Pediatric Interstitial Lung Disease Research Articles

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.

Persistent tachypnea of infancy is associated with neuroendocrine cell hyperplasia

We sought to determine the clinical course and histologic findings in lung biopsies from a group of children who presented with signs and symptoms of interstitial lung disease (ILD) without identified etiology. Patients were identified from the pathology files at the Texas Children's Hospital who presented below age 2 years with persistent tachypnea, hypoxia, retractions, or respiratory crackles, and with nonspecific and nondiagnostic lung biopsy findings. Age-matched lung biopsy controls were also identified. Their clinical courses were retrospectively reviewed. Biopsies were reviewed, and immunostaining with antibodies to neuroendocrine cells was done. Fifteen pediatric ILD patients and four control patients were identified for inclusion in the study. Clinically, the mean onset of symptoms was 3.8 months (range, 0-11 months). Radiographs demonstrated hyperinflation, interstitial markings, and ground-glass densities. Oxygen was initially required for prolonged periods, and medication trials did not eliminate symptoms. After a mean of 5 years, no deaths had occurred, and patients had improved. On review of the lung biopsies, all had a similar appearance, with few abnormalities noted. Immunostaining with antibodies to neuroendocrine cell products showed consistently increased bombesin staining. Subsequent morphometric analysis showed that immunoreactivity for bombesin and serotonin was significantly increased over age-matched controls. In conclusion, we believe this may represent a distinct group of pediatric patients defined by the absence of known lung diseases, clinical signs and symptoms of ILD, and idiopathic neuroendocrine cell hyperplasia of infancy. These findings may be important for the evaluation of ILD in young children.

Interstitial lung disease in children -- genetic background and associated phenotypes.

Interstitial lung disease in children represents a group of rare chronic respiratory disorders. There is growing evidence that mutations in the surfactant protein C gene play a role in the pathogenesis of certain forms of pediatric interstitial lung disease. Recently, mutations in the ABCA3 transporter were found as an underlying cause of fatal respiratory failure in neonates without surfactant protein B deficiency. Especially in familiar cases or in children of consanguineous parents, genetic diagnosis provides an useful tool to identify the underlying etiology of interstitial lung disease. The aim of this review is to summarize and to describe in detail the clinical features of hereditary interstitial lung disease in children. The knowledge of gene variants and associated phenotypes is crucial to identify relevant patients in clinical practice.

Serum KL-6 and Surfactant Proteins A and D in Pediatric Interstitial Lung Disease

To determine if serum KL-6, surfactant protein A (SP-A), and surfactant protein D (SP-D) levels are elevated in pediatric interstitial lung disease (ILD) and associated with pulmonary function and disease severity score. Serum KL-6, SP-A, and SP-D levels were measured by enzyme-linked immunosorbent assay in 10 children with ILD and in 10 healthy volunteers. In the ILD group, FEV1 percentage of predicted, FVC percentage of predicted, and ILD disease severity score were measured and correlated with serum KL-6, SP-A, and SP-D levels. For the ILD and control groups, respectively, mean serum KL-6 was 4,523 U/mL and 206 U/mL (p = 0.007), mean serum SP-A was 133 ng/mL and 21 ng/mL (p = 0.003), and mean serum SP-D was 304 ng/mL and 75 ng/mL (p = 0.004). There was an inverse relationship between SP-A and FVC (p = 0.05), and between SP-D and FEV1 (p = 0.05). There was a direct relationship between SP-D and ILD score (p = 0.05). Serum KL-6, SP-D and SP-D levels are elevated in children with ILD. SP-A and SP-D levels appear to correlate with some measures of disease severity.

