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Abstract
Unrecognised airway infection and inflammation may begin early in life in children with cystic fibrosis (CF). This may lead to lung function decline and irreversible lung disease before conventional investigations such as chest x-rays and spirometry become abnormal. Bronchoalveolar lavage (BAL), the current standard for assessing airway infection and inflammation in young children, is invasive, resource-intensive and not easily repeated. Sensitive, non-invasive measures to detect and monitor early CF lung disease are required. The main aim of this thesis was to determine whether the lung clearance index (LCI), a measure of ventilation inhomogeneity reflecting peripheral airway disease, the neutrophilic S100 proteins, S100A8/A9 (calprotectin) and S100A12 measured in serum and urinary desmosine, a measure of (lung) elastin breakdown, were sensitive, non-invasive markers of airway infection and inflammation in newborn-screened infants and young children with CF. A secondary aim was to determine whether distal gastro-oesophageal reflux and BAL pepsin were associated with early lung disease.
The LCI was measured in sedated infants and young children with CF and healthy children of the same age using a multiple breath washout method and a portable, commercially available ultrasonic flowmeter. S100A8/A9 and S100A12 were measured by a commercially available and an “in-house” assay respectively. Urinary desmosine was measured by a modified high performance liquid chromatography technique and pepsin activity by fluorometric assay.
This thesis has shown for the first time that the LCI is elevated in CF infants and young children especially in the presence of P. aeruginosa infection and airway inflammation. Further, the LCI was assessed to have good within and between test repeatability. The S100 proteins were elevated in BAL fluid and serum in the presence of infection and inflammation but serum levels were insufficiently sensitive to be useful non-invasive markers of early lung disease. Urinary desmosine was not elevated in clinically stable CF infants and young children. BAL Pepsin was associated with airway infection and inflammation. These findings suggest that the LCI but not the S100 proteins or urinary desmosine are useful, sensitive markers of early disease in minimally symptomatic young children with CF and that microaspiration may contribute to airway inflammation.