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Research | Cole/Hamvas LAB

Neonatal respiratory distress syndrome is the most frequent respiratory cause of death and morbidity in infants less than 1 year of age in the United States. Of approximately 28,000 infant deaths in 2001, 5,421 (19.7%) were diagnosed with respiratory distress as either the primary (1,011 – 3.7%) or secondary (4,410 – 16%) cause of death. Despite consistent improvement in infant mortality rates over the last 20 years, survivors of respiratory distress syndrome with chronic respiratory disease consume twenty times more annualized dollars than unaffected children ($19,104 vs. $955) and 5.9% of all dollars spent on children from 0-18 years of age. More recent estimates from California and New York suggest that 80,000 cases of neonatal respiratory distress occur in the United States annually with 8,500 resulting deaths at a hospital cost of $4.4 billion. These medical costs do not include the economic consequences of infant respiratory morbidity for families, e.g., absence from work. In addition, despite 2-3 fold greater risk of infant mortality for Black infants than White infants from all other causes, White infants have greater risk of death from respiratory distress than Black infants, and this increased risk is not attributable to differences in phospholipid composition, birth weight, gestational age, or confounding socioeconomic factors. Understanding the mechanisms that cause respiratory distress syndrome is critical for improving outcomes of children in the United States, reducing costs of their health care, and reducing racial disparity in infant mortality.

Since the original description of deficiency of the pulmonary surfactant in premature newborn infants by Avery and Mead in 1959, respiratory distress syndrome has most commonly been attributed to developmental immaturity of surfactant production. The pulmonary surfactant is a mixture of phospholipids and protein synthesized, packaged, and secreted exclusively by type 2 pneumocytes that line the distal airways. This mixture forms a monolayer at the air-liquid interface in the alveolus that lowers surface tension at end expiration of the respiratory cycle and thereby prevents atelectasis and ventilation-perfusion mismatch. In premature infants, type 2 pneumocytes do not appear prior to 32-34 weeks of gestation, and these infants lack the ability to produce mature or functional surfactant. Availability of surfactant replacement therapy has been associated with a decline over the last 15 years in the mortality due to respiratory distress syndrome among premature infants. However, despite improvement in neonatal survival, long-term respiratory morbidity has persisted. Although persistence of respiratory morbidity has been attributed to developmental pulmonary immaturity, oxygen toxicity, and barotrauma, the fact that only a fraction of infants (5%-25%) develops these problems strongly suggests that genetic factors play an important role. By ameliorating pulmonary dysfunction immediately after birth, surfactant replacement therapy has unmasked the contribution of genetic causes of respiratory distress syndrome to morbidity and mortality in infancy. In addition, studies of different ethnic groups, gender, targeted gene ablation in murine lineages, and recent clinical reports of monogenic causes of neonatal respiratory distress syndrome have strongly suggested that genetic mechanisms contribute significantly to risk of respiratory distress syndrome in newborn infants. In contrast to developmental causes of respiratory distress which may improve as infants mature, genetic causes result in both acute and chronic (and potentially irreversible) respiratory failure.

Our laboratory has focused on understanding the contributions of candidate genes (surfactant protein B (SFTPB), surfactant protein C (SFTPC, and ABCA3 (ABCA3)) to risk of neonatal respiratory distress. Using high throughput, automated sequencing to genotype, we have used population-based and case-control cohorts to evaluate correlation between specific alleles or haplotypes and neonatal respiratory distress syndrome.

Contact Information

F. Sessions Cole, M.D.Division of Newborn MedicineSt. Louis Children's HospitalOne Children's PlaceSt. Louis, Missouri 63110Office -- 314-454-6148Laboratory -- 314-286-2866Facsimile -- 314-454-4633Electronic mail --