Claire Langston

Thoracoscopic and open lung biopsies are being performed with increasing frequency in neonates and infants and are an important component of the diagnostic evaluation of respiratory compromise in these very young children. Diffuse lung disease in infancy includes a wide spectrum of developmental, genetic, inflammatory, infectious, and reactive disorders. The majority of the entities diagnosed in infancy (68%) in this retrospective lung biopsy series are seen almost exclusively in this age group and not in older children and adults. These include primary disorders of pulmonary and pulmonary vascular development, secondary disorders affecting prenatal and/ or postnatal lung growth, genetic disorders of surfactant function, pulmonary interstitial glycogenosis, and neuroendocrine cell hyperplasia of infancy. Although the diagnostic approach to infant lung biopsies is guided primarily by the clinical history and imaging findings, all cases require careful assessment of alveolar growth, vascular architecture, interstitial cellularity, and histologic patterns associated with genetic abnormalities of surfactant metabolism. Recognition of one or more of these processes assists not only in treatment planning but also in further diagnostic evaluation and prognostication and may have implications for subsequent siblings and other family members. In this study, we have applied a classification system developed by a North American multicenter multidisciplinary group to lung biopsies seen at our institution and have used this material to describe and illustrate the spectrum of diffuse lung disease in infancy.

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.

This is the first of a series on pediatric pulmonary disease that will appear as Perspectives in Pediatric Pathology over the coming months. The series will include practical issues, such as this protocol for handling lung biopsies and another on bronchoalveolar lavage in childhood, as well as reviews of advances in various areas in pediatric pulmonary pathology. It has been 11 years since the last Perspectives on pulmonary disease. Much has happened since then in this area, and this collection will highlight some emerging and rapidly advancing areas in pediatric lung disease. These will include a review of molecular mechanisms of lung development, and another of mechanisms of pulmonary vascular development. The surfactant system and its disorders, as well as recent advances in the biology of the pulmonary neuroendocrine system and mechanisms of respiratory viral disease, will be addressed. Articles on pulmonary hypertension, pulmonary neoplasia, and pediatric lung transplantation, with their implications for the pediatric pathologist, are also planned. The contributors to this series are a diverse group with special interests and expertise in these areas. As Dr. William Thurlbeck noted in his foreword to the previous volume, Pulmonary Disease, volume 18 of Perspectives in Pediatric Pathology, pediatric pathology had been largely concerned with phenomenology, rather than with mechanisms, model systems, and experimental investigation. I think he would have been pleased to see the changes that have occurred over the past 10 years in pediatric lung biology and pathology in particular, because these were particularly favored interests of his later years.

Objectives. To identify the causes of mortality in children with vertically transmitted human immunodeficiency virus (HIV) infection and to study age-related mortality trends. Methods. In the multicenter P²C²HIV Study, 816 children born to HIV-infected mothers were followed for a median of 3.6 years. Two hundred five study participants with HIV infection were enrolled at a median age of 23 months; 611 were enrolled either prenatally or in the neonatal period before their HIV infection status was known. There were 121 deaths in study patients. The cause of death for all patients, its relationship to HIV infection, and pulmonary or cardiac involvement were determined. Age trends in disease-specific mortality were summarized for the HIV-related deaths. Results. Ninety-three children died of HIV-related conditions. Infection was the most prevalent cause of death for children under 6 years of age with 32.3% caused by pulmonary infection and another 16.9% caused by nonpulmonary infection. The frequency of pulmonary disease as the underlying cause of death decreased significantly with increasing age: 5/9 (55.6%) by age 1, 1/12 (8.3%) after age 10 years. The frequency of chronic cardiac disease as the underlying cause increased with age—0% by age 1 year, 3/12 (25.0%) after age 10 years, as did the frequency of wasting syndrome with disseminated Mycobacterium avium complex—0% by age 1 year, 6/12 (50.0%) after age 10 years. Conclusions. Children with HIV who survive longer are less likely to die of pulmonary disease or infection and more likely to die of cardiac causes or with wasting syndrome. pediatric acquired immunodeficiency syndrome, mortality, human immunodeficiency virus.