Improving standards of clinical care in cystic fibrosis

For the clinician involved in the care of cystic fibrosis patients, the last decade has been an exciting period. The discovery of the gene coding for the cystic fibrosis (CF) transmembrane conductance regulator (CFTR) protein [1] gave a novel impulse to CF care and research. The function of the CFTR protein was first described as a simple chloride channel. Soon evidence accumulated that the chloride channel regulates other ion channel functions [2]. The knowledge about epithelial salt and water movement across respiratory membranes greatly improved. Novel functions of the CFTR protein continue to be discovered such as a possible role in bacterial phagocytosis [3]. To a certain extent, the basic defect in CF is understood [4]. There are more than 800 known mutations in the gene that can lead to the production of an abnormal protein and hence abnormal ion transport across epithelial membranes. The abnormal composition of airway secretions can predispose patients to airway obstruction and infection with Pseudomonas aeruginosa (P. aeruginosa) and Staphylococcus aureus. The relentless neutrophil-driven lung infection and inflammation that follows culminates in organ destruction and death. The hope for a quick cure by gene therapy proved unrealistic. But the search for the basic defect and the efforts to circumvent the hurdles in gene therapy brought new insights into cell physiology and possibilities of novel therapies. All these new therapies have one thing in common that is they are likely to stop the pathophysiological process at an earlier level, before chronic infection sets in. The most basic approach would still be a correction of the defect by gene therapy. But other possibilities abound. The classification of mutations into functional groups is helpful to situate possible therapies [5]. For full function, the CFTR gene has to be translated, in sufficient amounts, into a full length protein. The protein has to travel to the cell membrane, be activated in the appropriate way, permit sufficient chloride efflux and interact normally with other ion channels. Class one mutations, usually nonsense mutations, may be overcome by drugs that read through these premature stop codons [6]. In class two mutations, including the most frequent mutation DF508, the CFTR protein is structurally abnormal and is degraded by the cell's quality control system. Chemical chaperones could assist the abnormal protein to escape from degradation and "to make it to the cell membrane" as a functional chloride channel [7]. Class three mutations interfere with the activation of the CFTR chloride channel. Compounds such as the protein phosphatase inhibitor genistein may influence the gating of the CFTR channel [8]. Improving chloride channel conductance would be the goal for class four mutations, usually mutations in the protein's transmembrane domain. Restoring the efficiency of splice mutations to normal would be the goal for class five mutations, in which insufficient amounts of functional CFTR protein are being produced. Inhibiting the excessive sodium reabsorption by amiloride may be seen as a therapy aimed at compensating for some of the control function of CFTR on other ion channel functions [9]. A spin off from unravelling the link between abnormal secretions and chronic infections are the discovery of defensins [10] and the manufacturing of synthetic defensins for future therapy. This boom of information has led to innumerable papers and several new, well structured textbooks that assist the clinician in keeping up to date with current knowledge [11±14]. The hope for a cure has strengthened clinical interest in managing the patient optimally; only patients in a fairly good condition will optimally benefit from new therapies. There has already been a vast improvement in patient survival, without using the knowledge about the basic defect but by better follow-up, more intensive treatment and attention to all aspects of this multi-system disease [15]. A central issue that remains is the correct treatment of lung infection because relentless pulmonary infection will be the cause of respiratory insufficiency and death in the majority of patients. Although knowledge has greatly improved, critical information is missing. How exactly to bridge the gap between altered chloride secretion and pulmonary infection? Why is Pseudomonas lung infection so typical for CF patients? Is it a matter of dehydrated mucus incapable of maintaining normal airway clearance? Is there an increased salt content in the secretions inhibiting the normal defensins? Do CF patients carry specific P. aeruginosa binding sites on their cell membranes? Is some preliminary lung damage required before chronic Pseudomonas infection sets in? Is there a primary overactive inflammatory status in CF lung tissue? Whilst scientists try to close the gap in knowledge, clinicians focus on optimal management of chronic lung infection. Many trials have studied aspects of antibiotic therapy for P. aeruginosa lung infection in CF. But in different countries different definitions for chronic colonization are used, different treatment protocols for Dept of Pediatrics, Pediatric Pulmonology, University Hospital of Leuven, Leuven, Belgium.