•We present two cases of adult CF patients, F508del/3849+10 kb C > T mutation status, who improved the faecal-elastase level after elexacaftor/tezacaftor/ivacaftor initiation.•Exocrine pancreatic insufficiency conversion has been demonstrated so far only in paediatric patients.•We need further studies on whether borderline exocrine pancreatic insufficiency in patients with mild mutation can be saved even in adult age. Cystic fibrosis (CF) is a quality-of-life-limiting disease due to multiorgan complications. Exocrine pancreatic insufficiency (EPI) is one of the most common characteristics of CF. Pancreatic function depends on a CFTR gene mutation's class [[1]Walkowiak J. Herzig K.H. Witt M. et al.Analysis of exocrine pancreatic function in cystic fibrosis: one mild CFTR mutation does not exclude pancreatic insufficiency.Eur J Clin Investig. 2001; 31: 796-801https://doi.org/10.1046/j.1365-2362.2001.00876.xCrossref PubMed Scopus (47) Google Scholar]. The milder mutation carriers confer a dominant effect on the exocrine pancreatic status. EPI typically occurs in people who carry two severe mutations, while pancreatic sufficiency typically occurs in either both mild or mild + severe mutation carriers [[2]McKay I.R. Ooi C.Y. The exocrine pancreas in cystic fibrosis in the era of CFTR modulation: a mini review.Front Pediatr. 2022; 10914790https://doi.org/10.3389/fped.2022.914790Crossref Scopus (4) Google Scholar]. F508del belongs to a II. class of CFTR pathogenic variant, which leads to reduction of CFTR protein function. 3849+10 kb C > T is in a class V, which is related to reduction in protein quantity. This pathogenic variant is considered mild according to the pancreatic insufficiency prevalence score; carriers of mild genotypes have a significant increase in risk of developing pancreatitis at any age [[3]Ooi C.Y. Dorfman R. Cipolli M. et al.Type of CFTR mutation determines risk of pancreatitis in patients with cystic fibrosis.Gastroenterology. 2011; 140: 153-161https://doi.org/10.1053/j.gastro.2010.09.046Abstract Full Text Full Text PDF PubMed Scopus (190) Google Scholar]. Carriers of this mutation combination are likely pancreatic sufficient, however, these patients may develop chronic pancreas inflammation and EPI in adulthood [3Ooi C.Y. Dorfman R. Cipolli M. et al.Type of CFTR mutation determines risk of pancreatitis in patients with cystic fibrosis.Gastroenterology. 2011; 140: 153-161https://doi.org/10.1053/j.gastro.2010.09.046Abstract Full Text Full Text PDF PubMed Scopus (190) Google Scholar, 4Stern R.C. Doershuk C.F. Drumm M.L. 3849+10 kb C–>T mutation and disease severity in cystic fibrosis.Lancet Lond Engl. 1995; 346: 274-276https://doi.org/10.1016/s0140-6736(95)92165-6Crossref PubMed Google Scholar, 5Duguépéroux I. De Braekeleer M. The CFTR 3849+10kbC->T and 2789+5G->A alleles are associated with a mild CF phenotype.Eur Respir J. 2005; 25: 468-473https://doi.org/10.1183/09031936.05.10100004Crossref PubMed Scopus (41) Google Scholar]. Fecal elastase (FE-1) 〈 100 μg/g together with the clinical signs is considered as EPI, 100 – 200 μg/g is considered borderline and 〉 200 μg/g indicates sufficient pancreatic function. It is widely thought to be irreversible in adults, and might be restored in the youngest children in the case of targeted therapy use [[2]McKay I.R. Ooi C.Y. The exocrine pancreas in cystic fibrosis in the era of CFTR modulation: a mini review.Front Pediatr. 2022; 10914790https://doi.org/10.3389/fped.2022.914790Crossref Scopus (4) Google Scholar]. The modest improvement of frequency and severity of gastrointestinal symptoms in CF was reported after CFTR modulator use, but to date, lumacaftor/ivacaftor, tezacaftor/ivacaftor and elexacaftor/tezacaftor/ivacaftor (ETI) combinations have not been demonstrated to affect exocrine pancreatic function in adults [[6]Schwarzenberg S.J. Vu P.T. Skalland M. et al.Elexacaftor/tezacaftor/ivacaftor and gastrointestinal outcomes in cystic fibrosis: report of promise-GI.J Cyst Fibros. 