Diffuse Lung Disease in Biopsied Children 2 to 18 Years of Age. Application of the chILD Classification Scheme.

RATIONALE: Children's Interstitial and Diffuse Lung Disease (chILD) is a heterogeneous group of disorders that is challenging to categorize. In previous study, a classification scheme was successfully applied to children 0 to 2 years of age who underwent lung biopsies for chILD. This classification scheme has not been evaluated in children 2 to 18 years of age. OBJECTIVES: This multicenter interdisciplinary study sought to describe the spectrum of biopsy-proven chILD in North America and to apply a previously reported classification scheme in children 2 to 18 years of age. Mortality and risk factors for mortality were also assessed. METHODS: Patients 2 to 18 years of age who underwent lung biopsies for diffuse lung disease from 12 North American institutions were included. Demographic and clinical data were collected and described. The lung biopsies were reviewed by pediatric lung pathologists with expertise in diffuse lung disease and were classified by the chILD classification scheme. Logistic regression was used to determine risk factors for mortality. MEASUREMENTS AND MAIN RESULTS: A total of 191 cases were included in the final analysis. Number of biopsies varied by center (5-49 biopsies; mean, 15.8) and by age (2-18 yr; mean, 10.6 yr). The most common classification category in this cohort was Disorders of the Immunocompromised Host (40.8%), and the least common was Disorders of Infancy (4.7%). Immunocompromised patients suffered the highest mortality (52.8%). Additional associations with mortality included mechanical ventilation, worse clinical status at time of biopsy, tachypnea, hemoptysis, and crackles. Pulmonary hypertension was found to be a risk factor for mortality but only in the immunocompetent patients. CONCLUSIONS: In patients 2 to 18 years of age who underwent lung biopsies for diffuse lung disease, there were far fewer diagnoses prevalent in infancy and more overlap with adult diagnoses. Immunocompromised patients with diffuse lung disease who underwent lung biopsies had less than 50% survival at time of last follow-up.

Desquamative interstitial pneumonia in a child related to cigarette smoke.

An 8-year-old white male was referred to our clinic for a 1-year history of decreased appetite and no weight gain. His entire workup failed to demonstrate cystic fibrosis, or any infectious or immune-related diseases. Chest imaging and clinical picture suggested parenchymal lung disease. Histopathology examination of the video-assisted thoracoscopic biopsy of his lungs showed a desquamative interstitial pneumonia (DIP)-like pattern that resembled that of adult smokers with the same disease. Genes for surfactant proteins B and C and the transporter ABCA3 were all negative. Furthermore, lack of any genetic disorder for surfactant proteins, along with his history of heavy exposure to 10 pack-years of indoor secondhand smoke suggests that this child's DIP is due to secondhand cigarette exposure. He had nearly complete resolution of his symptoms after a year of treatments with pulse steroid and hydroxycholoroquine. To the best of our knowledge this is the first case of cigarette smoke-related DIP reported in a child.

Pulmonary capillaritis in monozygotic twin boys.

Pulmonary hemorrhage can be classified as either proximal or distal (alveolar). Causes of proximal hemorrhage include infection, foreign body aspiration, pulmonary embolus, trauma, vascular malformation, and pulmonary hypertension. Causes of distal or diffuse alveolar hemorrhage are divided by the histologic presence or absence of capillaritis, which is characterized by inflammation of the alveolar interstitium and pulmonary capillary structure. Pulmonary capillaritis is a rare event in children and is associated with higher morbidity and mortality than diffuse alveolar hemorrhage without capillaritis. This is a report of 17-month-old previously healthy monozygotic twins presenting simultaneously with diffuse alveolar hemorrhage, pulmonary capillaritis, and an otherwise negative serologic workup. This suggests a role of genetic predisposition in this rare disease.

An official American Thoracic Society clinical practice guideline: classification, evaluation, and management of childhood interstitial lung disease in infancy.

BACKGROUND: There is growing recognition and understanding of the entities that cause interstitial lung disease (ILD) in infants. These entities are distinct from those that cause ILD in older children and adults. METHODS: A multidisciplinary panel was convened to develop evidence-based guidelines on the classification, diagnosis, and management of ILD in children, focusing on neonates and infants under 2 years of age. Recommendations were formulated using a systematic approach. Outcomes considered important included the accuracy of the diagnostic evaluation, complications of delayed or incorrect diagnosis, psychosocial complications affecting the patient's or family's quality of life, and death. RESULTS: No controlled clinical trials were identified. Therefore, observational evidence and clinical experience informed judgments. These guidelines: (1) describe the clinical characteristics of neonates and infants (<2 yr of age) with diffuse lung disease (DLD); (2) list the common causes of DLD that should be eliminated during the evaluation of neonates and infants with DLD; (3) recommend methods for further clinical investigation of the remaining infants, who are regarded as having "childhood ILD syndrome"; (4) describe a new pathologic classification scheme of DLD in infants; (5) outline supportive and continuing care; and (6) suggest areas for future research. CONCLUSIONS: After common causes of DLD are excluded, neonates and infants with childhood ILD syndrome should be evaluated by a knowledgeable subspecialist. The evaluation may include echocardiography, controlled ventilation high-resolution computed tomography, infant pulmonary function testing, bronchoscopy with bronchoalveolar lavage, genetic testing, and/or lung biopsy. Preventive care, family education, and support are essential.

