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Chorioamnionitis, Surfactant, and Lung Disease in Very Low Birth Weight Infants
Chorioamnionitis, Surfactant, and Lung Disease in Very Low Birth Weight Infants
I
n recent years the survival of infants with birth weights of nosis of RDS currently is confounded by effective less than 1 kg has been remarkable, and the focus now must postdelivery interventions to prevent and treat the disease. be directed toward decreasing short- and long-term comAnimal experiments have demonstrated that proinflamplications in survivors. Two of the major interventions to immatory cytokines can affect components of pulmonary surprove outcomes for very preterm fetuses at risk of delivery are factant.7 For example, tumor necrosis factor–a can inhibit synthesis of surfactant protein-C, and interantenatal corticosteroids and postnatal See related article, p 10 leukin-6 can increase synthesis of surfactant surfactant. Both of these interventions protein-B. Intraamniotic exposure to the gram-negative bacwere developed to target primarily respiratory distress synterial cell wall component endotoxin or interleukin-1 indrome (RDS), although antenatal corticosteroid therapy creases syntheses of surfactant lipids and surfactant also has pleiotropic effects on the fetus.1 RDS has been viewed as simply lung immaturity, with the different elements of the proteins. Deficiency of granulocyte/macrophage-colony immaturity contributing to the clinical syndrome.2 For examstimulating factor decreases catabolism of surfactant causing ple, the primary surfactant deficiency results in poor complipulmonary alveolar proteinosis. ance and atelectasis. Lung structural immaturity increases In this issue of The Journal, Been et al8 add another piece to the puzzle of effects of inflammation on surfactant. They report lung injury with ventilation, and alveolar proteinaceous edema that very preterm infants exposed to chorioamnionitis with results from epithelial and endothelial injury. Very preterm ina fetal inflammatory response had surfactant treatment fants are anticipated to have severe RDS if they have been exresponses that were inferior than for infants with a chorioamposed to minimal ‘‘fetal stress’’ and have not received nionitis exposure (no fetal inflammatory response) or no expoantenatal corticosteroids. Infants exposed to more stress (presure. The infants with the chorioamnionitis exposure and term labor, chorioamnionitis, preeclampsia, preterm rupture systemic inflammation also progressed more frequently to of membranes, etc) and corticosteroids may have less severe bronchopulmonary dysplasia (BPD). This observation is reRDS because the lungs have matured to various degrees. finement of the reports of Watterberg et al9 and Van Marter Some remarkable very preterm infants have no RDS. et al10 that chorioamnionitis can increase the risk of BPD. In the recent past, fetuses at risk for preterm delivery were Been et al8 have divided the chorioamnionitis exposure group routinely evaluated with the Lecithin/Sphingomyelin ratio or into those infants with and without a fetal inflammatory reother tests to guide delivery plans to decrease the risk of sponse. This categorization may contribute to explanations RDS.3 Obstetricians currently delay very preterm deliveries for as long as possible, and assessments of risk of RDS are of the lung injury patterns of very preterm infants in the first less helpful. Also, RDS is a less lethal disease now because days of life that progress to BPD initially described by Charaof surfactant treatments and newer approaches to ventilator feddine et al.11 Recently, Laughton et al5 found that oxygen 4 need in the first days of life predicted BPD in a large number assistance. Currently, the diagnosis of RDS in very preterm of very preterm infants. However, they did not find a good corinfants is quite imprecise because the diagnosis depends on relation between chorioamnionitis and disease progression. how the infant is treated immediately after birth. For examThey did not evaluate surfactant response. The results of ple, for centers that routinely intubate and ventilate infants Been et al8 are consistent with experimental data which showed with very low birth weight, virtually all infants will be diag5 inactivation of surfactant by proteinaceous edema fluid. nosed as having RDS, at least for statistical purposes. In contrast, in a recent trial of continuous positive airway pressure If very preterm infants have a range of RDS severity from se(CPAP), only 46% of infants transitioned after birth to vere to mild/no RDS and the risk is quite unpredictable in inbreathing with CPAP were treated with surfactant, although dividual cases,5 then we should revisit the diagnosis of RDS. 6 The results of Been et al8 suggest that chorioamnionitis with some of these infants had RDS managed with CPAP. If infants are treated with surfactant shortly after birth, then the a fetal inflammatory response categorizes infants at risk for sediagnosis of RDS cannot be reliably made. In the context of vere RDS that is less responsive to surfactant treatment. In consurfactant treatments at birth, RDS may be viewed as a surfactrast, infants exposed to chorioamnionitis but who did not tant treatment failure. The conclusion must be that the diaghave a fetal inflammation had less severe RDS than did infants
