Early interventions in CF

CF lung disease is characterised by depletion of the periciliary liquid layer that impairs mucociliary transport and favours recurrent and persistent infections with bacterial pathogens (1). These infections are associated with an intense inflammatory response that persists over time. While there is ongoing debate, whether inflammation is present even in the absence of infectious organisms, BAL studies have shown that most patients with clinically stable disease and little symptoms have signs of active neutrophil inflammation in the lower airways. This neutrophil dominated airway inflammation is already found in infants with CF who were diagnosed by neonatal screening (2,3). Studies using fetal CF airways that were transplanted into immunodeficient mice have demonstrated increased production of the proinflammatory cytokine IL-8 and migration of neutrophils into the airway lumen even in the absence of pathogens (4,5). BAL studies in CF infants have also shown that both bacterial and viral infections can lead to a massive neutrophilic influx into the lung that exceeds that of normal individuals (6,7). Therefore, a vicious cycle exists between infection and inflammation in CF that ultimately leads to bronchiectasis and lung tissue destruction. Treatment strategies addressing infection or inflammation early in the course of the disease may be successful in preventing permanent damage to the lung. Bacterial infections in CF are mainly caused by 2 organisms: Staph. aureus and P. aeruginosa. Staph. aureus is the predominant organism in younger children with CF. Treatment strategies for Staph. aureus remain highly controversial. There is general agreement to treat patients in the presence of a pulmonary exacerbation with anti-staphylococcal antibiotics for 2 to 4 weeks. Many CF centres try to eradicate bacteria from CF airways with courses of oral antibiotics even in the absence of symptoms. This view is supported by BAL studies that found evidence for higher neutrophil cell counts in patients colonised with bacterial pathogens compared to those with sterile BAL fluid (8,9). AN earlier study reported that anti-staphylococcal treatment for at least 2 weeks eradicates the organism in approximately 75% of culture positive patients (10). This approach, combined with frequent respiratory cultures, results in a low rate of patients harbouring Staph. aureus for more than 6 months (9). However, Staph. aureusmay persist intracellularly as small colony variants and these variants are often missed on routine cultures (11). Prophylactic anti-staphylococcal therapy with flucloxacillin initiated from the time of diagnosis is favoured in the United Kingdom. Its efficacy has been assessed in a controlled study (12). Flucloxacillin treatment resulted in a lower rate of Staph. aureus cultures, less cough and a lower rate of hospital admissions during the observation period. There were no differences in the rate of colonisation with other bacteria in this study, but a retrospective analysis has subsequently found that continuous antistaphylococcal therapy is associated with a higher rate of P. aeruginosa acquisition in the first 6 years of life (13). Similarly, a placebo controlled multi-centre study on prophylactic cephalexin therapy from the time of diagnosis up to the age of 6 years failed to demonstrate any beneficial effect of cephalexin on pulmonary function; but a higher incidence of P. aeruginosa was observed in treated patients (14). Whether this increased risk of P. aeruginosa colonisation is specific for cephalosporins that have a broader anti-microbial efficacy or whether this finding also applies to other anti-staphylococcal agents such as flucloxacillin is still unknown. However, given the lack of convincing data proving its efficacy and in view of the potential deleterious effect of earlier P. aeruginosa acquisition, continuous prophylactic anti-staphylococcal therapy is currently not recommended. Whereas the prevalence of Staph. aureus infection in CF patients decreases with age, that of P. aeruginosa increases rendering this micro-organism the major pathogen in older patients with CF. P. aeruginosa infection increases pulmonary inflammation and has a negative effect on lung function, when this pathogen persists. The incidence of P. aeruginosa infection differs between centres and hygiene measures such as cohort isolation appear to be important for the prevention of early P. aeruginosa acquisition (15). After an initial transient colonisation period with non-mucoid strains, untreated patients generally become chronically infected with mucoid strains of P. aeruginosa that persist in