Ivacaftor in a young boy with the rare gating mutation S549R - use of lung clearance index to track progress: a case report

An 8-year-old boy with S549R/1717-1G > A genotype was started on ivacaftor (150 mg b.i.d.) on compassionate use. At the age of 9 months he was diagnosed with CF due to failure to thrive. His previous history was remarkable for recurring nasal polyposis requiring endoscopic surgery and exocrine pancreatic insufficiency necessitating enzyme replacement therapy. He grew with body weight and height along the 10^th percentile. He suffered from rather mild respiratory symptoms, primarily intermittent productive cough, and had close to normal lung function parameters in previous years as measured by body plethysmography and spirometry (minimal z-score of FEV1: −1.2). Sputum cultures grew Haemophilus influenzae and Staphylococcus aureus on several occasions. After 6 weeks of ivacaftor treatment, the patient reported clinical improvements in cough frequency, sputum production, physical performance, and less salt cravings. He gained 1.4 kg in body weight without changing the dose of his pancreatic enzyme replacement therapy. His sweat chloride level (Macroduct®) decreased from 115 mmol/l before ivacaftor to 40 mmol/l after 6 weeks and 52 mmol/l after 41 weeks (normal < 30 mmol/l [11]) of treatment. His FEV1 increased from 1.25 L (−1.2 z-score) to 1.65 L (+0.5 z-score) after 41 weeks of ivacaftor therapy. The LCI (normal < 8) measured by N₂-MBW decreased from 14.5 to 8.3 after 6 weeks and 7.8 after 41 weeks of ivacaftor treatment (Table 1 and Fig. 1).

Ivacaftor is the first authorized drug that improves defective CFTR function in rare mutations by potentiating the CFTR channel gating function. In vitro data suggests that ivacaftor has a similar effect on 9 of 10 CFTR gating mutations. However, the weakest drug effect was described for the S549R mutation [5]. S549R was initially considered a class II mutation leading to defective CFTR protein processing [12]. Recent electrophysiological studies using Fischer rat thyroid cells have suggested the presence of a predominant gating defect besides a mild processing defect of CFTR in S549R [5]. The processing defect may account for the lower ivacaftor response observed in vitro. Against this background, the impressive clinical and functional improvement in our patient with the S549R mutation was better than expected. These results are in line with a recently published clinical trial study including four patients with S549R mutation [6].

One limitation of this report is that no nasal potential differences or intestinal current measurement have been performed as further functional parameters. The benefit of using LCI as an outcome measure should not be over generalised from this case. However this report highlights the additional value of LCI as a sensitive parameter in relation to the traditional lung function parameter FEV1. Other studies have shown that the LCI of N₂MBW is particularly useful in monitoring the early course of lung disease in young children with CF, particularly in those with normal spirometry [13, 14]. The LCI is already elevated in presymptomatic or minimally symptomatic infants and young children with CF [9]. In our patient, the LCI decreased after 41 weeks of ivacaftor treatment from a z-score of 14.2 to 1.5, while the z-score for FEV1 remained within the normal range (z-score −1.2 to 0.5). This is in agreement with previous work indicating that LCI is a more sensitive parameter to detect treatment success in young CF patients compared to spirometry, especially in children with little respiratory symptoms and near-normal spirometric lung volumes such as FEV1 [15].