BPD CPAP RDS
Bronchopulmonary dysplasia Continuous positive airway pressure Respiratory distress syndrome
The authors received support from grant HD057869 from the National Institute of Child Health and Human Development. 0022-3476/$ - see front matter. Copyright ª 2010 Mosby Inc. All rights reserved. 10.1016/j.jpeds.2009.08.009
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THE JOURNAL OF PEDIATRICS
www.jpeds.com
without the chorioamnionitis exposure. The decreased surfactant response with the fetal inflammatory response may reflect more lung inflammation at birth. The progression to BPD may result from suppression or activation of inflammatory responses in the newborn.12 Our hunch is that these different responses result from fetal exposures to different organisms for different intervals before the preterm delivery; said another way, chorioamnionitis is an umbrella diagnosis for multiple fetal inflammatory and injury responses. Antenatal corticosteroid therapy can also modulate the acute inflammation in the fetal lung and subsequent inflammatory responses to interventions such as oxygen exposure and ventilation.13 The ‘‘RDS’’ associated with preterm birth resulting from preterm labor of unknown origin, abruption, elective deliveries for preeclampsia, and chorioamnionitis (different organisms for different durations) may not be the same. These infants with quite distinct fetal exposure histories may have varying degrees of ‘‘maturation’’ of lung structure, of the surfactant system, and of other systems that affect lung function—inflammatory responses or cardiovascular responses for example. Perhaps the diagnosis RDS should be refined. It is unlikely that very preterm infants have just one lung disease at birth, although RDS is the diagnosis assigned to most of them. n
Alan H. Jobe, MD, PhD Suhas G. Kallapur, MD Cincinnati Children’s Hospital Division of Neonatology/Pulmonary Biology University of Cincinnati Cincinnati, Ohio Reprint requests: Alan H. Jobe, MD, PhD, Cincinnati Children’s Hospital, Division of Neonatology/Pulmonary Biology, University of Cincinnati, 3333 Burnet Avenue, ML 7029, Cincinnati, OH 45229-3039. E-mail: alan.jobe@ chmcc.org.
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Vol. 156, No. 1
References 1. Roberts D, Dalziel S. Antenatal corticosteroids for accelerating fetal lung maturation for women at risk of preterm birth. Cochrane Database Syst Rev 2006;3:CD004454. 2. Jobe AH. Why surfactant works for respiratory distress syndrome. NeoReviews 2006;7:e95-105. 3. Gluck L, Kulovich MV, Borer RC Jr., Keidel WN. The interpretation and significance of the lecithin-sphingomyelin ratio in amniotic fluid. Am J Obstet Gynecol 1974;120:142-55. 4. Bloom BT, Clark RH. Comparison of Infasurf (calfactant) and Survanta (beractant) in the prevention and treatment of respiratory distress syndrome. Pediatrics 2005;116:392-9. 5. Laughon M, Allred EN, Bose C, O’Shea TM, Van Marter LJ, Ehrenkranz RA, et al. Patterns of respiratory disease during the first 2 postnatal weeks in extremely premature infants. Pediatrics 2009;123: 1124-31. 6. Morley CJ, Davis PG, Doyle LW, Brion LP, Hascoet JM, Carlin JB. Nasal CPAP or intubation at birth for very preterm infants. N Engl J Med 2008; 358:700-8. 7. Kallapur SG, Jobe AH. Contribution of inflammation to lung injury and development. Arch Dis Child Fetal Neonatal Ed 2006;91:F132-5. 8. Been JV, Rours IG, Kornelisse RF, Jonkers F, Krieger RR, Zimmernan LJ. Chorioamnionitis alters the repsonse to surfactant in preterm infants. J Pediatr 2009;156:10-4. 9. Watterberg KL, Demers LM, Scott SM, Murphy S. Chorioamnionitis and early lung inflammation in infants in whom bronchopulmonary dysplasia develops. Pediatrics 1996;97:210-5. 10. Van Marter LJ, Dammann O, Allred EN, Leviton A, Pagano M, Moore M, et al. Chorioamnionitis, mechanical ventilation, and postnatal sepsis as modulators of chronic lung disease in preterm infants. J Pediatr 2002;140:171-6. 11. Charafeddine L, D’Angio CT, Phelps DL. Atypical chronic lung disease patterns in neonates. Pediatrics 1999;103(Pt 1):759-65. 12. Kallapur SG, Jobe AH, Ball MK, Nitsos I, Moss TJ, Hillman NH, et al. Pulmonary and systemic endotoxin tolerance in preterm fetal sheep exposed to chorioamnionitis. J Immunol 2007;179:8491-9. 13. Kallapur SG, Kramer BW, Moss TJ, Newnham JP, Jobe AH, Ikegami M, et al. Maternal glucocorticoids increase endotoxin-induced lung inflammation in preterm lambs. Am J Physiol Lung Cell Mol Physiol 2003;284: L633-42.
