing.

Index of Suspicion in the Nursery: Persistent Tachypnea

At 2 days of age, a term female newborn infant is evaluated for tachypnea. She was born at 40 weeks’ gestation, with birthweight 4.6 kg, to a 34-year-old G2P2 woman via normal spontaneous vaginal delivery. Maternal history is pertinent for well-controlled gestational diabetes mellitus and hypothyroidism treated with levothyroxine. Prenatal laboratories are significant for group B Streptococcus positivity for which the mother was adequately treated. All other prenatal laboratories are unremarkable. The delivery was complicated by a nuchal cord and apnea requiring positive pressure ventilation for 10 seconds. Apgar scores were 6 at 1 minute and 9 at 5 minutes. A review of her vital signs from the newborn nursery reveal the following: heart rate, 128 beats per minute; respiratory rate, 52 breaths per minute; and oxygen saturation, 89% in room air that had improved without supplemental oxygen. Her respiratory rate is 82 breaths per minute, and pre- and postductal oxygen saturations are 97% in room air. On physical examination, she is consistently tachypneic, as noted by multiple caregivers, with minimal subcostal retractions but without grunting or flaring. The remainder of her examination is within normal limits. Basic metabolic panel, capillary blood gas, and complete blood count are all normal. A chest radiograph is read as unremarkable (Fig 1A). Blood cultures are drawn, but given a low risk for sepsis, antibiotics are not started. A cardiologist is consulted for sustained tachypnea and a new grade I/VI systolic murmur in the left lower sternal border. An echocardiogram …

Genetic testing in children with surfactant dysfunction

ObjectivesTo present the UK experience in genetic diagnoses of surfactant protein dysfunction disorders and develop a referral algorithm for neonates and children with persistent respiratory problems.Materials and methodsBetween 2006 and...

Interstitial lung disease in children

In this review, we discuss the recent advances in our understanding of the cause, pathogenesis, presentation, diagnosis, treatment, and prognosis of interstitial lung disease (ILD) in children. The classification of ILD syndromes in children greater than 2 years of age is based largely on adult classification schemes. In children less than 2 years of age, classification has been developed and evaluated pathologically. Entities can be categorized into developmental disorders, growth abnormalities, and surfactant dysfunction disorders based on pathologic findings. Two distinctive entities, neuroendocrine cell hyperplasia of infancy and pulmonary interstitial glycogenosis, present early in life with characteristic findings. These two disorders appear to have a favorable prognosis. Diagnosis of ILD syndromes is based on the summation of history and physical findings and both noninvasive and invasive studies. Newer approaches are being evaluated to decrease the need for lung biopsy. Children's interstitial lung diseases are rare diffuse lung diseases resulting from a variety of pathogenic processes that include genetic factors, association with systemic disease processes, and inflammatory or fibrotic responses to stimuli. There are unique causes and presentations seen in infancy. Diagnosis in these disorders is made by the summation of clinical, radiologic, and pathologic findings.

Paediatric Interstitial Lung Disease: Classification and Definitions

Classifications of interstitial (diffuse) lung disease in adults and children have undergone significant revision in recent years, with advances in our understanding of new entities and the biology and prognostic significance of certain histologic patterns. The contributions of the European Respiratory Society Task Force on Interstitial Lung Disease in Children and the North American Children's Interstitial Lung Disease Group are reviewed, and a clinicopathologic classification of paediatric diffuse lung disease is summarized. Clinical characteristics and histologic definitions are also presented for selected entities within this classification, specifically, acinar dysgenesis, congenital alveolar dysplasia, alveolar capillary dysplasia with misalignment of pulmonary veins, abnormalities of alveolar growth, pulmonary interstitial glycogenosis, neuroendocrine cell hyperplasia of infancy, surfactant dysfunction disorders, obliterative bronchiolitis, hypersensitivity pneumonitis, and immunologic disorders. More uniform application of this diagnostic terminology in the future will allow more meaningful comparisons of different patient populations, radiologic-pathologic correlation, and development of disease-specific therapeutic strategies.

Diffuse lung disease in young children: application of a novel classification scheme.

Considerable confusion exists regarding nomenclature, classification, and management of pediatric diffuse lung diseases due to the relative rarity and differences in the spectrum of disease between adults and young children. A multidisciplinary working group was formed to: (1) apply consensus terminology and diagnostic criteria for disorders presenting with diffuse lung disease in infancy; and (2) describe the distribution of disease entities, clinical features, and outcome in young children who currently undergo lung biopsy in North America. Eleven centers provided pathologic material, clinical data, and imaging from all children less than 2 years of age who underwent lung biopsy for diffuse lung disease from 1999 to 2004. Multidisciplinary review categorized 88% of 187 cases. Disorders more prevalent in infancy, including primary developmental and lung growth abnormalities, neuroendocrine cell hyperplasia of infancy, and surfactant-dysfunction disorders, constituted the majority of cases (60%). Lung growth disorders were often unsuspected clinically and under-recognized histologically. Cases with known surfactant mutations had characteristic pathologic features. Age at biopsy and clinical presentation varied among categories. Pulmonary hypertension, presence of a primary developmental abnormality, or ABCA3 mutation was associated with high mortality, while no deaths occurred in cases of pulmonary interstitial glycogenosis, or neuroendocrine cell hyperplasia of infancy. This retrospective cohort study identifies a diverse spectrum of lung disorders, largely unique to young children. Application of a classification scheme grouped clinically distinct patients with variable age of biopsy and mortality. Standardized terminology and classification will enhance accurate description and diagnosis of these disorders.