2023; 22: 282-289https://doi.org/10.1016/j.jcf.2022.10.003Abstract Full Text Full Text PDF PubMed Scopus (15) Google Scholar]. Here, we present 2 cases of adult CF patients who improved their pancreatic function serum values after ETI commencement. The first case is a 38-year-old female who was referred to the CF centre at the age of 16, diagnosed with cystic fibrosis according to genetic testing resulting in F508del/3849+10 kb C > T. Her sweat test value was 82 mmol/l and FE-1 value was 45 μg/g (2/2001). She did not suffer any symptoms of maldigestion (no steatorrhea, bowel movements 1–2 times a day, no failure of thrive, no severe fat-soluble vitamin deficiencies). At this time, her body weight was 51 kg and BMI was at the 68th percentile. Pancreatic enzyme replacement therapy (PERT) was initiated (125,000 UI/day). At the age of 26, the patient was diagnosed with CF-related diabetes with incipient neuropathy. At the age of 35, the combination of tezacaftor/ivacaftor was introduced to her and one year later, at her age 36, she started treatment with the triple combination of ETI. Her body weight at this time was 66 kg, BMI 23.9 kg/m2. We failed to measure the FE-1 before the start of the CFTR modulator and following tezacaftor/ivacaftor initiation. She tolerated the treatment well, with no side effects. After 24 weeks, her sweat test decreased to 12 mmol/l, suggesting a positive response to the treatment. Moreover, after the same interval, the FE-1 increased to 419.4 μg/g, in week 32 even to 442.1 μg/g. She was able to be completely weaned off PERT with no side effects. After PERT withdrawal, her body weight was 2 kg higher than at the time of ETI initiation (68 kg, BMI 24.6 kg/m2). Her gastrointestinal signs remained stable (stable bowel movement, no abdominal discomfort). Inspired by this case, we retested a second patient with the mentioned genotype. A 40-year-old female was diagnosed with CF (genotype F508del/3849 + 10 kb C > T, sweat test 63 mmol/l) at the age of 11. Her first FE-1 value consistent with EPI was at the age of 31 (86.7 μg/g) in 9/2013. She did not suffer from steatorrhea, cramps or abdomen pain, had no signs of failure of thrive, only intermittently bloating and flatulence. At the beginning, she used 75,000 UI/day of PERT. However, after several years, without consulting the CF specialist, she refused to take it anymore, and instead preferred to use alternative medicine treatment (chlorella, barley grass). Although her FE-1 value was in EPI range, without PERT, her gastrointestinal symptoms have not worsened (steatorrhea or any other clinical problems did not appear) and the body weight did not change either (51 kg, BMI 18.7 kg/m2). At the age of 38, she started to use tezacaftor/ivacaftor, and later the triple combination at the age of 39. After 6 months, the sweat test value dropped to 39 mmol/l, after 1 year of use even to 15 mmol/l. This drop to a physiological level indicated a particularly good response to the medication as well. Almost 2 years after initiation of ETI, the FE-1 improved to > 1200 μg/g. She has had no gastrointestinal problems. During this period, her nutritional status has not significantly changed (50 kg, BMI 18.5 kg/m2). Both cases are common in a good sweat test response to the CFTR modulators and a fairly delayed pancreatic insufficiency onset. It might suggest a slower acinar cells function burn out [[7]Krasovskiy S. Usacheva M. Amelina E. Phenotypic characteristics in adult cystic fibrosis (CF) patients carrying 3849+10kbC>T mutation in Russia.Eur Respir J. 2015; 46https://doi.org/10.1183/13993003.congress-2015.PA1311Crossref Google Scholar]. There might be a possibility to rescue borderline pancreatic insufficient patients and individuals with mild mutation with good responses to CFTR modulator therapy. ARRIVAL trial reported the mean absolute change in FE-1 by 164.7 μg/g in children 12 to <24 months old, 6 of 9 patients improved FE-1 to ≥ 200 μg/g level, a value consistent with sufficient pancreatic function [[8]Rosenfeld M. Wainwright C.E. Higgins M. et al.Ivacaftor treatment of cystic fibrosis in children aged 12 to <24 months and with a CFTR gating mutation (ARRIVAL): a phase 3 single-arm study.Lancet Respir Med. 2018; 6: 545-553https://doi.org/10.1016/S2213-2600(18)30202-9Abstract Full Text Full Text PDF PubMed Scopus (185) Google Scholar]. KIWI trial demonstrated an increase of FE-1 average by 99.8 μg/g in children aged 2–5 years [[9]Davies J.C. Cunningham S. Harris W.T. 