Cystic fibrosis (CF) is a devastating, chronic disease that affects over 100,000 people worldwide. The consequences patients need to bear with them for the rest of their lives are even more devastating. A CF patient is signed for continuous care, daily treatments, hours of daily physiotherapy sessions and regular hospital check-ups or visits, next to their other day-to-day activities. To increase quality of life and life expectancy, millions of euros have been invested in research to improve medication and care. And it has been worthwhile given that in the course of the past sixty years, life expectancy has increased enormously from 10 years to almost 40 years old. The main cause of death still, however, are lung related complications that occur at more advanced stages of the disease [1,2]. Nonetheless, up at this very moment, people are continuously working on the further enhancement of treatment.
An important cause of these lung complications are bacteria. Pseudomonas aeruginosa (Pa) being the main pathogen , is found to be associated with pulmonary deterioration in CF . In healthy lungs, bacteria (such as Pa) are usually killed by airway surface liquid antimicrobials, are eradicated by mucociliary transport, or are eliminated by other defences including phagocytic cells to keep a sterile lung. On the other hand in CF, antimicrobial activity and mucociliary transport are much less effective than in healthy lungs and other defences may also be impaired.
Ultimately, the continuous bacterial infection triggers chronic inflammation airway wall inflammation which will result in remodelling of the airways in the long term, causing bronchiectasis, i.e. a localised airway dilation . Bronchiectasis (or airway enlargement) manifests itself heterogeneously, both between and within patients, which is illustrated in Figure 1.
The following video further illustrates the functional (inhalation and exhalation) and geometrical differences of segmented airways and lobes between a healthy person and an end-stage cystic fibrosis patient.
A cornerstone treatment for Pa infection is the use of inhaled antibiotics. The aim is to bring high dosages of these antibiotics into the airways, to assist in the natural process of bacterial eradication. In order to ensure the delivery of these high dosages, nebulization is often the preferred choice as compared to other inhaler devices. However, as discussed earlier in the previous FRI deposition blogpost , there are many factors that complicate the arrival of inhaled drugs into the desired lung regions. Specifically in CF patients, good aerosol deposition is impaired by the airways deformations that are present throughout the lungs. It is known that the presence of bronchiectasis will cause patients with more severe lung disease to have more central airway deposition compared to healthy individuals , and hence a worse treatment of the downstream or deep lung regions. Consequently, this may result in airways receiving a concentration of the inhaled agent below the minimal inhibitory concentration (i.e. the concentration needed to appropriately eradicate the pseudomonas). A previous study by Bos et. al , assessed FRI deposition in 40 children with cystic fibrosis. They confirmed this risk, where one out of five airways showed a potential undertreatment of the Pa infection. Even more worrisome, was the finding that lung deposition is lower in those zones where the disease manifestation is more advanced. These findings, that display continuous undertreatment and consequently leave room for further deterioration, don’t seem improbable. Especially since more than 90% of deaths are caused by progressive lung disease . If these worst regions of the peripheral airways are indeed continuously undertreated, what can be done to overcome this and improve the effectiveness of treatments and compounds?
Figure 2 Results of the study Bos et. al, showing the relative AZLI concentration as compared to 10 x MIC90 (the concentration needed to adequately eradicate Pa). Regions which are coloured blue to green have an AZLI concentration below this threshold value. Colours ranging from orange to white show a zone with concentrations above this threshold value.
Figure 1 Illustration the heterogeneity of segmented airways and lobes of a set of cystic fibrosis patients.
An encouraging finding from Bos et. al, is the fact that, next to dose adjustments and particle size optimization, a correct inhalation technique can improve aerosol delivery to the site of infection. Especially deep and long inhalation seems to be important to avoid deposition concentrations below the treatment threshold. This stresses the importance of good patient education and compliance. Novel nebulizers with high aerosol output are able to optimise the delivery even further by limiting inhalation flow rate and delivering the aerosol only during inhalation (hence preventing environmental waste). The video below shows the difference in airway concentration for a nebulizer with continuous aerosol delivery versus such a novel nebulizer with pulsed aerosol delivery in a CF patient’s airways, under different inhalation regimes (as defined by the I:E ratio). The increased concentrations of the anti-Pa therapy in the airways may offer an opportunity to improve patient outcomes in CF lung disease. Furthermore, it would lower the importance of optimal breathing manoeuvres as an influencing factor on deposition, over which little control can typically be exercised.
The association of end-stage disease with the presence of Pa  and small-airway deformation , makes clear that inhaled antibiotics should be targeting the deep lungs and airways where the CF expression is most present. In the mission to improve patient outcomes and to prolong patient’s lives even further, it is essential that the research and optimization of aerosol deposition in this population is continued. Clinicians should be presented with a pallet of treatments (or treatment strategies) that ensures effective delivery of inhaled therapies in all patients and minimize the risk of persistent Pa colonization in CF. But given the high variability in airway geometries (even within the different lung regions), and the resulting changes in regional drug delivery, a personalized medicine approach to identify localized antibiotic concentrations would add even more value to CF patients. FRI deposition is the appropriate tool to investigate this, as its measurements are effectively showing the same as in-vivo tests (such as scintigraphy), in the individual’s regional and peripheral airways. As part of the work in cystic fibrosis, FLUIDDA will be present at the European Cystic Fibrosis Society (ECFS) conference. Feel free to contact us or meet us there to elaborate further on this topic.
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