The role of pulmonary infection in progression of cystic fibrosis lung disease

Abstract

Cystic fibrosis (CF) is a life-shortening genetic disease characterized by variability in the age of death. This is largely due to variability in the rate of progression of lung disease, the primary cause of mortality. In most patients with cystic fibrosis (CF) life expectancy is limited due to a progressive loss of functional lung tissue. 80% of premature deaths continue to result directly or indirectly from loss of lung function. The factors associated with an increased risk of lung disease progression are: young age, high lung function, being of the female sex, certain CFTR genotypes, pancreatic insufficiency, poor nutritional status, lower socioeconomic status, respiratory viral infections, and infection of Pseudomonas aeruginosa or Burkholderia cepacia. Virtually all patients with CF are chronically infected with one or more bacterial species, and the inflammatory response to infection appears to be more intense in patients with CF. Early infection of CF in the airways is mostly caused by Staphylococcus aureus and Haemophilus influenza, than from P. aeruginosa or other gram negative stains. Recent studies, especially those following patients diagnosed by neonatal screening, have shown that infection of P. aeruginosa usually occurs at very young age. Positive antibody response to P. aeruginosa was found in children, with the mean age of 15 months, about 12 months before first cultures were positive. Also in young, non-sputum producing children it was found that throat swabs frequently showed positive cultures for P. aeruginosa. Chronic infection is prevalent in about 80% of all patients with CF. In patients with chronic infection and alginate-coated mucous strains of Ps. aeruginosa, eradication is nearly impossible. CF and Ps. aeruginosa, an unfavorable relationship, can be explained by the possibility of CFTR acting as a specific receptor for Ps. aeruginosa. CFTR may influence bacterial adherence to epithelial cells. The “overproduction” of pro-inflammatory cytokines and significantly lower levels of the anti-inflammatory cytokine IL-10, which inhibits the production of pro-inflammatory cytokines, results in excessive and persistent inflammation in the CF airways. As a result, lung functioning deteriorates more rapidly in Ps. aeruginosa-positive CF patients compared with Ps. aeruginosa-negative CF patients. Patients with cystic fibrosis are often colonized with bacteria other than PA, causing bronco-pulmonary infections that lead to the deterioration of lung functioning such as: Burkholderia cepacia complex, Achromobacter xylosoxidans and Stenotrophomonas maltophilia. Patients chronically infected with S. maltophilia are cable of rising a specific antibody response against this bacteria associated with worsening lung function. Chronic infection of S. maltophilia is correlated with a decline in lung functioning, but this decline was already present prior to the chronic infection, where the high prevalence of Aspergillus and ABPA and NTM may have contributed a role in this result. Staphylococcus aureus (S. aureus) is one of the earliest bacteria detected in infants. Treatment with anti-staphylococcal agents reduces the infection rate of MSSA but may lead to a higher rate of infection of Ps. aeruginosa. S. aureus which isolates harbor to a multitude of virulence factors, overlapping to a large degree in MSSA and MRSA. To date there are no conclusive studies demonstrating that the early aggressive treatment of MRSA respiratory infection can prevent chronic infection or if this approach ultimately improves outcomes.