Longitudinal Assessment of Patients With Cystic Fibrosis Lung Disease With Multivolume Noncontrast MRI and Spirometry.

BACKGROUND: MRI has been suggested as a radiation-free imaging modality to investigate early structural alterations and regional functional impairment in cystic fibrosis (CF) lung disease. PURPOSE/HYPOTHESIS: To compare functional and morphological MRI changes over the course of the disease to changes in spirometry. STUDY TYPE: Longitudinal retrospective study. POPULATION: Twenty patients with CF lung disease (at baseline, age = 16.5 (13.3-20.6) years, forced expiratory volume in 1 second (as % of predicted [%pred]) FEV1 = 71 (59-87) %pred, forced expiratory flow at 25-75% of forced vital capacity FEF25-75 = 39 (25-63) %pred. FIELD STRENGTH/SEQUENCE: 1.5T / T2 -weighted HASTE; T2 -weighted TSE-PROPELLER; T2 -weighted bSSFP; T1 -weighted 3D GRE. ASSESSMENT: Nonenhanced chest MRI and spirometry were retrospectively collected over a 3-year period from the initial recruitment visit. Images acquired at end-inspiration and end-expiration were registered by software using the optical flow method to measure expiratory-inspiratory differences in MR signal-intensity (Δ1 H-MRI). Measures of CF functional impairment were defined from Δ1 H-MRI: Δ1 H-MRI median, Δ1 H-MRI quartile coefficient of variation (QCV), and percent low-signal-variation volume (LVV). MR images were also evaluated by three readers using a CF-specific scoring system. STATISTICAL TESTS: Spearman correlation analysis, Spearman rank correlation analysis, linear mixed-effect model analysis, intraclass correlation coefficient. RESULTS: Functional imaging parameters and total morphological score correlated with all spirometric measures, as did subscores of bronchial wall thickening/bronchiectasis, mucus plugging, and consolidation. Overall, the percent change of Δ1H-MRI median correlated with the percent change of FEV1 (ΔFEV1 , r = 0.41, P < 0.01) and the percent change of FEF25-75 (ΔFEF25-75%, r = 0.38, P < 0.01). The percent change of LVV correlated with ΔFEV1 (r = -0.47, P < 0.001) and ΔFEF25-75 (r = -0.50, P < 0.001). DATA CONCLUSION: These preliminary results suggest that nonenhanced multivolume MRI may provide a feasible tool to regionally map early pulmonary alterations for longitudinal evaluation of CF lung disease, without exposing the patients to ionizing radiation. LEVEL OF EVIDENCE: 3T TECHNICAL EFFICACY STAGE: 5.

Quantitative multivolume proton-magnetic resonance imaging in patients with cystic fibrosis lung disease: comparison with clinical indicators.

This cross-sectional study aims to verify the relationship between quantitative multivolume proton-magnetic resonance imaging (1H-MRI) and clinical indicators of ventilatory abnormalities in cystic fibrosis (CF) lung disease.Non-enhanced chest MRI, spirometry and multiple breath washout was performed by 28 patients (10-27 years) with CF lung disease. Images acquired at end-inspiration and end-expiration were registered by optical flow to estimate expiratory-inspiratory proton-density change (Δ1H-MRI) as a measure of regional ventilation. Magnetic resonance images were also evaluated using a CF-specific scoring system.Biomarkers of CF ventilation impairment were defined from the Δ1H-MRI as follows: Δ1H-MRI median, Δ1H-MRI quartile coefficient of variation (QCV) and percentage of low-ventilation volume (%LVV). Imaging biomarkers correlated to all the clinical measures of ventilation abnormality, with the strongest correlation between Δ1H-MRI median and forced expiratory volume in 1 s (r2=0.44, p<0.001), Δ1H-MRI QCV and lung clearance index (LCI) (r2=0.51, p<0.001) and %LVV and LCI (r2=0.66, p<0.001). Correlations were also found between imaging biomarkers of ventilation and morphological scoring.The study showed a significant correlation between quantitative multivolume MRI and clinical indicators of CF lung disease. MRI, as a non-ionising imaging technique, may be particularly attractive in CF care for longitudinal evaluation, providing a new imaging biomarker to detect early ventilatory abnormalities.

