Programme Contents

Early lung disease in cystic fibrosis

Cystic fibrosis (CF) is the most common life-shortening genetic disease in Caucasians with a carrier frequency of 1/25 and 1/2500-3000 newborn infants affected. The accumulation of thick, tenacious secretions in the lungs leads early in life to recurrent chest infections associated with neutrophilic airway inflammation and structural lung damage resulting in bronchiectasis and air trapping. Eventually progressive structural damage leads to respiratory failure and pulmonary hypertension, the need for lung transplantation, or premature death. CF affects around 3200 Australians and for a chronic disease it has one of the nation's highest health costs/patient. Lung disease starts in infancy and despite the combined effects of improved clinical outcomes following newborn screening, treatment in specialist centres and aggressive early management, structural lung damage is found in most Australian CF children by age 5 years. Spirometry using forced expiratory volume in one second (FEV₁) is usually normal in early childhood and falls over time, with the greatest fall in FEV₁ seen during the adolescent and young adult years.

The Australasian CF bronchoalveolar lavage (ACFBAL) study was completed in 2009. This multicentre trial was designed to examine the safety and clinical value of bronchoalveolar lavage BAL to diagnose early airway infection in infants and preschool children with CF. Children were randomized at mean age of 3.6 (SD 1.6) months to either (i) BAL-directed therapy or (ii) standard management of clinical features and oropharyngeal cultures, and intensively followed and monitored for 5 years. Overall, 157 children completed the study to 5 years of age. At age 5 years all children completed a BAL, chest computed tomography (CT) scan, clinical and audiology assessment, lung function and health related quality of life assessment (HRQOL). At the 5 year assessments there was no difference in any clinical outcomes between the randomized groups. In the ACFBAL study, a doubling of pulmonary exacerbations in the first 2 years of life was associated with reduced FEV₁. Exacerbations that required hospitalisation over the first 5 years of life were associated with bronchiectasis at age 5 (OR 2.74, 95% CI 1.42, 5.31, P=0.003). These data suggest that airway wall remodelling may occur following recurrent respiratory exacerbations in the first 2 years of life and that matrix destruction is more related to severity of exacerbation. Chest CT scans of infants and young patients show trapped air in almost 50% of children, even from 3 months of age and this proportion remains roughly constant to age 5 years, while the proportion of children with bronchial dilatation and bronchiectasis increases over the first 5 years of life, suggesting varying processes with different progression rates.

The CF lung microenvironment is characterized by depleted periciliary fluid, abnormal mucus and submucosal gland hypertrophy. Mucociliary transport is impaired with viscid mucus retention and formation of microaerophilic mucous plugs. This leaves the airways susceptible to infection. In the first 2 years of life S. aureus and H. influenzae are the most commonly isolated pathogens. However, P. aeruginosa is the major CF lung pathogen, affecting almost 80% of adults patients. Chronic P. aeruginosa infection is associated with increased morbidity and mortality. Age of developing chronic infection is also important and if this begins in children aged <6 years there is a much greater risk of severe lung disease and early death. Up to 50% of preschool children with CF will have at least one transient episode of P. aeruginosa infection. While early, aggressive antibiotic therapy can delay the onset of chronic infection, even these initial, intermittent infections are associated with increased levels of airway neutrophil elastase and an increased risk of bronchiectasis. Other organisms are now more commonly isolated from respiratory cultures and may be associated with declining lung function. Understanding longitudinal changes in microbial communities within the CF airways is vital in examining these issues. In the ACFBAL study at age 5 years, only children who had received previously eradication therapy for P. aeruginosa had S. maltophilia infection detected on BAL (7/89 (8%) vs 0/67 respectively; P=0.02 Fisher's exact test). Similarly 22/89 (25%) children who received eradication therapy had Aspergillus fumigatus in their BAL fluid at age 5 years compared with 3/67 (4.5%) (P< 0.001 Chi²) children who had not received this treatment. The long term risks of emerging organisms on health outcomes and the potential effects of early therapeutic interventions, such as P. aeruginosa eradication, are not well understood. Culture-independent methodology demonstrates that complex microbial communities exist within the airways. In CF, their composition varies with age, the presence of dominant organisms, such as P. aeruginosa and antibiotic exposure and understanding how microbial communities interact and change with time will be vital across many conditions including CF.