(121) The evaluation of lung disease progression after the introduction of lumacaftor/ivacaftor in young children

Background: The introduction of CFTR modulator therapy has ushered in a new era in CF treatment. As progressive lung damage is the most prominent cause of morbidity and mortality in CF, the possibility of preventing this progression is a major argument for starting modulator therapy in young patients. However, evaluating the efficacy of modulators on pulmonary disease in pre-school children is challenging. While neutrophil influx and structural damage to the lungs have been shown to already occur in the first years of life, improvement of respiratory symptoms can be difficult to identify in early disease stages. Additionally, objective parameters such as spirometry are difficult to reliably obtain in children under the age of 5.



Aim: To compare two objective measures of pulmonary disease, specifically chest CT and neutrophil count in broncho-alveolar lavage fluid (BALF) in a cohort of young children before and after start of lumacaftor/ivacaftor (Lu/Iva) therapy, and to compare them with untreated peers.

Methods: As part of our monitoring program, children with CF undergo a bronchoscopy and chest CT at age 1, 3 and 5 years (I-BALL cohort). For children aged 2-5 with dF/dF mutations, Lu/Iva was introduced in the Netherlands in 2019. Paired samples were collected from 25 patients in total (age 1-3: n = 14, age 3-5: n = 11), of which 9 patients started Lu/Iva between visits (age 1-3: n = 4, age 3-5: n = 5), and 17 did not. Data at ages 1 and 3 yrs, or 3 and 5 yrs were included for post hoc analysis, with varying treatment duration. Cell count of BALF was collected, and the amount of neutrophilic inflammation was expressed as the percentage neutrophils of total BALF cells (%Neu). CF lung disease was assessed in the chest CTs using the Perth-Rotterdam Annotated Grid Morphometric Analysis for CF (PRAGMA-CF) score, measuring percentages of bronchiectasis (%BE) and total airways disease (%Dis = %BE, mucus plugging, abnormal airway wall thickening). Pearson correlation, one-way ANOVA and Student’s t test were used for statistical analysis.

Results: Overall, mean BALF %Neu was 15.8%, 25.3% and 38% at ages 1, 3 and 5 years, respectively, showing an increase with age (p = 0.021). %BE increased from 0.16% at age 1 to 0.75% at age 5 (p = 0.0026). %Dis was 0.99%, 1.76% and 2.89% at ages 1, 3 and 5 respectively (p = 0.0013). %Dis positively correlated with %Neu (r = 0.59, p < 0.0001). When comparing visits 1 and 2 from paired samples of control subjects (either age 1-3 or 3-5), a mean increase in %Dis of 1.05% was found, compared to a mean increase of 0.47% in Lu/Iva treated subjects (p = 0.62). In control subjects, mean %Neu increase was 8.9% between visits, compared to 3.9% in Lu/Iva-treated (p = 0.55).

Conclusions: In our cohort of young children with CF, an increase of neutrophilic inflammation and structural lung disease were observed with age. We found a slightly lower increase of %Neu or %Dis in children treated with Lu/Iva compared to untreated, but this was not a significant difference. The differences in lung disease progression might become more pronounced with longer follow-up, or with a larger sample size. Still, these findings suggest that progression of CF lung disease continues to occur despite Lu/Iva therapy in young children, and that more effective CFTR modulators are needed. Furthermore, our findings highlight the need for objective monitoring tools in young children in which functional tests are not yet feasible.

Acknowledgements: Funded by NIH R01HL126603, CFF award #TIROU19A0 and NCFS-HITCF1.

References: