The triple-combination of ETI has been associated to significant improvement in lung function and rate of pulmonary exacerbations (Middleton, NEJM 2019). Conventional MRI has been proposed as a radiation-free imaging modality to investigate functional and morphological lung changes over the course of the disease (Pennati, JMRI 2021). The study aims to evaluate changes in MRI-ventilation measures in patients with CF lung disease treated with ETI. We performed a longitudinal retrospective study on 7 consecutive patients with severe CF lung disease (25±4 years, FEV1 40±9%), over 1-year treatment with ETI. MRI was available at months 0 and 12 in 5 patients. End-inspiration (INSP) and end-expiration (EXP) images were registered to estimate Δ1H-MRI (EXP-INSP) as a measure of regional ventilation. We defined low ventilation volume (%LVV) as the percent volume with Δ1H-MRI<5%. From month 0 to 12, FEV1 and FEF25-75 increased by 45% and 65% (p=0.01). Lung clearance index decreased by 45%. Δ1H-MRI increased by 45%(p=0.01) and %LVV decreased by 12% (p=0.19) (Fig.1). MRI-ventilation measures improved in patients treated with ETI. Preliminary results suggest that MRI may provide a sensitive tool for the evaluation of CF lung disease under treatment with no radiation exposure. Supported by Italian Cystic Fibrosis Research Foundation (Grant FFC#21/2020)

The earliest characteristic of the liver in Wilson disease (WD) includes steatosis. A genetic polymorphism in rs738409, in the patatin-like phospholipase domain (PNPLA3), seems to have a role in NAFLD and a recent paper also support its influence in steatosis in WD patients. This study evaluated the role of PNPLA3 variant in large cohort of WD patients as potential modifiers of metabolic syndrome and neurologic phenotype.

Objectives: To report the usefulness of lung MR in the diagnosis and follow-up of endobronchial invasive aspergillosis in 3 young pts.Methods: We reviewed 79 lung MR examinations performed between January and December 2014 in 64 CF pts (age range 6-30 yrs).Results: 3 out of 64 pts (2 girls and 1 boy, age range 11-12 yrs) demonstrated endobronchial mucous plugs with hyperintense T1 signal and hypointense T2 signal associated with parenchymal consolidation distal to the occluded bronchi.Two pts had right inferior lobe alterations and in the other both upper lobes were involved.These alterations suggested extensive mycotic endobronchial invasion.All pts had mild lung disease, hematological changes suggestive for Aspergillosis and positivity of antibodies vs A. fumigatus which was present in sputum in two of them.They did not show specific pulmonary symptoms with a mismatch between lung involvement on MR images and clinical evidence.2 pts underwent lung CT in the same period that confirmed hyperdense endobronchial mucous and antimycotic therapy was started.BAL during bronchoscopy (flexible bronchoscope with direct DNase instillation) revealed presence of A. fumigatus only in one pt sensible at all antimycotic agents (amphotericin and azoles MIC-EUCAST) and lung MR was the method chosen to follow pulmonary disease. Conclusion:Lung MRI performed to monitor pulmonary disease was the first examination suggesting mycotic bronchial colonization and can be considered a safe and accurate method for the detection of endobronchial aspergillosis and for its short and long-term follow-up.

