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INVITED REVIEW SERIES: RESPIRATORY DISEASE: USING LUNG FUNCTION MEASUREMENTS TO GREATER ADVANTAGE SERIES EDITORS: GRAHAM L HALL AND CHARLES G IRVIN
Lung function following very preterm birth in the era of ‘new’ bronchopulmonary dysplasia SHANNON J. SIMPSON,1 GRAHAM L. HALL1 AND ANDREW C. WILSON2 1
Telethon Kids Institute, The University of Western Australia and 2Department of Respiratory Medicine, Princess Margaret Hospital for Children, Perth, Western Australia, Australia
ABSTRACT One of the most significant complications of preterm birth is bronchopulmonary dysplasia (BPD). The pathophysiology of BPD has changed in recent years as advances in neonatal care have led to increased survival of smaller, more preterm, infants who display alterations to alveolar and pulmonary microvascular development. It is becoming clear that infants with ‘new’ BPD experience lung disease that persists into later childhood, however, the oldest of these children are just now entering young adulthood and therefore the longer term pulmonary implications remain unknown. The role of lung function testing in the identification and subsequent management of patients with lung disease resulting from a neonatal classification of BPD is reviewed based on the underlying pathophysiology of the disease. Key words: bronchopulmonary dysplasia, infant lung function, lung development, lung function, preterm. Correspondence: Shannon Simpson, Paediatric Respiratory Physiology, Telethon Kids Institute, PO Box 855, West Perth 6872, Western Australia. Email: shannon.simpson @telethonkids.org.au The Authors: Shannon Simpson completed her PhD in developmental respiratory physiology at the Menzies Institute for Medical Research, University of Tasmania. She is currently a National Health and Medical Research Council Peter Doherty Fellow working across a range of projects with infants and children who were born very preterm as part of the Paediatric Respiratory Physiology group at the Telethon Kids Institute, Perth, Australia. Graham Hall heads the Paediatric Respiratory Physiology research group at the Telethon Kids Institute in Perth, Australia. His main areas of research are characterizing lung growth and development in early life and in assessing the clinical utility of lung function testing approaches through childhood. Andrew Wilson is a Paediatric Respiratory and Sleep Physician at Princess Margaret Hospital, and an Honorary Research Fellow at the Telethon Kids Institute in Perth, Australia. He has a long-standing clinical and research interest in the long-term respiratory outcomes of preterm birth and bronchopulmonary dysplasia. Received 20 October 2014; invited to revise 24 November and 7 December 2014; revised 2 and 11 December 2014; accepted 29 December 2014 Article first published online: 27 February 2015 © 2015 Asian Pacific Society of Respirology
Abbreviations: BPD, bronchopulmonary dysplasia; DLCO, diffusing capacity of the lung for carbon monoxide; FEF, forced expiratory flow; FEV1, forced expiratory volume in 1 s; FRC, functional residual capacity; FVC, forced vital capacity; LCI, lung clearance index; NO, nitric oxide; PMA, post-menstrual age; TLC, total lung capacity; RV, residual volume.
INTRODUCTION Rates of preterm birth have increased in almost all countries over the past 20 years,1 such that approximately 15 million (11.1%) of the world’s babies were delivered preterm (before 37 completed weeks of gestation) in 2010.2 Complications of preterm birth are the leading cause of child death in most high and middle-income countries3 and those who go on to survive often face a lifetime of ongoing health problems. One of the most significant complications of preterm birth and the most common form of chronic lung disease in infancy is bronchopulmonary dysplasia (BPD).4 Preterm infants generally have a significant burden of respiratory disease in the first years of life which is accentuated by lower gestational age and the coexistence of BPD,5 with increased respiratory symptoms, health-care utilization and hospital admissions consistently reported.6–8
Definition and risk factors for BPD Many potential risk factors have been identified for the development of BPD (see Fig. 1) including lower gestational age,9 low birth weight for gestational age,10 white race,11 male gender,12 genetic factors13 and other common sequelae during the neonatal period such as intraventricular haemorrhage, necrotizing enterocolitis, patent ductus arteriosis or sepsis.14–16 The current consensus definition determines BPD at 36 weeks post-menstrual age (PMA) in infants born less than 32 weeks gestation who required supplementary oxygen for at least 28 days. Further sub-categories are defined as mild/moderate/severe based on the amount of supplemental oxygen and method of Respirology (2015) 20, 535–540 doi: 10.1111/resp.12503
536
SJ Simpson et al.