Pediatric Interstitial Lung Disease Masquerading as Difficult Asthma: Management Dilemmas for Rare Lung Disease in Children

Idiopathic nontransplant-related childhood bronchiolitis obliterans is an uncommon disease. Most patients present with chronic recurrent dyspnea, cough and wheezing, which are also features of asthma, by far a much more common condition. The present case study reports on a six-year-old girl who presented to a tertiary care centre with recurrent episodes of respiratory distress on a background of baseline tachypnea, chronic hypoxemia and exertional dyspnea. Her past medical history revealed significant lung disease in infancy, including respiratory syncytial virus bronchiolitis and repaired gastroesophageal reflux. She was treated for 'asthma exacerbations' throughout her early childhood years. Bronchiolitis obliterans was subsequently diagnosed with an open lung biopsy. She did not have sustained improvement with systemic corticosteroids, hydroxychloroquine or clarithromycin. Cardiac catheterization confirmed the presence of secondary pulmonary hypertension. Treatment options remain a dilemma for this patient because there is no known effective treatment for this condition, and the natural history is not well understood. The present case demonstrates the need for careful workup in 'atypical asthma', and the urgent need for further research into the rare lung diseases of childhood.

Pediatric interstitial lung disease revisited.

The spectrum of pediatric interstitial lung disease (PILD) includes a diverse group of rare disorders characterized by diffuse infiltrates and disordered gas exchange. Children with these conditions typically present with tachypnea, crackles, and hypoxemia. Recent advances have been made in the identification of different types of PILD that are unique to infancy. More exciting has been the discovery of genetic abnormalities of surfactant function, now described in both children and adults. A systematic evaluation of the child presenting with diffuse infiltrates of unknown etiology is essential to the diagnosis. Most often, lung biopsy is required. Current treatment options remain less than satisfactory, and morbidity and mortality remain considerable.

The pathogenesis of interstitial lung diseases in children.

The pathological changes observed in interstitial lung disease (ILD) are characterised by derangements of the alveolar walls. For a long time, the prevailing hypothesis has emphasised the key role of a persistent alveolitis that injures the lung and modulates fibrogenesis, regardless of initiating agents. The current concept on ILD pathogenesis relies on an epithelial/fibroblastic pathway with epithelial injury and activation, formation of subepithelial fibroblast/myofibroblast foci and excessive accumulation of extracellular matrix. An essential step in the restoration of alveolar integrity is the rapid re-epithelialisation of the altered surface, mainly through epithelial proliferation and migration. In the context of lung growth and development in paediatric ILD, it is suggested that the programmed production of mitogenic factors may promote the process of re-epithelialisation and may help to counteract the altered secretion of mediators involved in migration and proliferation of fibroblasts and differentiation into myofibroblasts. This is supported by clinical observations indicating that paediatric ILD is more responsive to therapeutic strategies than adult ILD.

Clinical presentation of interstitial lung disease in children.

Interstitial lung disease (ILD) in children represents a heterogeneous group of rare lung disorders characterised by an inflammatory process of the alveolar wall and the pulmonary interstitium, which share common clinical, radiological and histological findings. Clinical presentation of paediatric ILD is non-specific and variable. Respiratory signs and symptoms include tachypnoea, rapid shallow breathing, retractions, cyanosis and crackles. Failure to thrive and respiratory distress are common in infants. Dyspnoea on exertion is a symptom encountered in older children. Non-respiratory symptoms can be present when ILD is part of a systemic disorder. Although non-specific and variable, the clinical presentation at the time of diagnosis has some prognostic value.

Diagnosis of interstitial lung disease in children.

Chronic interstitial lung disease (ILD) in infants and children is a challenging diagnostic clinical problem. There are many unresolved and controversial issues in the diagnosis of this heterogeneous group of uncommon disorders in children. Diagnosis requires a high index of suspicion as the initial clinical manifestations are subtle, highly variable and non-specific. There is no consensus for the clinical diagnostic criteria of paediatric ILD. The spectrum of clinical findings is highly variable. The diagnostic evaluation of a child with suspected ILD includes a comprehensive history, physical examination, oxygen saturation (at rest, during exercise or during feeding), a plain chest x ray and a high-resolution thin-cut tomography scan of the chest. Pulmonary function studies can be useful in older children; these typically show a restrictive pattern with a decreased forced expiratory volume in 1 s (FEV(1)), forced vital capacity (FVC) and total lung capacity, but normal FEV(1)/FVC. A systematic approach to diagnosis is useful in the evaluation of an infant or child with suspected chronic ILD. Due to the rarity of most of these disorders, multi-centre collaboration is needed to improve our understanding of this orphan lung disease.

