Exploration of the relationship between hypoxia and measures of clinical status and inflammation in children with cystic fibrosis.
Doctoral thesis, UCL (University College London).
Hypoxia in cystic fibrosis (CF) may occur during sleep, and also during exercise, chest exacerbations and air travel. No standardised definition of nocturnal hypoxia in CF exists. Theoretical evidence suggests hypoxia may have a deleterious impact on clinical status in CF, due to effects on upregulation of pro-inflammatory cytokines, changes in Pseudomonas aeruginosa growth patterns, and causation of pulmonary hypertension. It was hypothesised that hypoxia, and resultant inflammation would adversely affect clinical phenotype in CF. Forty-one children with CF were studied, each undergoing home oximetry before attending for a day of clinical testing (exercise testing, lung function, respiratory and skeletal muscle testing, echocardiography, and quality of life assessment). In vitro work was undertaken to assess the effects of hypoxia on cell growth and interleukin-8 (IL-8) secretion in wild-type and CF airway epithelial cells. The effects of hypoxia were compared to a known proinflammatory stimulus - lipopolysaccharide (LPS) from Pseudomonas aeruginosa. ROC statistics were used to derive the most sensitive and specific definition of sleep hypoxia in the detection of elevated levels of inflammation (WBC, CRP, neutrophil counts and IL-8 levels). This definition (SpO2 <93% for>10% sleep) was used to dichotomise the study population. Hypoxic CF subjects (n=9) had, when compared to normoxic controls (n=32): lower exercise capacity, lower BMI, lower FEV1 and FVC, elevated RV/TLC ratio, and higher Chrispin-Norman scores. Hypoxic subjects also had reduced quality of life, bone density, and increased RV thickness on echocardiogram. Hypoxic cell culture was suggested to be pro-inflammatory, with increased IL-8 production, and synergistically increased IL-8 secretion when cells were co-incubated with LPS under hypoxic conditions. Hypoxia is associated with reduced clinical well-being and increased inflammation in childhood CF. The paradigm exists of whether hypoxia is merely an endpoint of severe CF lung disease; or whether hypoxia may be a causative factor (as suggested by the in vitro work), as well as an effect of CF lung inflammation. A trial of restoration of normoxia in children with CF, with careful re-evaluation of clinically-relevant outcomes is suggested from this preliminary work.
|Title:||Exploration of the relationship between hypoxia and measures of clinical status and inflammation in children with cystic fibrosis|
|Open access status:||An open access version is available from UCL Discovery|
|UCL classification:||UCL > School of Life and Medical Sciences > Faculty of Population Health Sciences > Institute of Child Health > Department of Cardiorespiratory Sciences > ICH - Portex Anaesthesia|
Archive Staff Only