I
n recent years the survival of infants with birth weights of nosis of RDS currently is confounded by effective less than 1 kg has been remarkable, and the focus now must postdelivery interventions to prevent and treat the disease. be directed toward decreasing short- and long-term comAnimal experiments have demonstrated that proinflamplications in survivors. Two of the major interventions to immatory cytokines can affect components of pulmonary surprove outcomes for very preterm fetuses at risk of delivery are factant.7 For example, tumor necrosis factor–a can inhibit synthesis of surfactant protein-C, and interantenatal corticosteroids and postnatal See related article, p 10 leukin-6 can increase synthesis of surfactant surfactant. Both of these interventions protein-B. Intraamniotic exposure to the gram-negative bacwere developed to target primarily respiratory distress synterial cell wall component endotoxin or interleukin-1 indrome (RDS), although antenatal corticosteroid therapy creases syntheses of surfactant lipids and surfactant also has pleiotropic effects on the fetus.1 RDS has been viewed as simply lung immaturity, with the different elements of the proteins. Deficiency of granulocyte/macrophage-colony immaturity contributing to the clinical syndrome.2 For examstimulating factor decreases catabolism of surfactant causing ple, the primary surfactant deficiency results in poor complipulmonary alveolar proteinosis. ance and atelectasis. Lung structural immaturity increases In this issue of The Journal, Been et al8 add another piece to the puzzle of effects of inflammation on surfactant. They report lung injury with ventilation, and alveolar proteinaceous edema that very preterm infants exposed to chorioamnionitis with results from epithelial and endothelial injury. Very preterm ina fetal inflammatory response had surfactant treatment fants are anticipated to have severe RDS if they have been exresponses that were inferior than for infants with a chorioamposed to minimal ‘‘fetal stress’’ and have not received nionitis exposure (no fetal inflammatory response) or no expoantenatal corticosteroids. Infants exposed to more stress (presure. The infants with the chorioamnionitis exposure and term labor, chorioamnionitis, preeclampsia, preterm rupture systemic inflammation also progressed more frequently to of membranes, etc) and corticosteroids may have less severe bronchopulmonary dysplasia (BPD). This observation is reRDS because the lungs have matured to various degrees. finement of the reports of Watterberg et al9 and Van Marter Some remarkable very preterm infants have no RDS. et al10 that chorioamnionitis can increase the risk of BPD. In the recent past, fetuses at risk for preterm delivery were Been et al8 have divided the chorioamnionitis exposure group routinely evaluated with the Lecithin/Sphingomyelin ratio or into those infants with and without a fetal inflammatory reother tests to guide delivery plans to decrease the risk of sponse. This categorization may contribute to explanations RDS.3 Obstetricians currently delay very preterm deliveries for as long as possible, and assessments of risk of RDS are of the lung injury patterns of very preterm infants in the first less helpful. Also, RDS is a less lethal disease now because days of life that progress to BPD initially described by Charaof surfactant treatments and newer approaches to ventilator feddine et al.11 Recently, Laughton et al5 found that oxygen 4 need in the first days of life predicted BPD in a large number assistance. Currently, the diagnosis of RDS in very preterm of very preterm infants. However, they did not find a good corinfants is quite imprecise because the diagnosis depends on relation between chorioamnionitis and disease progression. how the infant is treated immediately after birth. For examThey did not evaluate surfactant response. The results of ple, for centers that routinely intubate and ventilate infants Been et al8 are consistent with experimental data which showed with very low birth weight, virtually all infants will be diag5 inactivation of surfactant by proteinaceous edema fluid. nosed as having RDS, at least for statistical purposes. In contrast, in a recent trial of continuous positive airway pressure If very preterm infants have a range of RDS severity from se(CPAP), only 46% of infants transitioned after birth to vere to mild/no RDS and the risk is quite unpredictable in inbreathing with CPAP were treated with surfactant, although dividual cases,5 then we should revisit the diagnosis of RDS. 6 The results of Been et al8 suggest that chorioamnionitis with some of these infants had RDS managed with CPAP. If infants are treated with surfactant shortly after birth, then the a fetal inflammatory response categorizes infants at risk for sediagnosis of RDS cannot be reliably made. In the context of vere RDS that is less responsive to surfactant treatment. In consurfactant treatments at birth, RDS may be viewed as a surfactrast, infants exposed to chorioamnionitis but who did not tant treatment failure. The conclusion must be that the diaghave a fetal inflammation had less severe RDS than did infants