Lung transplantation for childhood diffuse lung disease.

BACKGROUND: Pediatric diffuse lung diseases comprise a heterogeneous group of rare lung disorders which may lead to end stage lung disease and referral for lung transplantation. Previous studies are limited by small numbers of patients with specific forms of diffuse lung disease. Children with all forms of diffuse lung disease who underwent lung transplantation at two pediatric centers were evaluated in terms of several pre- and post-transplant factors and compared to children with other end stage lung disorders. METHODS: A retrospective chart review was performed on all patients transplanted between October 1, 2002 and June 15, 2007 at Texas Children's Hospital and St. Louis Children's Hospital. Multiple pre-transplant characteristics and post-transplant morbidities and mortality were compared between diffuse lung disease, cystic fibrosis, and pulmonary vascular disease groups. RESULTS: There were 31 diffuse lung disease (DLD), 57 cystic fibrosis (CF), and 16 pulmonary vascular disease (PVD) patients included in our analysis. Patients with DLD had significantly higher pre-transplant morbidity including lower percent predicted of forced expiratory volume in first second (P = 0.013) and more patients with pulmonary hypertension (P = 0.001) and hypercapnia (P = 0.031). Compared to CF patients, more DLD and PVD patients required invasive ventilation (P = 0.001) and care in the pediatric intensive care unit (P = 0.001). After transplant, there was a difference among the three groups with regards to number of acute allograft rejections but statistical limitations preclude knowing between which group the difference lies. A difference in time to bronchiolitis obliterans was found between the PVD and CF groups but not when compared to the DLD patients. The three groups had similar time to post-transplant lymphoproliferative disease, rate of infections, and survival. CONCLUSION: Lung transplantation is as successful for patients with end stage diffuse lung disease as compared to other lung transplant candidates.

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.

Diagnosis and management of diffuse lung disease in children.

Diffuse lung disease [DLD] in children comprises a group of heterogeneous, rare disorders. Despite the rarity of these diseases there has been a considerable increase in our knowledge of DLD in children including their diagnosis and management. Diagnosis of these diseases requires a detailed history and physical examination, diagnostic imaging, pulmonary function testing, selected and directed laboratory testing, bronchoalveolar lavage and in most cases an open lung biopsy. Once a diagnosis is made, treatment is centred on supportive care including nutritional and supplemental oxygen therapy when needed. Medications including corticosteroids and other immunomodulatory medications are often used. Lung transplantation has been used for final treatment in some cases of DLD. Formation of research collaborations will continue to further our understanding of these diseases.

Interstitial lung disease in children.

PURPOSE OF REVIEW: 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. RECENT FINDINGS: 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. SUMMARY: 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.

Frequency, treatment, and functional outcome in children with hypersensitivity pneumonitis.

BACKGROUND: Hypersensitivity pneumonitis is a rare interstitial lung disease and very few data regarding frequency, treatment and outcome exist for children. Children identified with hypersensitivity pneumonia from a Danish national cohort with diffuse interstitial lung disease form the basis of this study focused on disease frequency, treatment, and functional outcome. METHODS: Seventy-three children with clinical and radiological signs of interstitial lung disease verified by lung biopsy were identified over a 12-year period. Histologic material from all cases was reviewed by pathologists from the ChILD Clinical and Research Network, USA. Diagnosis of hypersensitivity pneumonitis was confirmed in 19 cases. MEASUREMENTS AND MAIN RESULTS: Incidence of hypersensitivity pneumonitis was approximately 2/year and with a point prevalence of 4/1,000,000 children. The median (range) number of monthly courses with intravenous methylprednisolone was 15 courses (8-34) in resolved cases, but in the vast majority (92%), mono-therapy with high dose pulse methylprednisolone treatment was not sufficient for acceptable improvement. Lung function, DLco and DLco/VA increased significantly after 3 and 6 months of treatment compared to baseline (P < 0.05). However, without reaching normal values [mean SDS (range) FEV(1) -0.66 (-1.88 to 0.41) and FVC -0.67(-1.94 to 0)]. No mortality was seen. CONCLUSIONS: Incidence and point prevalence of hypersensitivity pneumonitis in Denmark was 2/year and 4/1.000.000 children. High dose intravenous methylprednisolone constituted the basic treatment, but in most cases supplemental anti-inflammatory therapy was necessary. Outcome was acceptable without any mortality. Nevertheless, both lung function and diffusion capacity were in subnormal level though without any clinically functional impact.