Figure 1 Pathophysiology of ‘new’ bronchopulmonary dysplasia (BPD). The immature lung is subjected to many insults in the neonatal period following preterm birth. Some of these insults are known to be associated with a subsequent diagnosis of BPD (grey). While the mechanisms are not entirely understood, inflammation and oxidative stress have previously been implicated in the process. Infants receiving a diagnosis of bronchopulmonary dysplasia show altered lung development (blue), the severity of which may be reflected in their lung function outcomes.
respiratory support at 36 weeks PMA.17 The definition of BPD based on oxygen requirement has some limitations and results in a heterogeneous disease phenotype since oxygen requirement could be reflective of obstructive or central apnoea rather than gas exchange impairment alone. This is further compounded by the levels of oxygenation that are considered acceptable by different clinicians in different institutions.
Disease pathophysiology The pathophysiology of BPD has considerably changed since it was first described as a disease characterized by severe respiratory failure following ventilation with high pressure and oxygen concentrations during infancy by Northway.18 Advances in neonatal care such as increasing use of antenatal maternal corticosteroids, widespread use of exogenous surfactant therapy and the development of less aggressive ventilation strategies has led to increased survival of smaller infants of lower gestational age such that half of live born babies under 25 weeks now survive in high-income countries.2 As a result of the earlier interruption to normal lung development and the subsequent lung injury arising from life-saving measures in the critically ill preterm neonate, the contemporary disease is characterized by disruption of the alveolar and microvascular development of the peripheral lung.19 The predominant histological findings from autopsy and lung biopsies in infants with ‘new’ BPD are a decreased number of alveoli, which are larger and more simplified in strucRespirology (2015) 20, 535–540
ture, as well as blunted pulmonary microvascular growth.20 Animal models of preterm birth also display fewer and larger alveoli21 and altered deposition of elastic fibres.22 In addition, animal models suggest alterations in alveolar epithelial cells, particularly thickened cytoplasmic extensions of type–I cells leading to thicker air-blood barriers for gas exchange,23,24 and the presence of pulmonary inflammation,25 though it is unclear whether preterm birth or factors associated with the life-saving interventions are associated with such observations. It is becoming clear that children with new BPD experience lung disease that persists into later childhood; however, it remains unknown whether these modern survivors of preterm birth experience accelerated lung function decline and what the long-term implications of lower ‘peak’ lung function is as the preterm individual ages and consequently undergoes the natural loss of lung function. This review will focus on respiratory physiology testing for the identification and subsequent management of patients with lung disease resulting from a neonatal diagnosis of BPD in the modern era, with reference to the underlying pathophysiology of the disease.
Measurement of forced flows and volumes Measurements of forced flows and volumes have been performed from infancy through to children, adolescents and adults born preterm. In general, the results suggest that older children and adolescents born very preterm (
INVITED REVIEW SERIES: RESPIRATORY DISEASE: USING LUNG FUNCTION MEASUREMENTS TO GREATER ADVANTAGE SERIES EDITORS: GRAHAM L HALL AND CHARLES G IRVIN
Lung function following very preterm birth in the era of ‘new’ bronchopulmonary dysplasia SHANNON J. SIMPSON,1 GRAHAM L. HALL1 AND ANDREW C. WILSON2 1
Telethon Kids Institute, The University of Western Australia and 2Department of Respiratory Medicine, Princess Margaret Hospital for Children, Perth, Western Australia, Australia
ABSTRACT One of the most significant complications of preterm birth is bronchopulmonary dysplasia (BPD). The pathophysiology of BPD has changed in recent years as advances in neonatal care have led to increased survival of smaller, more preterm, infants who display alterations to alveolar and pulmonary microvascular development. It is becoming clear that infants with ‘new’ BPD experience lung disease that persists into later childhood, however, the oldest of these children are just now entering young adulthood and therefore the longer term pulmonary implications remain unknown. The role of lung function testing in the identification and subsequent management of patients with lung disease resulting from a neonatal classification of BPD is reviewed based on the underlying pathophysiology of the disease. Key words: bronchopulmonary dysplasia, infant lung function, lung development, lung function, preterm. Correspondence: Shannon Simpson, Paediatric Respiratory Physiology, Telethon Kids Institute, PO Box 855, West Perth 6872, Western Australia. Email: shannon.simpson @telethonkids.org.au The Authors: Shannon Simpson completed her PhD in developmental respiratory physiology at the Menzies Institute for Medical Research, University of Tasmania. She is currently a National Health and Medical Research Council Peter Doherty Fellow working across a range of projects with infants and children who were born very preterm as part of the Paediatric Respiratory Physiology group at the Telethon Kids Institute, Perth, Australia. Graham Hall heads the Paediatric Respiratory Physiology research group at the Telethon Kids Institute in Perth, Australia. His main areas of research are characterizing lung growth and development in early life and in assessing the clinical utility of lung function testing approaches through childhood. Andrew Wilson is a Paediatric Respiratory and Sleep Physician at Princess Margaret Hospital, and an Honorary Research Fellow at the Telethon Kids Institute in Perth, Australia. He has a long-standing clinical and research interest in the long-term respiratory outcomes of preterm birth and bronchopulmonary dysplasia. Received 20 October 2014; invited to revise 24 November and 7 December 2014; revised 2 and 11 December 2014; accepted 29 December 2014 Article first published online: 27 February 2015 © 2015 Asian Pacific Society of Respirology
Abbreviations: BPD, bronchopulmonary dysplasia; DLCO, diffusing capacity of the lung for carbon monoxide; FEF, forced expiratory flow; FEV1, forced expiratory volume in 1 s; FRC, functional residual capacity; FVC, forced vital capacity; LCI, lung clearance index; NO, nitric oxide; PMA, post-menstrual age; TLC, total lung capacity; RV, residual volume.