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: 107-115https://doi.org/10.1016/S2213-2600(15)00545-7Abstract Full Text Full Text PDF PubMed Scopus (262) Google Scholar]. 6 of 27 patients converted to exocrine pancreatic sufficient. Included participants all had the gating mutation and were treated with ivacaftor for 24 weeks. Recovery of the pancreatic function was not seen in older children or adults yet. Only a single case of a 48-year-old CF male patient (genotype G551D/R347H) was described to improve the FE-1 from 66 μg/g to 236 μg/g after the ivacaftor initiation [[10]Kounis I. Lévy P. Rebours V. Ivacaftor CFTR potentiator therapy is efficient for pancreatic manifestations in cystic fibrosis.Am J Gastroenterol. 2018; 113: 1058-1059https://doi.org/10.1038/s41395-018-0123-7Crossref PubMed Scopus (14) Google Scholar]. Moreover, in this case, the need for PERT decreased to half of the need. Pathogenic variant R347H is also considered as mild according to the pancreatic insufficiency prevalence score, and might be potentially amenable to the rescue of pancreatic function [[3]Ooi C.Y. Dorfman R. Cipolli M. et al.Type of CFTR mutation determines risk of pancreatitis in patients with cystic fibrosis.Gastroenterology. 2011; 140: 153-161https://doi.org/10.1053/j.gastro.2010.09.046Abstract Full Text Full Text PDF PubMed Scopus (190) Google Scholar]. All the presented cases are demonstrated on ivacaftor use. Rescue and restoration of EPI in adult patients with CF appears possible, especially among those who carry at least 1 functionally milder CFTR mutation. Based on the author's case of carriage one mutation of 3849 + 10 kb C > T, especially in cases when EPI has developed over several years, monitoring of EPI should be considered. This especially includes re-evaluation (e.g., by FE-1 testing) among those who are on CFTR modulators and carry at least 1 CFTR mutation with mild pancreatic insufficiency prevalence score, and/or are known to have significant residual function. Symptoms alone do not suffice. Further research needs to determine the effect of ETI on exocrine pancreatic function effect in this specific patient population. The author made no use of generative AI or AI-assisted technologies in the writing process. This research did not receive any specific grant from funding agencies in the public, commercial, or non -profit sectors.
Abstract Background Allergic bronchopulmonary candidiasis (ABPC) is an uncommon clinical syndrome associated with immune hypersensitivity to Candida species. Case presentation The case presentation describes a 58-year-old man with acute respiratory failure and bilateral lung infiltrates. Due to high inflammatory markers and a chest X-ray indicating lung infiltration, he was initially treated for pneumonia with combined antibiotics. Despite comprehensive treatment at the ICU, the patient’s clinical status deteriorated rapidly, and further investigations provided a rare diagnosis of ABPC. After several days of combined corticosteroid and antifungal therapy, we observed rapid clinical improvement and subsequent resolution of the pulmonary infiltrates. Conclusion This case report presented a rare case of ABPC mimicking bilateral pneumonia and acute respiratory failure. Our case highlighted the importance of prompt corticosteroid and antifungal treatment initiation as it resulted in rapid clinical improvement and a near complete reversal of the bilateral lung infiltrates.
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