Abstract RATIONALE: Mutations in cystic fibrosis (CF) transmembrane conductance regulator affect the epithelial innate immune function in the lung, resulting in exaggerated and ineffective airway inflammation that fails to eradicate pathogenic fungi. The appreciation of whether they are primarily responsible for or a consequence of an ineffective airway inflammation is important for future therapeutics development. OBJECTIVE: To characterize the impact of the tryptophan kynurenine pathway on pathogenic airway inflammation preventing effective fungal clearance in CF. METHODS: We studied the expression of the indoleamine 2,3-dioxygenase (IDO), the first enzyme in the kynurenine pathway of tryptophan degradation, in human and murine CF, the impact of IDO on lung inflammation and immunity in murine CF, and the potential role of tryptophan catabolism in pathogenesis and therapy of fungal-associated lung inflammation. MAIN RESULTS: IDO was defective in murine and human CF. Genetic and transcriptional regulatory mechanisms contributed to dysfunctional IDO activity that, in turn, correlated with imbalanced Th17/Treg cell responses to Aspergillus fumigatus in murine CF. Treatments enhancing IDO function or prevention of pathogenic Th17 cell activation, restored protective immunity to the fungus and improved lung inflammation in murine CF. CONCLUSIONS: This study provides a link between tryptophan catabolism and lung immune homeostasis in murine CF, representing a proof-of-concept that targeting pathogenic inflammation via IDO mimetic drugs may benefit CF patients.

OBJECTIVE Diabetes frequently complicates cystic fibrosis (CF) without fasting hyperglycemia or despite spontaneous hypoglycemia (anecdotally ascribed to malnutrition), whose prevalence, clinical meaning, and relationship with glucose tolerance and clinical/nutritional status were not previously investigated. The relationship of CF genotype with insulin secretion control is also unclear. DESIGN AND METHODS A total of 129 CF patients without stable diabetes received 188 oral glucose tolerance tests. Distribution of fasting plasma glucose (FPG), glucose, insulin and C-peptide responses, clinical/nutritional variables, and their relationships were analyzed. RESULTS FPG < 60 mg/dl (3.3 mmo/l) was detected in 14% of studies and reactive hypoglycemia (PG < 50 mg/dl (2.8 mmo/l)) in 15%. OGTT-based diabetes frequency was similar in the lowest quartile (Q1) and Q2-3 for FPG (10 and 8%), with higher glucose increment and area under the curve in Q1. Insulin and C-peptide levels were similar among FPG quartiles. Class I cystic fibrosis transmembrane conductance regulator mutation carriers had higher insulin concentrations than class II, especially in Q1 for FPG. Age, sex, nutritional, and anthropometric parameters including fat and lean body mass were unrelated to FPG. Lower FPG was associated with more frequent hospitalization rates (P = 0.002) and lower Shwachman scores (P = 0.041). Steroids weaning was accurately evaluated but then excluded as a possible cause of hypoglycemia. CONCLUSIONS/INTERPRETATION Fasting asymptomatic hypoglycemia is frequent and possibly related to inappropriate insulin secretion control in class I mutation carriers. Low FPG does not exclude impaired glucose tolerance (IGT) and diabetes in CF and reflects worse clinical status.

