Monitoring sputum properties in cystic fibrosis patients by means of Low-Field NMR before after kaftrio treatment

Background. Cystic fibrosis (CF) is an autosomal recessive disease caused by mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR), responsible for chloride and sodium ion exchange across epithelial membranes. Dysfunctional CFTR induces the production of thick/viscous mucoid secretions in multiple organs, in particular the airways, where an augmented mucus viscosity is determined by the pathological increase in proteins, mucin and biological polymers. This process impairs muco-ciliary clearance, promoting chronic inflammation and bacterial infection leading to airway remodeling; these, in turn, can progress to respiratory failure, the most common cause of death for CF patients. Therefore, as sputum composition depends on lung condition, the determination of its properties represents a relevant parameter to indirectly monitoring lung disease. We previously (Abrami et al Magn Res Med, p.427, 2020; Abrami et al Magn Res Med, p. 2323, 2018;) employed Low Field Nuclear Magnetic Resonance (LF-NMR) to measure the spin-spin relaxation time (T2m) of the water hydrogens present in the CF sputum. These data showed that T2m measured in CF sputum indirectly correlated with circulating/local inflammation markers and a directly correlated with FEV1 (forced expiratory volume in the first second, i.e. the amount of air that is exhaled in the first second purposefully trying to breath out as much air as possible). Thus, the assessment of sputum by T2m, provides a useful tool for the indirect monitoring of lung disease in CF patients. Here, we explore the possibility of T2m to detect lung function improvements following treatment by the novel drug Kaftrio. This is a triple modulator (Tezacaftor/Ivacaftor/Elaxacaftor) able to improve CFTR protein function. Approved by E.M.A in 2020, Kaftrio has been shown to have beneficial effects not only in CF patients with mild-to-moderate disease but also in those with more severe pulmonary status. Methods. Sputum samples from 17 CF subjects, provided by Burlo Garofolo Hospital -Centro Regionale Fibrosi Cistic-, following a procedure approved by the Ethics Committee (prot n. 0005431/2020, CEUR-2019-Em-408), were collected (by voluntary expectoration) before and after Kaftrio administration (total samples 34). Sputum samples were studied by LF-NMR to determine T2m. The data obtained were related to lung function evaluated by FEV1. Results. In 58% of cases, Kaftrio administration improved both FEV1 and T2m, thus indicating a positive effect of the drug on lung function. In 25% of cases Kaftrio determined a reduction of both FEV1 and T2m, indicating no significant benefic effect on lung function. Finally, in only 17% of cases, Kaftrio treatment resulted in discordant variation of FEV1 and T2m, i.e. FEV1 increase and T2m decrease. This odd observation may be attributed to the fact that Kaftrio caused the dehydration of the mucus reducing its quantity (FEV1 increase) but worsening its nano-structure thus resulting in T2m decrease. Conclusions. Here we demonstrate that T2m can be effectively used to evaluate CF lung function following Kaftrio administration. Thus, besides being able to monitor lung disease exacerbation (our previous results) in CF patients, here we show that T2m can monitor lung function following drug therapy. Considering that T2m determination is very inexpensive does not require specialized personnel and it is not of any discomfort for the patient, it can become a valuable monitoring tool of lung function in CF diseases.