Pediatric Interstitial Lung Disease Research Articles

Neonatal Respiratory Insufficiency Caused by an (Homozygous) ABCA3-Stop Mutation: a Systematic Evaluation of Therapeutic Options

Autosomal recessive ABCA3 (ATP-binding cassette protein A3) gene mutations have been associated with neonatal respiratory distress and pediatric interstitial lung disease. The clinical course of the disease depends on the underlying mutations. Therefore, knowledge of course, symptoms and treatment of the disease is important. A term newborn suffered from progressive respiratory insufficiency, which led to death at the age of 4.8 months. The girl developed interstitial lung disease. Infections as well as structural and functional disorders of the lung were systematically excluded. A homozygous c.4681C > T (Arg 1561 Stop) mutation of the ABCA3 gene was identified. A literature review of the pathophysiology and treatment options of the disease was done. Therapeutic approaches with corticosteroids, macrolide, and hydroxychloroquine did not improve the clinical course. Therapeutic strategies for chronic interstitial lung disease have been used successfully in cases of a mild clinical course in juvenile patients with ABCA3 gene mutation. In our patient with homozygous ABCA3 gene mutation,they were not effective. Lung transplantation remains as a therapeutic option, but because of donor organ shortage and associated morbidity and mortality it is rarely feasible. More experience in the treatment of newborns with ABCA3 gene mutations is needed. Randomized, prospective evaluation of the different therapeutic approaches in a specific registry may improve prognosis and treatment of affected individuals.

Research in progress: put the orphanage out of business

Paediatric interstitial lung disease (ILD) is rare and diverse, meaning no single centre will see sufficient children to perform the studies needed to make progress. This EU FP-7 grant will...

Rapid and Progressive Pulmonary Fibrosis in 2 Families with DNA Repair Deficiencies of Undetermined Etiology

Known genetic causes of pediatric interstitial lung disease include disorders of surfactant metabolism, telomerase, and DNA repair. We report 4 children from 2 families with rapidly progressive and fatal pulmonary fibrosis. A novel DNA repair defect unrelated to the ataxia-telangiectasia mutated gene was found in 1 child from each family.

A national internet-linked based database for pediatric interstitial lung diseases: the French network

BackgroundInterstitial lung diseases (ILDs) in children represent a heterogeneous group of rare respiratory disorders that affect the lung parenchyma. After the launch of the French Reference Centre for Rare Lung Diseases (RespiRare®), we created a national network and a web-linked database to collect data on pediatric ILD.MethodsSince 2008, the database has been set up in all RespiRare® centres. After patient's parents' oral consent is obtained, physicians enter the data of children with ILD: identity, social data and environmental data; specific aetiological diagnosis of the ILD if known, genetics, patient visits to the centre, and all medical examinations and tests done for the diagnosis and/or during follow up. Each participating centre has a free access to his own patients' data only, and cross-centre studies require mutual agreement. Physicians may use the system as a daily aid for patient care through a web-linked medical file, backed on this database.ResultsData was collected for 205 cases of ILD. The M/F sex ratio was 0.9. Median age at diagnosis was 1.5 years old [0–16.9]. A specific aetiology was identified in 149 (72.7%) patients while 56 (27.3%) cases remain undiagnosed. Surfactant deficiencies and alveolar proteinosis, haemosiderosis, and sarcoidosis represent almost half of the diagnoses. Median length of follow-up is 2.9 years [0–17.2].ConclusionsWe introduce here the French network and the largest national database in pediatric ILDs. The diagnosis spectrum and the estimated incidence are consistent with other European databases. An important challenge will be to reduce the proportion of unclassified ILDs by a standardized diagnosis work-up. This database is a great opportunity to improve patient care and disease pathogenesis knowledge. A European network including physicians and European foundations is now emerging with the initial aim of devising a simplified European database/register as a first step to larger European studies.

