It has been shown that lung damage induced by inflammation precedes FEV1 decline [10]. LCI derived from MBW not only reflects ventilation defects in the respiratory tract, but also helps identify early dysfunction in small airways that are not easily identified with traditional spirometry methods [13]. Therefore, the present study assessed the clinical utility of LCI for assessing the response to inhaled tobramycin antibiotic therapy in patients with CF positive for P. aeruginosa. In the present study, three patients had a significantly elevated LCI despite having a normal FEV1% at baseline. In addition, the single normalized differences in LCI at week 4 versus baseline for individual patients were higher than the respective normalized FEV1 differences (Table 2 and Fig. 2), indicating a higher sensitivity of lung function assessment with MBW compared to classical spirometry. Similar findings from previously published data also showed that LCI provides a more sensitive overall estimate of ventilation inhomogeneity compared to FEV1, at least in patients with mild lung disease [16].
There is increasing evidence on the clinical utility of LCI. In addition to LCI being used as a clinical endpoint [5, 15], it has also been used to assess mucociliary clearance in young children [17] treated with CFTR-modulators [15] and to monitor disease progression [18], or both [19]. However, this study with inhaled tobramycin demonstrated that changes in LCI, FEV1 and CFU at week 1, 4 and 8 were not statistically significant. There was no specific trend observed with respect to correlation between the changes of LCI, FEV1 and CFU after week 1, 4 and 8 versus baseline. This may be attributed to the heterogeneity in LCI response to antibiotic treatment seen in the individual data for MBW and spirometry shown in Fig. 2. These results are in line with previously published studies [20, 21] and pooled analyses [22]. Despite the use of a more efficient therapy (inhaled formulation) in terms of an increased bioavailability of tobramycin in sputum we observed heterogeneity in the present study which is comparable to the findings seen with intravenous antibiotic treatment in children with CF [20]. In contrast to the outcome from the present study, a short-term study (one month) with 32 CF children on intravenous antibiotic treatment showed a significant improvement in LCI compared with FEV1 [23]. However, data about LCI as outcome measure for short-term efficacy of antibiotics in CF remains very limited.
The observed heterogeneity in lung function response to therapy can partly be attributed to the non-responders, which could be due to a few patients becoming refractory to inhaled antibiotics [24]. Further, there were single cases of negative, or positive change in CFU in some patients however, such findings are not conclusive, also because not all patients were able to expectorate sputum and thus, CFU data was missing for some patients. In addition, CFU assessment in general is characterized by huge intraindividual variation and therefore, any non-significant findings have to be evaluated with caution. Based on this data, one may speculate that therapy response in these patients with mild to moderate lung disease, chronically treated with inhaled tobramycin was weak and/or heterogeneous. At least 3 patients showed worsening of LCI despite an improvement in FEV1, which could be due to increased ventilation inhomogeneity in newly ventilated lung regions following inhaled antibiotic therapy (eg. by reduced air-trapping) [21, 25].
In addition, chest physiotherapy to remove sticky mucus from the airways, prior to lung function testing may also lead to heterogeneity in LCI response. The inherent ventilation inhomogeneity combined with the clearance of mucus plugged airways (after chest physiotherapy) which were previously poorly ventilated (at baseline) leads to an increased LCI [26]. Indeed, a mean reduction of 0.2 in LCI response 30 min after physiotherapy was observed in CF patients with lung disease of varying severity, suggesting unpredictability of short-term physiotherapy on LCI responses [27]. Similar to previously reported studies, the standard physiotherapy performed in the present study is strongly dependent on the therapist’s discretion as well as on the daily performance and adherence of the individual CF patient. Although chest physiotherapy is typically performed before inhalation and is done at least 1 h prior to MBW, there is no guidance on the timing for the physiotherapy at each visit. Hence, chest physiotherapy could have affected the outcome of lung function testing in this study to a certain degree. A detailed documentation of the timing and type of physiotherapy relative to MBW lung function testing in future clinical trials using LCI as a study endpoint is therefore recommended [26].
Based on the results from the present study as well as from available literature, it can be hypothesized that LCI can be an appropriate endpoint for efficacy trials in CF patients if the heterogeneity in lung function is limited by enrolling only drug naïve patients. Furthermore, including younger patients with milder lung disease and specifically defined time points for chest physiotherapy; while excluding false negative changes in lung function outcomes resulting from physiotherapy is recommended.
Overall, treatment with tobramycin showed a favorable safety profile. During the study period six AEs were reported, all of which were mild and moderate in severity, which is in line with previously published phase III data [28, 29].
A major limitation of the present study is the small sample size because of difficulties with patient enrollment and recruitment. The standard of care changed during the setup of the study, i.e., the majority of P. aeruginosa positive CF patients were to be treated with continuous inhaled sequential antibiotic combinations [30]. Hence, enrollment of patients on monotherapy was a challenge and thus, the study could include only 17 patients versus 35 patients that were planned to be enrolled.