Acta PaediatricaVolume 96, Issue 3 p. 477-479 Is early identification of asymptomatic infants with ‘mild’ CFTR genotypes clinically useful? C Colombo, C Colombo IRCCS Ospedale Maggiore Policlinico, Mangiagalli, Regina Elena, CF CenterSearch for more papers by this authorD Costantini, D Costantini IRCCS Ospedale Maggiore Policlinico, Mangiagalli, Regina Elena, CF CenterSearch for more papers by this authorMC Russo, MC Russo IRCCS Ospedale Maggiore Policlinico, Mangiagalli, Regina Elena, CF CenterSearch for more papers by this authorL Claut, L Claut IRCCS Ospedale Maggiore Policlinico, Mangiagalli, Regina Elena, CF CenterSearch for more papers by this authorL Porcaro, L Porcaro IRCCS Ospedale Maggiore Policlinico, Mangiagalli, Regina Elena, Molecular Genetic Laboratory, Milan, ItalySearch for more papers by this authorR Nobili, R Nobili IRCCS Ospedale Maggiore Policlinico, Mangiagalli, Regina Elena, CF CenterSearch for more papers by this author C Colombo, C Colombo IRCCS Ospedale Maggiore Policlinico, Mangiagalli, Regina Elena, CF CenterSearch for more papers by this authorD Costantini, D Costantini IRCCS Ospedale Maggiore Policlinico, Mangiagalli, Regina Elena, CF CenterSearch for more papers by this authorMC Russo, MC Russo IRCCS Ospedale Maggiore Policlinico, Mangiagalli, Regina Elena, CF CenterSearch for more papers by this authorL Claut, L Claut IRCCS Ospedale Maggiore Policlinico, Mangiagalli, Regina Elena, CF CenterSearch for more papers by this authorL Porcaro, L Porcaro IRCCS Ospedale Maggiore Policlinico, Mangiagalli, Regina Elena, Molecular Genetic Laboratory, Milan, ItalySearch for more papers by this authorR Nobili, R Nobili IRCCS Ospedale Maggiore Policlinico, Mangiagalli, Regina Elena, CF CenterSearch for more papers by this author First published: 23 February 2007 https://doi.org/10.1111/j.1651-2227.2007.00142.xCitations: 1 Correspondence Carla Colombo, IRCCS “Ospedale Maggiore Policlinico, Mangiagalli e Regina Elena, Department of Pediatrics, CF Center, Via Commenda 9, I-20122 Milano, Italy. Tel: + 39 02 5503 2456 | Fax: +39 02 5503 2814 | Email: [email protected] Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onEmailFacebookTwitterLinkedInRedditWechat References 1 Padoan R, Corbetta C, Bassotti A, Seia M. Identification of the 5T-12TG allele of the cystic fibrosis transmembrane conductance regulator gene in hypertrypsinaemic newborns. Acta Paediatr 2006; 95: 871–3. 2 Sun W, Anderson B, Redman J, Milunsky A, Buller A, McGinniss MJ, et al. CFTR 5T variant has a low penetrance in females that is partially attributable to its haplotype. Genet Med 2006; 8: 339–45. 3 De Boeck K, Wilschanski M, Castellani C, Taylor C, Cuppens H, Dodge J, et al. Cystic Fibrosis:terminology and diagnostic algorithms. Thorax 2006; 61: 627–35. 4 Derichs N, Schuster A, Grund I, Ernsting A, Stolpe C, Kortge-Jung S, et al. Homozygosity for L997F in a child with normal clinical and chloride secretory phenotype provides evidence that this cystic fibrosis transmembrane conductance regulator mutation does not cause cystic fibrosis. Clin Genet 2005; 67: 529–31. 5 Desmarquest P, Feldmann D, Tamalat A, Boule M, Fauroux B, Tournier G, et al. Genotype analysis and phenotypic manifestations of children with intermediate sweat chloride results. Chest 2000; 188: 1591–97. 6 Salvatore D, Tomaiuolo R, Vanacore B, Elce A, Castaldo G, Salvatore F. Isolated elevated sweat chloride concentrations in the presence of the rare mutation S1455X: an extremely mild form of CFTR dysfunction. Am J Med Genet A 2005; 133: 207–8. 7 Epaud R, Girodon E, Corvol H, Niel F, Guigonis V, Clement A, et al. Mild cystic fibrosis revealed by persistent hyponatremia during the French 2003 heat wave, associated with the S1455X C-terminus CFTR mutation. Clin Genet 2005 Dec; 68: 552–3. 8 Mussaffi H, Prais D, Mei-Zahav M, Blau H. Cystic fibrosis mutations with widely variable phenotype: the D1152H example. Pediatr Pulmonol 2006 Mar; 41: 250–4. 9 Cuppens H, Cassiman JJ. CFTR mutations and polymorphisms in male infertility. Int J Androl 2004; 27: 251–6. 10 Price JF. Newborn screening for cystic fibrosis: do we need a second IRT? Arch Dis Child 2006; 91: 209–10. 11 Newborn screening: toward a uniform screening panel and system. http://mihb.hrsa.gov/screening/summary.htm 12 Farrel MH, Farrel PM. Newborn screening for cystic fibrosis: ensuring more good than harm. J Pediatr 2003; 143: 707–12. Citing Literature Volume96, Issue3March 2007Pages 477-479 ReferencesRelatedInformation