From youth to adult : studies on chronic airway obstruction with special reference to events in the neonatal period

Sammanfattning: Introduction: In western countries, 6-12% of all pregnancies end preterm, i.e. before 37 weeks of gestation. After the introduction of antenatal corticosteroids and improvements of neonatal intensive care, survival rates for children born preterm have increased worldwide. In Sweden, 80% of infants born extremely preterm, i.e. before 28 weeks of gestation, survive. There is, however, an association between preterm birth and later sequelae. Pulmonary complications, such as bronchopulmonary dysplasia (BPD), may result in lung function impairment later in life. It has also been demonstrated that a significant proportion, around 20-25%, of patients with chronic obstructive pulmonary disease (COPD) have never smoked, suggesting other risk factors for developing chronic airway obstruction in adulthood. As there are now more survivors reaching adult life, individuals born preterm are expected to be an increasing group of patients in the future, contributing to the non- smoking proportion of patients with COPD. The overall aim of this thesis was therefore to extensively characterise clinical, functional and mechanistic aspects of pulmonary outcomes in adolescence and in adult age in individuals born preterm with and without BPD. Patients and methods: Individuals born before 32 weeks of gestation between 1992 and 1998 in Stockholm County were investigated both in adolescence (n= 51) and at adult age (n= 49). Half of the individuals born preterm had a diagnosis of BPD. In adult age two control groups of patients with allergic asthma (n= 23) and healthy individuals (n=24) were included. Information on perinatal data, medical history and health related quality of life (HRQoL) was collected. Lung function was measured using dynamic spirometry, body plethysmography diffusing capacity for carbon monoxide (DLCO), impulse oscillometry (IOS) and lung clearance index (LCI) for ventilation inhomogeneity. Bronchoscopy was performed in adults (mean age 20.0 years) including sampling of the large (bronchial wash), and small airways (bronchoalveolar lavage, BAL). Results: Both adolescents and adults with BPD demonstrated airway obstruction in contrast to individuals born preterm without BPD, but both groups had more airway hyper- responsiveness compared to healthy controls. In adulthood, the preterm group had lower DLCO irrespective of BPD status, but only those with BPD had signs of inhomogeneous ventilation. Adults with BPD reported fewer physical symptoms than asthmatic controls, despite lower lung function in the former group. Both preterm groups reported lower scores in the mental component summary of a questionnaire compared to healthy controls. In contrast to the asthmatic group, no eosinophilic inflammation was seen in the preterm group. In BAL, the preterm BPD group showed an increased proportion of activated cytotoxic T cells (CD8+), a decreased proportion of T helper cells (CD4+), and, as a consequence, a decreased CD4/CD8 ratio, when compared to the healthy controls. T-cell subsets in BAL correlated with measures of airflow limitation in individuals with BPD. Further, in bronchial wash, elevated proportion of lymphocytes was observed. A correlationof lymphocyte count with measures of airflow obstruction in the preterm born individuals was seen predominantly in males. Conclusions: Individuals born preterm with a history of BPD have obstructive airflow limitations engaging the small airways. Lymphocytes may have a sex-specific role, as an increased amount was found in the large airways in males with BPD. The increased proportion of cytotoxic (CD8+) T cells in BAL resemble features of COPD, and are compatible with the hypothesis that T-cells may play a mechanistic role in development of airway obstruction in adults with a history of BPD. 5

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