While previous studies had shown that ETI improves lung function and reduces symptom burden, data on how inflammatory activity evolves over longer periods had so far been lacking. The current study closes this gap by observing children, adolescents, and adults for up to 24 months after therapy initiation. A marked reduction in key inflammatory markers in the blood—including C-reactive protein (CRP), neutrophil granulocytes, and various cytokines—was already evident after three months, and this effect was maintained over two years in large parts of the cohort. The inflammatory parameters examined decreased to approximately 40–80% of baseline values within three months. At the same time, lung function parameters improved significantly and remained stable, and close associations were observed between clinical improvements and reductions in inflammatory markers.

“It is particularly noteworthy that the study was conducted in a real-world care setting. It therefore confirms that the positive effects of triple therapy are not limited to the controlled conditions of clinical trials but are also evident in patients’ everyday lives,” says Dr. Olga Halle. “This new evidence complements earlier reports that primarily emphasized the superiority of triple therapy over older dual combinations in terms of clinical and functional parameters, by adding the important aspect of systemic inflammation.” With the data now available, the effects of ETI can be described much more precisely: the therapy does not merely act symptomatically and improve mucus clearance, but apparently also influences fundamental biological processes of the disease—especially chronic inflammation, which plays a central role in long-term tissue damage. After no later than 24 months, almost all inflammatory markers examined corresponded on average to the levels of a healthy comparison group.

At the same time, the study shows that in many affected individuals, a certain degree of residual inflammation persists despite substantial improvements. Some markers remained above the levels seen in healthy individuals in certain people even after 24 months, suggesting ongoing or recurrent residual inflammation. It was also notable that children aged between 6 and 11 years already exhibited lower inflammatory activity before therapy initiation than adolescents and adults.

This opens up new research questions, for example regarding the significance of this residual inflammatory activity and potential adjunct therapies that could further slow long-term disease progression. For BREATH and the DZL, the work therefore underscores not only the importance of precise long-term observations, but also the need to further develop future therapeutic strategies. The data suggest that additional anti-inflammatory or anti-infective approaches could be valuable in further reducing remaining inflammatory activity.

“With this study, we show for the first time in routine clinical care that triple therapy not only relieves the lungs, but also sustainably reduces systemic inflammation—an important step toward understanding the biological benefits of this treatment,” says senior author Prof. Anna Maria Dittrich.

The results mark an important advance in CF research and highlight the potential of systematic, cross-site collaboration within the DZL. They also provide a solid scientific basis for assessing how sustainably ETI can influence disease progression—particularly in young patients, whose long-term prognosis strongly depends on early control of inflammation.

Original Publication:

Halle O. et al. Longitudinal real-world effects of elexacaftor/tezacaftor/ivacaftor on systemic inflammation in cystic fibrosis. European Respiratory Journal 2025 66(6): 2500150; DOI: https://doi.org/10.1183/13993003.00150-2025

Text: BREATH/AB,OH,AMD

Figure: Seo C, Thornton CS: Cooling the flames, clearing the airways: systemic inflammation in the era of elexacaftor/tezacaftor/ivacaftor, European Respiratory Journal 2025 66(6): 2501805, with kind permission from ERS Publications. https://publications.ersnet.org/content/erj/66/6/2501805?implicit-login=true%26447