Current concepts on interstitial lung disease in children.

Pediatric interstitial lung disease comprises a diverse group of rare conditions characterized by an infiltrative process, abnormal gas exchange, and restrictive lung disease. Although the disorder is similar to its adult counterpart, its course is complicated by the continued need for lung growth and differentiation in infants and children. Knowledge about the pathogenesis, prognosis, and treatment of pediatric interstitial lung disease is limited. Investigators are focusing on defining the cellular mediators of the interstitial damage and describing the role of viral infections in and possible genetic predisposition to interstitial lung disease. Clinicians continue to define the various types of interstitial lung disease and to evaluate the roles of bronchoalveolar lavage, radiography, and biopsy in diagnosis. Together, investigators are working toward the development of specific, targeted therapy that will reduce the significant morbidity and mortality seen in pediatric interstitial lung disease.

Diagnostic value of transbronchial, thoracoscopic, and open lung biopsy in immunocompetent children with chronic interstitial lung disease

Objectives: To evaluate the diagnostic value of transbronchial biopsy (TBB), video-assisted thoracoscopy (VAT), and open lung biopsy (OLB) in immunocompetent children with chronic, diffuse infiltrates; to identify factors that may predict diagnosis in children requiring biopsy; to determine whether age, number of biopsies, or type of procedure are associated with diagnostic yield in children undergoing transthoracic biopsy; and to compare morbidity of VAT with that of OLB. Study design: As part of a prospective, descriptive study to define the clinical spectrum of pediatric interstitial lung disease, 30 immunocompetent children required TBB, VAT, and/or OLB for diagnosis of diffuse infiltrates. We reviewed and analyzed the following clinical variables: age; preoperative diagnosis; type of procedure; number of lobes undergoing biopsies; durations of surgery, chest tube insertion, and hospitalization; tissue diagnosis; and complications. Results: Specific diagnoses were made in 50%, 60%, and 53% of patients undergoing TBB, VAT, and OLB, respectively. A variety of rare disorders was found, and tissue diagnosis confirmed the preoperative diagnosis in 25% of all procedures. For patients who underwent transthoracic biopsy, patient age of greater than 24 months was significantly associated with increased diagnostic yield, but the number of lobes biopsied and type of procedure were not. VAT was associated with shorter operating time, chest tube placement, and hospitalization when compared with OLB. The complications of VAT and OLB were comparable. Conclusion: Lung biopsy is an important tool for the diagnosis of interstitial lung disease in immunocompetent children, but the diagnosis of many children, particularly those aged 2 years or younger, remains uncertain. (J Pediatr 1997;131:565-9)

Congenital and pediatric interstitial disease.

Congenital and pediatric interstitial lung disease (ILD) is set in the context of the maturing lung and immune system, and thus differs completely from its adult equivalents in presentation, therapy, and outcome. We first establish the background by briefly reviewing normal maturational changes and then describe recent advances in diagnosis. We then highlight three specific topics: drugs and the lung (treatment and iatrogenic ILD); the histiocytic disorders of the lung; and congenital ILD (specifically congenital surfactant protein deficiency).

Clinical spectrum of chronic interstitial lung disease in children

To describe the clinical spectrum of interstitial lung disease in children, we reviewed our experience with 48 patients during a 12-year period. Most patients initially had typical findings of restrictive lung disease and hypoxemia. Growth failure or pulmonary hypertension or both were found in more than one third. Specific diagnosis, made in 35 patients (70%), most often required invasive studies, particularly open lung biopsy. Although the diagnostic yield from open lung biopsy was high, the diagnosis of many patients remained uncertain. Many different disorders were encountered. The response to corticosteroids, bronchodilators, and chloroquine was inconsistent. Six patients died, five within 1 year after the initial evaluation. The spectrum of pediatric interstitial lung disease includes a large, heterogeneous group of rare disorders associated with high morbidity and mortality rates.