Partial restoration of pancreatic function in a child with cystic fibrosis

Abstract

The long-term use and respiratory benefits (as shown by an increase in FEV1 and reduction in pulmonary exacerbations) of ivacaftor in patients aged 6 years and older with cystic fibrosis with the G551D mutation are well established.1McKone EF Borowitz D Drevinek P et al.Long-term safety and efficacy of ivacaftor in patients with cystic fibrosis who have the Gly551Asp-CFTR mutation: a phase 3, open-label extension study (PERSIST).Lancet Respir Med. 2014; 2: 902-910Summary Full Text Full Text PDF Scopus (181) Google Scholar Of the comorbidities observed over time in cystic fibrosis, gastrointestinal symptoms and exocrine pancreatic dysfunction are prominent features; exocrine pancreatic insufficiency is traditionally regarded as irreversible on serial testing.2Plant BJ Goss CH Plant WD Bell SC Management of comorbidities in older patients with cystic fibrosis.Lancet Respir Med. 2013; 1: 164-174Summary Full Text Full Text PDF Scopus (78) Google Scholar, 3Meyts I Wuyts W Proesmans M De Boeck K Variability of fecal pancreatic elastase measurements in cystic fibrosis patients.J Cyst Fibros. 2002; 1: 265-268Summary Full Text Full Text PDF PubMed Scopus (17) Google Scholar Faecal elastase 1 (FE-1) is a glycoprotein that is synthesised in the pancreas and excreted in the stool. It is not degraded on passage through the gastrointestinal tract and is, therefore, regarded as a sensitive marker of exocrine pancreatic function (concentrations of <200 μg/g stool are considered indicative of pancreatic insufficiency). We read with interest the KIWI study,4Davies JC Cunningham S Harris WT et al.Safety, pharmacokinetics, and pharmacodynamics of ivacaftor in patients aged 2-5 years with cystic fibrosis and a CFTR gating mutation (KIWI): an open-label, single-arm study.Lancet Respir Med. 2016; 4: 107-115Summary Full Text Full Text PDF Scopus (230) Google Scholar which highlighted the safety and efficacy of ivacaftor in children aged 2–5 years with cystic fibrosis with gating mutations. At baseline, 93% of children had a FE-1 less than 50 μg/g, which is consistent with severe pancreatic insufficiency. Notably a 99·8 μg/g significant mean increase in FE-1 was observed after 24 weeks of treatment. Equally of interest was the observation that 26% of children had an FE-1 above the threshold of 200 μg/g at least once over the course of the study. This raises the biologically plausible possibility that commencement of cystic fibrosis transmembrane conductance regulator (CFTR) modulators in very young children (aged 2–5 years) might augment exocrine pancreatic function. However, no published studies exploring this possibility in older children or young adults exist. We have observed dynamic changes in FE-1 in an older child (aged 6·5 years) after commencing ivacaftor treatment. We present the case of a female (genotype F508del/G551D) diagnosed at 4 years and 9 months old, after hospital admission with increased respiratory effort and cough. FE-1 was measured at diagnosis and was consistent with severe pancreatic insufficiency at less than 15 μg/g. At this time, the patient was started on four 150 mg pancreatin capsules per day. The patient started ivacaftor therapy on her sixth birthday in accordance with local regulatory guidelines. The figure shows the change in % predicted FEV1 and BMI after ivacaftor. After 6 months of ivacaftor treatment, the patient reported abdominal pain and constipation. As a result, her treatment regimen was reduced by 50% to two 150 mg pancreatin capsules per day. FE-1 was measured and was in the normal range at 259 μg/g. Two subsequent FE-1 measurements were made after 7 months of treatment (118 μg/g and 121 μg/g) and were consistent with moderate pancreatic insufficiency (figure). The authors of the KIWI study have highlighted the potential for a partial restoration of pancreatic function in early life in some patients given ivacaftor.4Davies JC Cunningham S Harris WT et al.Safety, pharmacokinetics, and pharmacodynamics of ivacaftor in patients aged 2-5 years with cystic fibrosis and a CFTR gating mutation (KIWI): an open-label, single-arm study.Lancet Respir Med. 2016; 4: 107-115Summary Full Text Full Text PDF Scopus (230) Google Scholar We concur with this statement. However, until the potential effect of these therapies has been established in all patients starting CFTR modulatory therapy, we suggest serial monitoring of exocrine pancreatic function with FE-1 measurements in all age groups, because of the scarcity of data in relation to FE-1 change in adult patients given ivacaftor that exists despite case reports of a reduction in pancreatic enzyme replacement requirements in adults after ivacaftor.5Harrison MJ Murphy DM Plant BJ Ivacaftor in a G551D homozygote with cystic fibrosis.N Engl J Med. 2013; 369: 1280-1282Crossref PubMed Scopus (43) Google Scholar BJP reports personal fees from Vertex Pharmaceuticals, Gilead Sciences, and Novartis, during the conduct of the study. CH, NJR, MN, and DM declare no competing interests.