The pivotal studies for the new triple therapy already demonstrated how well the combination of the three so-called CFTR modulators, elexacaftor, tezacaftor, and ivacaftor affects the lung function and quality of life of cystic fibrosis patients. "So far, however, lung function in these studies has only been determined by spirometry, a method that only inaccurately reflects the typical functional changes in cystic fibrosis," says Prof. Dr. Anna-Maria Dittrich of the DZL BREATH site at Hannover Medical School. These changes, primarily caused by the obstruction of the small airways by viscous secretions, can be better determined using the gas washout method for determining the so-called Lung Clearance Index (LCI). Using this method, the researchers were able to show that the lungs are much better ventilated with triple therapy, right down to their most delicate ramifications. While the LCI was significantly elevated in most patients before treatment began, 40 percent of patients on treatment had an LCI similar to healthy individuals.
MRI shows for the first time that triple therapy reduces mucus
The underlying problem in cystic fibrosis is the formation of thick mucus that clogs the lungs' airways and internal organs such as the intestines. In the lungs, the mucus impedes breathing and serves as a breeding ground for bacteria. This causes chronic infection and inflammation, which leads to remodeling processes: The airways thicken, and irreversible bulges develop in the bronchi, so-called bronchiectasis. Study participants underwent magnetic resonance imaging (MRI) to study how the triple therapy affects the mucus and other changes in the lungs, study participants underwent magnetic resonance imaging (MRI). "These MRI studies were the first to show that triple therapy significantly reduces mucus plugs in the lungs. In addition, the results provide the first indications that inflammation-related thickening of the bronchi decreased," says Professor Marcus Mall, Director of the Clinic for Pediatrics, with a focus on pneumology, immunology, and intensive care medicine at Charité.
Where the CFTR modulators come in
In cystic fibrosis (CF), the gene for an ion channel on the surface of mucosal cells is genetically altered. As a result, the channel does not function or only to a limited extent. The affected ion channel is called Cystic Fibrosis Transmembrane Conductance Regulator (CFTR). More than 2,000 different genetic alterations, i.e., mutations, of the channel are known. Recently developed CFTR modulators make it possible to treat specific mutations in cystic fibrosis patients. These include the common F508del CFTR mutation in the 91 study participants. Forty-six of the patients studied carried this mutation on both CFTR gene copies, and 45 carried it on only one CFTR gene copy. The combination of three CFTR modulators can increase the impaired function of the ion channel by an average of 40 to 50 percent. This was shown by the DZL researchers in a previous paper.
Long-term study verifies effect on remodeling processes in the lung
"In our current study, we examined the rapid effects of the triple therapy on lung ventilation and mucus plugs in the airways after three months," said Dr. Simon Gräber, a physician and researcher at the Department of Pediatrics with a focus on pneumology, immunology, and intensive care medicine at Charité University Hospital, one of the study's first authors. "In the next step, we want to find out how the treatment affects the functional and structural changes of the lungs and the progression of lung disease in cystic fibrosis in the long term. To do this, we plan to re-examine patients on MRI both one and two years after starting triple therapy and determine LCI." According to Gräber, it is conceivable that improvements in the morphologic changes of the lungs seen on MRI will become even more apparent after a more extended treatment period. Despite a high degree of concordance, the effect on LCI after three months was more significant than the changes observed in the lungs on MRI would have suggested. This hypothesis will be tested in the long-term study already underway.
Original publication: Effects of Elexacaftor/Tezacaftor/Ivacaftor Therapy on Lung Clearance Index and Magnetic Resonance Imaging in Patients with Cystic Fibrosis and One or Two F508del Alleles. Graeber SY, Renz DM, Stahl M, Pallenberg ST, Sommerburg O, Naehrlich L, Berges J, Dohna M, Ringshausen FC, Doellinger F, Vitzthum C, Röhmel J, Allomba C, Hämmerling S, Barth S, Rückes-Nilges C, Wielpütz MO, Hansen G, Vogel-Claussen J, Tümmler B, Mall MA, Dittrich AM.Am J Respir Crit Care Med. 2022 May 10. DOI: 10.1164/rccm.202201-0219OC.