Molecular and cellular characteristics of ABCA3 mutations associated with diffuse parenchymal lung diseases in children

ABCA3 (ATP-binding cassette subfamily A, member 3) is expressed in the lamellar bodies of alveolar type II cells and is crucial to pulmonary surfactant storage and homeostasis. ABCA3 gene mutations have been associated with neonatal respiratory distress (NRD) and pediatric interstitial lung disease (ILD). The objective of this study was to look for ABCA3 gene mutations in patients with severe NRD and/or ILD. The 30 ABCA3 coding exons were screened in 47 patients with severe NRD and/or ILD. ABCA3 mutations were identified in 10 out of 47 patients, including 2 homozygous, 5 compound heterozygous and 3 heterozygous patients. SP-B and SP-C expression patterns varied across patients. Among patients with ABCA3 mutations, five died shortly after birth and five developed ILD (including one without NRD). Functional studies of p.D253H and p.T1173R mutations revealed that p.D253H and p.T1173R induced abnormal lamellar bodies. Additionally, p.T1173R increased IL-8 secretion in vitro. In conclusion, we identified new ABCA3 mutations in patients with life-threatening NRD and/or ILD. Two mutations associated with ILD acted via different pathophysiological mechanisms despite similar clinical phenotypes.

Pulmonary maturational arrest and death in a patient with pulmonary interstitial glycogenosis

We present the clinical presentation and pathological findings from a term infant with atypical neonatal lung disease. A full term Caucasian male presented at birth with signs of respiratory distress. The respiratory condition continued to deteriorate despite maximum intervention and the patient was placed on ECMO for further cardiorespiratory assistance. An open lung biopsy demonstrated findings consistent with severe lung growth abnormality with non-uniform pulmonary interstitial glycogenosis. The patient consequently developed a pulmonary hemorrhage that required discontinuation of ECMO. The patient died shortly after decannulation. Most literature suggests that PIG is one of the few pediatric interstitial lung diseases that has a favorable prognosis with rare mortality in the absence of co-morbidities. However, the current case suggests prognosis may depend more on the underlying diagnosis than on the histological finding of PIG. In addition, this case may provide insight into the pathogenesis and potential modifiers of this idiopathic disorder.

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.

Pulmonary interstitial glycogenosis in the setting of lung growth abnormality: radiographic and pathologic correlation

Pulmonary interstitial glycogenosis (PIG) is a rare pediatric interstitial lung disease. We report a case of a term boy presenting with tachypnea at birth requiring supplemental oxygen. Chest radiographs followed by high-resolution CT (HRCT) demonstrated hyperinflation and diffuse interstitial markings interspersed with multiple cystic spaces. An open lung biopsy demonstrated a minor component of PIG superimposed upon poor alveolarization. PIG in the setting of lung growth abnormality might be more common than previously described. Additionally, radiographic findings associated with most pediatric interstitial lung diseases are nonspecific, and histopathologic correlation is essential for diagnosis.

Interstitial lung diseases in children

Interstitial lung disease (ILD) in infants and children comprises a large spectrum of rare respiratory disorders that are mostly chronic and associated with high morbidity and mortality. These disorders are characterized by inflammatory and fibrotic changes that affect alveolar walls. Typical features of ILD include dyspnea, diffuse infiltrates on chest radiographs, and abnormal pulmonary function tests with restrictive ventilatory defect and/or impaired gas exchange. Many pathological situations can impair gas exchange and, therefore, may contribute to progressive lung damage and ILD. Consequently, diagnosis approach needs to be structured with a clinical evaluation requiring a careful history paying attention to exposures and systemic diseases. Several classifications for ILD have been proposed but none is entirely satisfactory especially in children. The present article reviews current concepts of pathophysiological mechanisms, etiology and diagnostic approaches, as well as therapeutic strategies. The following diagnostic grouping is used to discuss the various causes of pediatric ILD: 1) exposure-related ILD; 2) systemic disease-associated ILD; 3) alveolar structure disorder-associated ILD; and 4) ILD specific to infancy. Therapeutic options include mainly anti-inflammatory, immunosuppressive, and/or anti-fibrotic drugs. The outcome is highly variable with a mortality rate around 15%. An overall favorable response to corticosteroid therapy is observed in around 50% of cases, often associated with sequelae such as limited exercise tolerance or the need for long-term oxygen therapy.