A case of severe pulmonary exacerbation in a young patient with cystic fibrosis in the era of CFTR modulators.

The introduction of CFTR modulator drugs like elexacaftor-tezacaftor-ivacaftor (ETI) has transformed the management of cystic fibrosis (CF), significantly improving symptoms, lung function, and quality of life, while reducing reliance on intravenous antibiotics. However, respiratory exacerbations in the CFTR modulators era remain poorly understood from both pathophysiological and clinical perspectives. We present the case of a 20-year-old Caucasian woman with CF (F508del/L1077P) who, after three years of ETI treatment, experienced a severe episode of hemoptysis, despite being almost asymptomatic in the weeks leading up to admission, requiring bronchial artery embolization. Following ETI treatment, auscultatory findings and FEV1 changes may be less significant, making the detection of respiratory exacerbation more challenging. This highlights the need for heightened vigilance in managing such cases and underscores the challenge of diagnosing and managing exacerbations in the era of modulators. Long term real-world studies are essential to comprehend the evolving course of the disease during ETI treatment.

Multiple Breath Washout for Early Assessment of Pulmonary Complications in Patients With Primary Antibody Deficiencies: An Observational Study in Pediatric Age.

Background: In primary antibody deficiencies (PADs), pulmonary complications are the main cause of morbidity, despite immunoglobulin substitutive therapy, antibiotic treatment of exacerbations, and respiratory physiotherapy. Current Italian recommendations for surveillance of PADs respiratory complications include an annual assessment of spirometry and execution of chest high-resolution computed tomography (HRCT) every 4 years. Objective: This study aimed to evaluate the effectiveness of the lung clearance index (LCI) as an early marker of lung damage in patients with PADs. LCI is measured by multiple breath washout (MBW), a non-invasive and highly specific test widely used in patients with cystic fibrosis (CF). Methods: Pediatric patients with PADs (n = 17, 10 male, 7 female, and age range 5-15 years) underwent baseline assessment of lung involvement with chest HRCT, spirometry, and multiple breath nitrogen washout. Among them, 13 patients were followed up to repeat HRCT after 4 years, while performing pulmonary function tests annually. Their baseline and follow-up LCI and forced expiratory volume at 1 s (FEV1) values were compared, taking HRCT as the gold standard, using logistic regression analysis. Results: Lung clearance index [odds ratio (OR) 2.3 (confidence interval (CI) 0.1-52) at baseline, OR 3.9 (CI 0.2-191) at follow-up] has a stronger discriminating power between altered and normal HRCT rather than FEV1 [OR 0.6 (CI 0.2-2) at baseline, OR 1.6 (CI 0.1-13.6) at follow-up]. Conclusion: Within the context of a limited sample size, LCI seems to be more predictive of HRCT alterations than FEV1 and more sensitive than HRCT in detecting non-uniform ventilation in the absence of bronchiectasis. A study of a larger cohort of pediatric patients followed longitudinally in adulthood is needed to challenge these findings.

Ventilation inhomogeneity is associated with OGTT-derived insulin secretory defects in cystic fibrosis.

Progressive deterioration of ß-cell function is the main mechanism underlying diabetes in cystic fibrosis (CF). Diabetes negatively impacts the clinical status of CF patients years before its onset. We aimed to evaluate if OGTT-derived indices of ß-cell function are associated with early markers of lung disease. We carried out a cross-sectional study on 80 CF patients who performed OGTT, spirometry, and nitrogen-multiple breath washout test. ß-cell glucose sensitivity and the insulinogenic indices were used as markers of ß-cell function and first-phase insulin response to glucose stimulus. We used sex- and age-adjusted multiple linear regression models to estimate the association between OGTT-derived indices and lung function measures. An increment of ß-cell glucose sensitivity equal to its interquartile range was associated with an increase in ppFEV1 of 7.6 points (95%CI: 0.8; 14.4) as well as with a decrease in LCI of -1.96 units (95%CI: -3.40; -0.51) and in Scond of -0.016 L-1 (95%CI: -0.026; -0.007). The corresponding figures for insulinogenic index were: 8.6 (95%CI: 3.4; 13.9) for ppFEV1 , -2.03 (95%CI: -3.13; -0.94) for LCI, and -0.014 L-1 (95%CI: -0.021; -0.071) for Scond . When adjusting also for 2-h plasma glucose, both ß-cell glucose sensitivity and insulinogenic index remained inversely associated with Scond . Deterioration of ß-cell function is related to early lung disease in young patients with mild to normal pulmonary function. This relationship is independent from hyperglycemia and mainly involves conductive airways.