BPD CPAP RDS
Bronchopulmonary dysplasia Continuous positive airway pressure Respiratory distress syndrome
The authors received support from grant HD057869 from the National Institute of Child Health and Human Development. 0022-3476/$ - see front matter. Copyright ª 2010 Mosby Inc. All rights reserved. 10.1016/j.jpeds.2009.08.009
3
THE JOURNAL OF PEDIATRICS
www.jpeds.com
without the chorioamnionitis exposure. The decreased surfactant response with the fetal inflammatory response may reflect more lung inflammation at birth. The progression to BPD may result from suppression or activation of inflammatory responses in the newborn.12 Our hunch is that these different responses result from fetal exposures to different organisms for different intervals before the preterm delivery; said another way, chorioamnionitis is an umbrella diagnosis for multiple fetal inflammatory and injury responses. Antenatal corticosteroid therapy can also modulate the acute inflammation in the fetal lung and subsequent inflammatory responses to interventions such as oxygen exposure and ventilation.13 The ‘‘RDS’’ associated with preterm birth resulting from preterm labor of unknown origin, abruption, elective deliveries for preeclampsia, and chorioamnionitis (different organisms for different durations) may not be the same. These infants with quite distinct fetal exposure histories may have varying degrees of ‘‘maturation’’ of lung structure, of the surfactant system, and of other systems that affect lung function—inflammatory responses or cardiovascular responses for example. Perhaps the diagnosis RDS should be refined. It is unlikely that very preterm infants have just one lung disease at birth, although RDS is the diagnosis assigned to most of them. n
Alan H. Jobe, MD, PhD Suhas G. Kallapur, MD Cincinnati Children’s Hospital Division of Neonatology/Pulmonary Biology University of Cincinnati Cincinnati, Ohio Reprint requests: Alan H. Jobe, MD, PhD, Cincinnati Children’s Hospital, Division of Neonatology/Pulmonary Biology, University of Cincinnati, 3333 Burnet Avenue, ML 7029, Cincinnati, OH 45229-3039. E-mail: alan.jobe@ chmcc.org.
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Vol. 156, No. 1
References 1. Roberts D, Dalziel S. Antenatal corticosteroids for accelerating fetal lung maturation for women at risk of preterm birth. Cochrane Database Syst Rev 2006;3:CD004454. 2. Jobe AH. Why surfactant works for respiratory distress syndrome. NeoReviews 2006;7:e95-105. 3. Gluck L, Kulovich MV, Borer RC Jr., Keidel WN. The interpretation and significance of the lecithin-sphingomyelin ratio in amniotic fluid. Am J Obstet Gynecol 1974;120:142-55. 4. Bloom BT, Clark RH. Comparison of Infasurf (calfactant) and Survanta (beractant) in the prevention and treatment of respiratory distress syndrome. Pediatrics 2005;116:392-9. 5. Laughon M, Allred EN, Bose C, O’Shea TM, Van Marter LJ, Ehrenkranz RA, et al. Patterns of respiratory disease during the first 2 postnatal weeks in extremely premature infants. Pediatrics 2009;123: 1124-31. 6. Morley CJ, Davis PG, Doyle LW, Brion LP, Hascoet JM, Carlin JB. Nasal CPAP or intubation at birth for very preterm infants. N Engl J Med 2008; 358:700-8. 7. Kallapur SG, Jobe AH. Contribution of inflammation to lung injury and development. Arch Dis Child Fetal Neonatal Ed 2006;91:F132-5. 8. Been JV, Rours IG, Kornelisse RF, Jonkers F, Krieger RR, Zimmernan LJ. Chorioamnionitis alters the repsonse to surfactant in preterm infants. J Pediatr 2009;156:10-4. 9. Watterberg KL, Demers LM, Scott SM, Murphy S. Chorioamnionitis and early lung inflammation in infants in whom bronchopulmonary dysplasia develops. Pediatrics 1996;97:210-5. 10. Van Marter LJ, Dammann O, Allred EN, Leviton A, Pagano M, Moore M, et al. Chorioamnionitis, mechanical ventilation, and postnatal sepsis as modulators of chronic lung disease in preterm infants. J Pediatr 2002;140:171-6. 11. Charafeddine L, D’Angio CT, Phelps DL. Atypical chronic lung disease patterns in neonates. Pediatrics 1999;103(Pt 1):759-65. 12. Kallapur SG, Jobe AH, Ball MK, Nitsos I, Moss TJ, Hillman NH, et al. Pulmonary and systemic endotoxin tolerance in preterm fetal sheep exposed to chorioamnionitis. J Immunol 2007;179:8491-9. 13. Kallapur SG, Kramer BW, Moss TJ, Newnham JP, Jobe AH, Ikegami M, et al. Maternal glucocorticoids increase endotoxin-induced lung inflammation in preterm lambs. Am J Physiol Lung Cell Mol Physiol 2003;284: L633-42.