HRCT in paediatric diffuse interstitial lung disease—a review for 2009

HRCT in paediatric diffuse interstitial lung disease—a review for 2009

Identification and characterization of two new TTF-1 mutations associated with pediatric interstitial lung diseases

Introduction Pediatric interstitial lung diseases (pILD) represent a heterogeneous group of rare and poorly defined disorders. Genetic abnormalities of surfactant proteins B (SP-B) and C (SP-C) have been shown to be related to these pathologies. However, variability in the lung disease phenotype suggests the involvement of other surfactant-associated genes. The aim of this study was to examined the contribution of TTF-1 (Thyroid Transcription Factor 1), a transcription factor especially involved in lung development in pILD. Methods TTF-1 gene sequencing was performed in two children presenting with hypotonia, pILD and hyptothyroidism without a known etiology. Surfactant proteins were assessed in bronchoalveolar lavage (BAL) fluid by western blot analysis using proSP-B, SP-B and proSP-C antibodies. TTF-1 mutated plasmids were realized by mutagenesis. SP-B/SP-C promoter analysis was realized in A549 cells using co-transfection experiment with SP-C and SP-B luciferase plasmids with wild type or mutated TTF-1 expression plasmids. Results Two new spontaneous TTF-1 mutations (M1 and M2) have been identified by sequencing in two patients (P1 and P2). The measurement of SP-B and SP-C promoter activation by plasmids encoding mutated TTF-1 (TTF-1M1 and TTF-1M2) revealed two different mecanisms. TTF-1M1 do not induces either SP- B or SP-C promoter activation and has a dominant negative effect on the wild type TTF-1. In contrast, TTF-1M2 activates SP-B and SP-C promoters Also, SP-C promoter activation was higher with TTF1M2 that the wild type TTF-1. BAL from P1 is characterized by a normal pattern of pro-SP-B and SP-B contents but exhibits an accumulation of pro-SP-C. Conclusion In this study, we identified and characterized two new TTF-1 mutations responsible for pILD with two different mecanisms.

Aberrant catalytic cycle and impaired lipid transport into intracellular vesicles in ABCA3 mutants associated with nonfatal pediatric interstitial lung disease

The ATP-binding cassette transporter ABCA3 mediates uptake of choline-phospholipids into intracellular vesicles and is essential for surfactant metabolism in lung alveolar type II cells. We have shown previously that ABCA3 mutations in fatal surfactant deficiency impair intracellular localization or ATP hydrolysis of ABCA3 protein. However, the mechanisms underlying the less severe phenotype of patients with ABCA3 mutation are unclear. In this study, we characterized ABCA3 mutant proteins identified in pediatric interstitial lung disease (pILD). E292V (intracellular loop 1), E690K (adjacent to Walker B motif in nucleotide binding domain 1), and T1114M (8th putative transmembrane segment) mutant proteins are localized mainly in intracellular vesicle membranes as wild-type protein. Lipid analysis and sucrose gradient fractionation revealed that the transport function of E292V mutant protein is moderately preserved, whereas those of E690K and T1114M mutant proteins are severely impaired. Vanadate-induced nucleotide trapping and photoaffinity labeling of wild-type and mutant proteins using 8-azido-[(32)P]ATP revealed an aberrant catalytic cycle in these mutant proteins. These results demonstrate the importance of a functional catalytic cycle in lipid transport of ABCA3 and suggest a pathophysiological mechanism of pILD due to ABCA3 mutation.

Interstitial lung diseases in infants and children: Fig. 1—

Interstitial lung disease (ILD) in infants and children represents a heterogeneous group of respiratory disorders that are mostly chronic and associated with high morbidity and mortality. Typical features of ILD include dyspnoea, the presence of diffuse infiltrates on chest radiographs and abnormal pulmonary function tests with evidence of a restrictive ventilatory defect (in older children) and/or impaired gas exchange. ILD is difficult to diagnose, as no classification scheme is entirely satisfactory. Recently, it has been proposed to categorise paediatric ILD as either primary pulmonary disorders or systemic disorders with pulmonary involvement. However, this classification leaves the difficult problem of which clinical conditions should be included or excluded in infants and children. The present article reviews interstitial lung disease in infants and children, placing emphasis on current concepts of pathophysiological mechanisms and approaches to treatment.