Evaluation and management of pulmonary disease in ataxia-telangiectasia.

SUMMARY: Ataxia-telangiectasia (A-T) is a rare autosomal recessive disorder caused by mutations in the ATM gene, resulting in faulty repair of breakages in double-stranded DNA. The clinical phenotype is complex and is characterized by neurologic abnormalities, immunodeficiencies, susceptibility to malignancies, recurrent sinopulmonary infections, and cutaneous abnormalities. Lung disease is common in patients with A-T and often progresses with age and neurological decline. Diseases of the respiratory system cause significant morbidity and are a frequent cause of death in the A-T population. Lung disease in this population is thought to exhibit features of one or more of the following phenotypes: recurrent sinopulmonary infections with bronchiectasis, interstitial lung disease, and lung disease associated with neurological abnormalities. Here, we review available evidence and present expert opinion on the diagnosis, evaluation, and management of lung disease in A-T, as discussed in a recent multidisciplinary workshop. Although more data are emerging on this unique population, many recommendations are made based on similarities to other more well-studied diseases. Gaps in current knowledge and areas for future research in the field of pulmonary disease in A-T are also outlined.

Serial measurements of lung function in a cohort of young children with bronchopulmonary dysplasia.

OBJECTIVE: We aimed to prospectively and longitudinally measure lung function in a cohort of children with bronchopulmonary dysplasia (BPD) during their first 3 years of life. METHODS: Forty-four children with BPD with a mean (+ or - SD) gestational age of 25.6 (+ or - 1.7) weeks and birth weight of 0.767 (+ or - 0.2) kg underwent serial measurements of lung function (maximum flow at functional residual capacity [V(max)FRC] and functional residual capacity [FRC]) at 6, 12, and 24 months after initial discharge from the neonatal care unit. RESULTS: Compared with normative data, children with BPD had low partial expiratory airflow, measured by V(max)FRC, with mean z score (+ or - SD) of -1.92 (+ or - 1.04), -1.79 (+ or - 1.5), and -1.67 (+ or - 1.5) at 6, 12, and 24 months, respectively. Over time there was no significant improvement in z scores (P = .66), and 45% of the patients had a z score value of less than -2 (2 SDs below the mean) at the end of the study. FRC measurements steadily and significantly increased over time. Partial expiratory flow showed no correlation with gestational age, birth weight, or length of mechanical ventilation. Mean FRC was significantly higher in children who were using bronchodilators and inhaled steroids but showed no correlation with clinical symptoms. Bronchodilator response was initially present in 30% of the patients and declined to 20% at the end of the study. CONCLUSIONS: During the first 3 years of life, children with mostly moderate-to-severe BPD continue to show significant abnormalities with airflow limitation according to lung-function testing.

Interstitial Lung Disease in Children Older Than 2 Years.

The spectrum of childhood interstitial lung diseases (chILD) encompasses a group of heterogeneous, rare disorders in children characterized by diffuse pulmonary infiltrates and disordered gas exchange. Whereas the disorders that present in early life are unique to children, those that present in older children are also seen in adults. This review will concentrate on chILD presenting in children older than 2 years of age with a focus on the idiopathic interstitial pneumonias, connective tissue diseases, alveolar hemorrhage, and hypersensitivity pneumonitis. A systematic approach to diagnosis that includes a careful history and physical, computed tomography of the chest, bronchoalveolar lavage, and lung biopsy can be very helpful in establishing the correct diagnosis. Treatment approaches are described, including general supportive measures, indications for a trial of systemic corticosteroids, or other immunomodulating therapies, and when lung transplantation reserved for those with end-stage lung disease should be considered.

Neuroendocrine cell hyperplasia of infancy: diagnosis with high-resolution CT.

