Bronchopulmonary dysplasia from newborn disease to long-term sequelae

Bronchopulmonary Dysplasia (BPD) is a complication of premature birth that is associated with increased mortality and morbidity in infancy and impaired lung function and obstructive lung disease from childhood to adulthood. The pathogenesis of BPD is multifactorial, and may involve one or more of the following: a deficiency in surfactant production in the immature lung, chronic inflammatory processes before and after birth, oxidative stress, and trauma due to mechanical ventilation. Surfactant replacement therapy, which reduces acute lung injury in the preterm infant, could be one way to prevent later development of BPD. So far, surfactant therapy requires invasive intubation that may itself be traumatic. In this thesis, we evaluated an alternative, non-invasive way to deliver surfactant. This trial of surfactant inhalation via nasal CPAP in spontaneously breathing infants unfortunately did not prove beneficial.

Pre- and postnatal inflammatory processes may initiate and aggravate the course of BPD. Some of the underlying inflammatory processes e.g. activation of the neutrophil and macrophage systems, have been well described but other processes, such as the role of eosinophils and other inflammatory markers in the pathology of BPD, have not yet been well characterised. This thesis shows that levels of activated eosinophils in the circulation are elevated in infants with BPD, a sign of chronic, systemic inflammation. We also found that the degree of eosinophil activation was positively associated with the severity of BPD (as determined by the duration of supplementary O2 treatment). Future studies may establish whether a causal relationship exists between states of eosinophil activation in preterm infants and BPD.

Moderate and severe BPD is associated with an increased risk for airway obstruction and low forced expiratory volume in childhood. As shown herein, respiratory mechanics is also altered in children with mild BPD. This finding is important because it emphasizes the need for careful clinical follow up of all BPD children, regardless of the severity of the disease, in order to minimize further deterioration in lung function. BPD not only affects lung function but general development as well; thoseffected may develop cognitive and motor performance deficits and exhibit behavioural difficulties.

This thesis also sheds new light on public health consequences of very preterm birth. We know little about the possible long-term consequences of premature birth for lung function in old age. In a unique birth cohort born in 1925-49 in Sweden, we found that moderate to-very preterm birth is associated with obstructive lung disease in old age, the severity of which required frequent hospitalisation. The results from this historic cohort cannot be directly extrapolated to preterm infants born today. However, the much higher survival rate in the modern era of neonatal intensive care suggests that infants born preterm nowadays could be at even higher risk of developing obstructive airways disease in adult life than were previous generations. This finding emphasizes the importance of extending follow up programs into adult life.

Preterm birth is a global and serious health issue. A better understanding of its potential adverse impact in infancy and childhood may lead to better intervention and treatment strategies and improved long-term outcome.

List of scientific papers

I. Berggren E, Liljedahl M, Winbladh B, Andreasson B, Curstedt T, Robertson B, Schollin J (2000). "Pilot study of nebulized surfactant therapy for neonatal respiratory distress syndrome." Acta Paediatr 89(4): 460-4
https://pubmed.ncbi.nlm.nih.gov/10830460

II. Broström EB, Katz-Salamon M, Lundahl J, Halldén G, Winbladh B (2007). "Eosinophil activation in preterm infants with lung disease." Acta Paediatr 96(1): 23-8
https://pubmed.ncbi.nlm.nih.gov/17187598

III. Broström EB, Thunqvist P, Adenfelt G, Borling E, Katz-Salamon M (2009). "Obstructive lung disease in children with mild to severe BPD." Respir Med Nov 9: Epub ahead of print
https://pubmed.ncbi.nlm.nih.gov/19906521

IV. Berggren Broström E, Adenfelt G, Lindqvist C, Örtenstrand A, Farooqi A (2010). "Motor performance, cognitive development and behavioral characteristics in children at school age with mild to severe BPD." (Manuscript)

V. Berggren Broström E, Akre O, Katz-Salomon M, Jaraj D, Kaijser M (2010). "Obstructive Pulmonary Disease in old age among individuals born preterm." (Submitted)