Heterozygosity for ABCA3 Mutations Modifies the Severity of Lung Disease Associated with a Surfactant Protein C Gene (SFTPC) Mutation

Heterozygous SFTPC mutations have been associated with adult and pediatric interstitial lung disease (pILD). Inheritance is autosomal dominant, but de novo mutations may cause sporadic disease. SFTPC mutations have been associated with variable onset of symptoms, ranging from early infancy to late adulthood. The underlying mechanisms for this variability are unknown. Recently, mutations in ABCA3 (encoding member A3 of the adenosine triphosphate-binding cassette family of transporters) were identified as a cause of pILD. To test the hypothesis that ABCA3 mutations modify the severity of lung disease in individuals with SFTPC mutations, we sequenced ABCA3 from four symptomatic infants with the same SFTPC mutation, a substitution of isoleucine by threonine in codon 73 (I73T). Each infant developed respiratory symptoms by 2 mo of age and inherited the mutation from an asymptomatic parent. Three of the four infants were also heterozygous for an ABCA3 mutation, which was inherited from the parent without SFTPC I73T. The finding of heterozygosity for ABCA3 mutations in severely affected infants with SFTPC I73T, and independent inheritance from disease-free parents supports that ABCA3 acts as a modifier gene for the phenotype associated with an SFTPC mutation.

Targeted inactivation of the murine Abca3 gene leads to respiratory failure in newborns with defective lamellar bodies

Mutations in the human ABCA3 gene, encoding an ABC-transporter, are associated with respiratory failure in newborns and pediatric interstitial lung disease. In order to study disease mechanisms, a transgenic mouse model with a disrupted Abca3 gene was generated by targeting embryonic stem cells. While heterozygous animals developed normally and were fertile, individuals homozygous for the altered allele ( Abca3−/−) died within one hour after birth from respiratory failure, ABCA3 protein being undetectable. Abca3−/− newborns showed atelectasis of the lung in comparison to a normal gas content in unaffected or heterozygous littermates. Electron microscopy demonstrated the absence of normal lamellar bodies in type II pneumocytes. Instead, condensed structures with apparent absence of lipid content were found. We conclude that ABCA3 is required for the formation of lamellar bodies and lung surfactant function. The phenotype of respiratory failure immediately after birth corresponds to the clinical course of severe ABCA3 mutations in human newborns.

Genetics of pediatric interstitial lung disease

The interstitial lung diseases are a heterogeneous group of rare disorders of largely unknown etiology. The occurrence of familial cases of pediatric interstitial lung diseases with the onset of symptoms developing early in infancy has suggested a genetic basis for some forms of interstitial lung diseases in children. Mutations in the genes encoding surfactant protein C, SFTPC, and a member of the adenosine triphosphate-binding cassette family of proteins, ABCA3, have been shown to result in pediatric interstitial lung diseases inherited in autosomal-dominant and autosomal-recessive patterns, respectively. There is overlap in both the clinical and histopathologic features of these disorders. Identification of genes responsible for pediatric interstitial lung diseases provides the opportunity for noninvasive testing to establish an etiologic diagnosis, to counsel family members for their recurrence risk, and to classify these rare disorders more accurately. A better understanding of the cause and pathophysiology of these disorders may provide additional insights into the causes of other forms of pediatric interstitial lung diseases, and may suggest novel treatment approaches.

Pearls and Pitfalls in HRCT in Children

The aim of this talk is to discuss the role of thin slice high resolution CT in paediatric practice and to describe the various means by which these images can be acquired to a satisfactory [diagnostic] level in routine paediatric practice. It is also to highlight the utility of HRCT in paediatric practice to enable the various patterns of disease processes to be understood. The main role for HRCT is in the diagnosis and follow up of diffuse airways and interstitial lung diseases in children. We will focus on the utility of HRCT in diagnosis of paediatric diffuse interstitial lung disease [DILD] and the inherent strengths and weakness within the ultimate choices made to acquire images. We will emphasise and illustrate the specific conditions for which HRCT provides a powerful diagnostic tool.