INTRODUCTION Rates of preterm birth have increased in almost all countries over the past 20 years,1 such that approximately 15 million (11.1%) of the world’s babies were delivered preterm (before 37 completed weeks of gestation) in 2010.2 Complications of preterm birth are the leading cause of child death in most high and middle-income countries3 and those who go on to survive often face a lifetime of ongoing health problems. One of the most significant complications of preterm birth and the most common form of chronic lung disease in infancy is bronchopulmonary dysplasia (BPD).4 Preterm infants generally have a significant burden of respiratory disease in the first years of life which is accentuated by lower gestational age and the coexistence of BPD,5 with increased respiratory symptoms, health-care utilization and hospital admissions consistently reported.6–8
Definition and risk factors for BPD Many potential risk factors have been identified for the development of BPD (see Fig. 1) including lower gestational age,9 low birth weight for gestational age,10 white race,11 male gender,12 genetic factors13 and other common sequelae during the neonatal period such as intraventricular haemorrhage, necrotizing enterocolitis, patent ductus arteriosis or sepsis.14–16 The current consensus definition determines BPD at 36 weeks post-menstrual age (PMA) in infants born less than 32 weeks gestation who required supplementary oxygen for at least 28 days. Further sub-categories are defined as mild/moderate/severe based on the amount of supplemental oxygen and method of Respirology (2015) 20, 535–540 doi: 10.1111/resp.12503
536
SJ Simpson et al.
Figure 1 Pathophysiology of ‘new’ bronchopulmonary dysplasia (BPD). The immature lung is subjected to many insults in the neonatal period following preterm birth. Some of these insults are known to be associated with a subsequent diagnosis of BPD (grey). While the mechanisms are not entirely understood, inflammation and oxidative stress have previously been implicated in the process. Infants receiving a diagnosis of bronchopulmonary dysplasia show altered lung development (blue), the severity of which may be reflected in their lung function outcomes.
respiratory support at 36 weeks PMA.17 The definition of BPD based on oxygen requirement has some limitations and results in a heterogeneous disease phenotype since oxygen requirement could be reflective of obstructive or central apnoea rather than gas exchange impairment alone. This is further compounded by the levels of oxygenation that are considered acceptable by different clinicians in different institutions.
Disease pathophysiology The pathophysiology of BPD has considerably changed since it was first described as a disease characterized by severe respiratory failure following ventilation with high pressure and oxygen concentrations during infancy by Northway.18 Advances in neonatal care such as increasing use of antenatal maternal corticosteroids, widespread use of exogenous surfactant therapy and the development of less aggressive ventilation strategies has led to increased survival of smaller infants of lower gestational age such that half of live born babies under 25 weeks now survive in high-income countries.2 As a result of the earlier interruption to normal lung development and the subsequent lung injury arising from life-saving measures in the critically ill preterm neonate, the contemporary disease is characterized by disruption of the alveolar and microvascular development of the peripheral lung.19 The predominant histological findings from autopsy and lung biopsies in infants with ‘new’ BPD are a decreased number of alveoli, which are larger and more simplified in strucRespirology (2015) 20, 535–540
ture, as well as blunted pulmonary microvascular growth.20 Animal models of preterm birth also display fewer and larger alveoli21 and altered deposition of elastic fibres.22 In addition, animal models suggest alterations in alveolar epithelial cells, particularly thickened cytoplasmic extensions of type–I cells leading to thicker air-blood barriers for gas exchange,23,24 and the presence of pulmonary inflammation,25 though it is unclear whether preterm birth or factors associated with the life-saving interventions are associated with such observations. It is becoming clear that children with new BPD experience lung disease that persists into later childhood; however, it remains unknown whether these modern survivors of preterm birth experience accelerated lung function decline and what the long-term implications of lower ‘peak’ lung function is as the preterm individual ages and consequently undergoes the natural loss of lung function. This review will focus on respiratory physiology testing for the identification and subsequent management of patients with lung disease resulting from a neonatal diagnosis of BPD in the modern era, with reference to the underlying pathophysiology of the disease.
Measurement of forced flows and volumes Measurements of forced flows and volumes have been performed from infancy through to children, adolescents and adults born preterm. In general, the results suggest that older children and adolescents born very preterm (