OBJECTIVE: Neuroendocrine cell hyperplasia of infancy is a form of childhood interstitial lung disease originally reported as persistent tachypnea of infancy. Reports of small series of cases and anecdotal experience have suggested that this disorder may have a consistent CT pattern. The purpose of this study was to review the CT findings in children with neuroendocrine cell hyperplasia of infancy to determine the findings at high-resolution CT, the diagnostic accuracy of CT compared with biopsy, and interrater reliability. MATERIALS AND METHODS: Images from 23 CT examinations of children with biopsy-proven neuroendocrine cell hyperplasia of infancy and six CT examinations of children with other childhood interstitial lung diseases were reviewed by two pediatric radiologists with special expertise in thoracic imaging. Identifying digital data were removed, and images were reviewed without clinical data. A CT assessment form was completed for each patient. RESULTS: Ground-glass opacification was the most common finding in patients with neuroendocrine cell hyperplasia of infancy. The right middle lobe and lingula were most commonly involved. Air trapping with a mosaic pattern was the second most common finding. Interrater reliability was very good with a kappa value of 0.93. The sensitivity and specificity of CT in the diagnosis of neuroendocrine cell hyperplasia of infancy were at least 78% and 100%. CONCLUSION: Neuroendocrine cell hyperplasia of infancy can have a characteristic appearance on high-resolution CT scans, the imaging findings being useful in differentiating neuroendocrine cell hyperplasia of infancy from other types of childhood interstitial lung disease. The appearance aids radiologists in suggesting a specific diagnosis but does not exclude this diagnosis; in 17-22% of cases, the readers in this study did not suggest the diagnosis of neuroendocrine cell hyperplasia of infancy when it was present.

Pulmonary alveolar proteinosis caused by deletion of the GM-CSFRalpha gene in the X chromosome pseudoautosomal region 1.

Pulmonary alveolar proteinosis (PAP) is a rare lung disorder in which surfactant-derived lipoproteins accumulate excessively within pulmonary alveoli, causing severe respiratory distress. The importance of granulocyte/macrophage colony-stimulating factor (GM-CSF) in the pathogenesis of PAP has been confirmed in humans and mice, wherein GM-CSF signaling is required for pulmonary alveolar macrophage catabolism of surfactant. PAP is caused by disruption of GM-CSF signaling in these cells, and is usually caused by neutralizing autoantibodies to GM-CSF or is secondary to other underlying diseases. Rarely, genetic defects in surfactant proteins or the common beta chain for the GM-CSF receptor (GM-CSFR) are causal. Using a combination of cellular, molecular, and genomic approaches, we provide the first evidence that PAP can result from a genetic deficiency of the GM-CSFR alpha chain, encoded in the X-chromosome pseudoautosomal region 1.

Bronchiolitis obliterans in children.

PURPOSE OF REVIEW: In this review, we discuss recent advances in our understanding of the etiology, pathology and pathogenesis, clinical presentation, diagnosis, treatment, and outcome of bronchiolitis obliterans in the nontransplant, pediatric population. RECENT FINDINGS: The diagnosis of bronchiolitis obliterans in children can be made with confidence based on clinical presentation, particularly with a history of adenovirus bronchiolitis or pneumonia, fixed obstructive lung disease on pulmonary function testing, and characteristic changes of mosaic perfusion, vascular attenuation, and central bronchiectasis on chest high-resolution computed tomography, thus avoiding the need for lung biopsy in most patients. Patients with postinfectious bronchiolitis obliterans generally have chronic, nonprogressive disease; in contrast, patients with bronchiolitis obliterans from Stevens-Johnson syndrome often have progressive disease that may require lung transplantation. SUMMARY: Bronchiolitis obliterans is a rare form of chronic obstructive lung disease that follows a severe insult to the lower respiratory tract, resulting in fibrosis of the small airways. In the nontransplant pediatric population, adenovirus infection is the most common cause. Treatment is largely supportive and prognosis is mainly related to the underlying cause and to the severity of the initial insult.

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

RATIONALE: 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. OBJECTIVES: 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. METHODS: 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. MEASUREMENTS AND MAIN RESULTS: 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. CONCLUSIONS: 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.

Diffuse alveolar hemorrhage syndromes in children.

PURPOSE OF REVIEW: In this review we discuss the changing concepts of diffuse alveolar hemorrhage in children in terms of an expanded differential diagnosis and new approaches to diagnosis and treatment. RECENT FINDINGS: More commonly found in adults, pulmonary capillaritis, an immune-mediated form of diffuse alveolar hemorrhage often associated with systemic disease, has been recently reported in children. In a series of eight children with pulmonary capillaritis, serology for immune-mediated disorders was positive in only half. Acute idiopathic pulmonary hemorrhage is a unique condition of infants who present with acute pulmonary hemorrhage and respiratory failure. The hypothesis that acute idiopathic pulmonary hemorrhage is caused by toxigenic mold has not been proven, and its cause remains uncertain. SUMMARY: Classification of diffuse alveolar hemorrhage in children has been revised to include those conditions with and without pulmonary capillaritis. As idiopathic pulmonary hemosiderosis, the classic form of diffuse alveolar hemorrhage in children, is a diagnosis of exclusion and children with pulmonary capillaritis may have negative serology, lung biopsy should be strongly considered in any child with diffuse alveolar hemorrhage without a cardiovascular cause. Generally, patients with immune-mediated lung disease require more aggressive pharmacologic intervention.