How to evaluate and treat children's interstitial lung disease

New concepts are emerging for pediatric interstitial lung disease (ILD). ILD in children has classically been defined as a group of rare, heterogeneous and poorly understood disorders. Histology classification systems for children with ILD have not been well defined and by default, adult ILD classification systems employed. The recognition that ILD in infancy included unique entities specific to this age range and excluded common adult entities, such as Usual Interstitial Pneumonitis (UIP) with classic fibroblastic foci, highlighted the need for improved classification clarity in children’s interstitial lung disease (chILD). To address this need and to improve care, a multi-disciplinary working group of pediatric pathologists, radiologists and pulmonologists and neonatologists from throughout North America collaborated to form the chILD cooperative research group, with funding from the Rare Lung Disease Consortium (NIH RR019498). Other synergistic developments such as improved diagnostic techniques for infant pulmonary function and high resolution computerized tomography (HRCT) and the recognition of new forms of surfactant genetic lung disease have further energized chILD efforts. This review will incorporate newer concepts into the framework of evaluating young children and infants with ILD.

Paediatric interstitial lung disease

<h3>Key points</h3> Presentation of ILD is very non-specific. Imaging, especially HRCT, confirms the presence of ILD, but is rarely diagnostic. Invasive diagnosis is almost always needed. Bronchoscopy rarely gives diagnostic information in paediatric ILD. For most paediatric ILD, transbronchial or percutaneous lung biopsy gives insufficient tissue for diagnosis and carries increased risk. Open lung biopsy or VATS is the diagnostic investigation of choice. <h3>Educational aims</h3> To allow the reader to correctly identify infants and children with interstitial lung disease (ILD). To help the reader to appreciate the wide differential diagnosis, including that of disorders specific to infancy, comprising the surfactant protein disorders. To explain the strengths and weaknesses of the different investigative modalities used in establishing a firm diagnosis. To discuss the limited evidence for the different treatment options currently in use. <h3>Summary</h3> Paediatric interstitial disease is rare, and comprises many disparate diseases. This article aims to provide the reader with an update on how to recognise infants and children who should be considered as possibly having ILD. The diagnostic process, including the roles of HRCT and bronchoscopy, and the different methods of lung biopsy, will be set out. The newly recognised entities, such as neuroendocrine cell hyperplasia of infancy, pulmonary interstitial glycogenosis and the disorders of surfactant protein metabolism, are also described. Finally, the article reviews the evidence that exists to guide treatment of these conditions.

ABCA3 mutations associated with pediatric interstitial lung disease.

ABCA3 is a member of the ATP-binding cassette family of proteins that mediate the translocation of a wide variety of substrates, including lipids, across cellular membranes. Mutations in the gene encoding ABCA3 were recently identified in full-term neonates with fatal surfactant deficiency. To test the hypothesis that ABCA3 mutations are not always associated with fatal neonatal lung disease but are a cause of pediatric interstitial lung disease. DNA samples were obtained from 195 children with chronic lung disease of unknown etiology. The 30 coding exons of the ABCA3 gene were sequenced in four unrelated children with a referring diagnosis of desquamative interstitial pneumonitis and who were older than 10 years at the time of enrollment. Three of four patients (ages 16, 23, and 11 years) with desquamative interstitial pneumonitis had ABCA3 mutations identified on both alleles. All three had the same missense mutation (E292V) and a second unique mutation. The E292V mutation was not found on 200 control alleles from adults without lung disease, but seven additional patients of the remaining study patients had the E292V mutation on one allele. Immunohistochemical analysis of surfactant protein expression in three patients revealed a specific staining pattern for surfactant protein-B, which was the same pattern observed in several infants with fatal lung disease due to ABCA3 mutations. ABCA3 mutations cause some types of interstitial lung disease in pediatric patients.