Cystic Fibrosis 2012 Review
(More 2012 Topic Updates)
From the excellent summary by Felix Ratjen (U-Toronto) and Susanna McColley (Northwestern) in the May 2012 AJRCCM (Blue Journal), and our own cystic fibrosis literature review.
Pulmonary Infection in Cystic Fibrosis
The standard practice of early eradication of Pseudomonas aeruginosa in cystic fibrosis patients — giving inhaled antibiotics soon after detection of Pseudomonas on routine surveillance cultures in young children with CF — has reduced the prevalence and burden of this chronic infecting pathogen. However, the best method (drug, dose, course) of eradicating Pseudomonas and the best way to guide therapy (e.g, sputum culture intervals, lung function testing, etc.) are still debated.
One month of inhaled tobramycin was already known to be efficacious at eradicating Pseudomonas; adding oral ciprofloxacin did not seem to add any benefit to inhaled “tobi” for CF patients, in the randomized EPIC trial published in 2011. The trial also suggested that a less-aggressive surveillance and eradication strategy — continuing cycles of inhaled tobramycin only if a child produced Pseudomonas-positive sputum — led to equally good outcomes as compared to empiric cycles of tobramycin or requiring invasively-obtained (bronchoscopic) BAL samples for culture from children who could not produce sputum.
As Pseudomonas has become better-controlled, other organisms like Stenotrophomonas maltophilia and Burkholderia cepacia — are increasingly more commonly isolated from sputum cultures in patients with cystic fibrosis. What is their significance? No one really knows:
- Stenotrophomonas may or may not contribute to CF exacerbation risk.
- Some Burkholderia cepacia subspecies or phenotypes — but not all — accelerate decline of lung function in CF patients. The nonmucoid strains are more dangerous, perhaps because they are more likely to be invasive. (This is in contrast to Pseudomonas, in which mucoid subtypes are more harmful.)
- Antibiotics (ciprofloxacin and ceftazidime in one study), common treatments for CF exacerbations, may shift Burkholderia populations to a nonmucoid (more harmful) phenotype. What to do with this information is unclear.
Because the airways in CF represent a complex local ecosystem of competing/coexisting bacterial communities, the absolute numbers of bacteria grown in culture — and their sensitivities to antibiotics — are probably misleading indicators of infection or exacerbation and not helpful as guides to therapy decisions (although they are commonly used thusly, anyway).
Cystic Fibrosis and Airway Inflammation Research
Infection causes inflammation of course, but inflammation is being actively investigated as an independent contributor to lung function decline and exacerbations in cystic fibrosis, and as a possible target of therapy in its own right. Inhibition of arginase might reduce the functional nitric oxide deficiency that exists in CF patients. Cytokine pathways (IL-8, IL-17) are being investigated as potential targets of therapy. We’re years away from any conceivable human trial using drugs to influence these pathways.
New Treatments for Cystic Fibrosis
- Inhaled aztreonam lysine has become an accepted alternative to inhaled tobramycin for managing chronic Pseudomonas infection in cystic fibrosis.
- Once-daily inhaled levofloxacin is in a Phase III trial for treatment of chronic Pseudomonas infection in cystic fibrosis, as well.
- Denufosol, which activates chloride secretion without requiring functional CFTR, did not ultimately show improvement in lung function or reduction in exacerbations, and drug development was stopped.
- Ivacaftor (Kalydeco), a potentiator of CFTR that works in the ~5% of CF patients with the specific CFTR mutation G551D, worked well in small Phase III trials — it reduced CF exacerbations and improved lung function — and was approved by the FDA early in 2012 for cystic fibrosis patients with the G551D mutation. It is being tested as an adjunctive therapy in patients with other mutations, to try to expand its limited indication. (It is unlikely to work in patients with the most common mutation, F508-del, but might be tested as adjunctive therapy in this much larger group of patients).
Ivacaftor (Kalydeco) will cost about $300,000 per year, per patient. It was developed by Vertex Pharmaceuticals with support of $75 million in research funding from the Cystic Fibrosis Foundation, who will receive royalties from Kalydeco’s sales.
Prognosis and Outcomes in Cystic Fibrosis
Successful management of cystic fibrosis has ironically resulted in a lower sensitivity of the most common parameter to measure changes in status — FEV1 on spirometry, which is today may often be normal in patients with optimally-treated CF.
New CT imaging techniques to identify inhomogeneity in ventilation — such as the “lung clearance index” — are being developed and tested to improve surveillance of lung function even further.
Ratjen F, McColley SA. Update in Cystic Fibrosis 2011. Am J Respir Crit Care Med 2012;185:933-936.