Genetic Polymorphisms Affecting IDO1 or IDO2 Activity Differently Associate With Aspergillosis in Humans.

Aspergillus is the causative agent of human diseases ranging from asthma to invasive infection. Genetic and environmental factors are crucial in regulating the interaction between the host and Aspergillus. The role played by the enzyme indoleamine 2,3-dioxygenase 1 (IDO1), which catalyzes the first and rate-limiting step of tryptophan catabolism along the kynurenine pathway, is increasingly being recognized, but whether and how genetic variation of IDO1 influences the risk of aspergillosis in susceptible patients is incompletely understood. In addition, whether the closely related protein IDO2 plays a similar role remains unexplored. In the present study, we performed genetic association studies in two different cohorts of susceptible patients [cystic fibrosis (CF) patients and recipients of hematopoietic stem cell transplantation (HSCT)], and identified IDO1 polymorphisms that associate with the risk of infection in both cohorts. By using human bronchial epithelial cells and PBMC from CF and HSCT patients, respectively, we could show that the IDO1 polymorphisms appeared to down-modulate IDO1 expression and function in response to IFNγ or Aspergillus conidia, and to associate with an increased inflammatory response. In contrast, IDO2 polymorphisms, including variants known to profoundly affect protein expression and function, were differently associated with the risk of aspergillosis in the two cohorts of patients as no association was found in CF patients as opposed to recipients of HSCT. By resorting to a murine model of bone marrow transplantation, we could show that the absence of IDO2 more severely affected fungal burden and lung pathology upon infection with Aspergillus as compared to IDO1, and this effect appeared to be linked to a deficit in the antifungal effector phagocytic activity. Thus, our study confirms and extends the role of IDO1 in the response to Aspergillus, and shed light on the possible involvement of IDO2 in specific clinical settings.

A mast cell-ILC2-Th9 pathway promotes lung inflammation in cystic fibrosis.

T helper 9 (Th9) cells contribute to lung inflammation and allergy as sources of interleukin-9 (IL-9). However, the mechanisms by which IL-9/Th9 mediate immunopathology in the lung are unknown. Here we report an IL-9-driven positive feedback loop that reinforces allergic inflammation. We show that IL-9 increases IL-2 production by mast cells, which leads to expansion of CD25+ type 2 innate lymphoid cells (ILC2) and subsequent activation of Th9 cells. Blocking IL-9 or inhibiting CD117 (c-Kit) signalling counteracts the pathogenic effect of the described IL-9-mast cell-IL-2 signalling axis. Overproduction of IL-9 is observed in expectorates from cystic fibrosis (CF) patients, and a sex-specific variant of IL-9 is predictive of allergic reactions in female patients. Our results suggest that blocking IL-9 may be a therapeutic strategy to ameliorate inflammation associated with microbial colonization in the lung, and offers a plausible explanation for gender differences in clinical outcomes of patients with CF.

Genetics of McCune-Albright syndrome.

McCune-Albright syndrome (MAS) is a rare proteiform disease due to postzygotic, somatic mutations at codon R201 of the GNAS1 gene that results in cellular mosaicism. Different methods have been used in the molecular analysis of DNA samples from several tissues of patients with one or more MAS signs, with various mutation detection rates. We review data from the literature to investigate whether patient inclusion criteria for GNAS1 analysis, the molecular methods used to search for R201 mutations, and the type of tissues analysed, can influence the mutation detection rate in MAS. Our study indicates that to overcome the problems related to GNAS1 analysis in MAS, sensitive and specific molecular methods must be used to look for the mutation from all available affected tissues and from easily accessible tissues, and even more so in the presence of atypical and monosymptomatic forms of MAS.

Bowel ultrasound imaging in patients with cystic fibrosis: Relationship with clinical symptoms and CFTR genotype.

BACKGROUND: Ultrasound imaging is used to assess bowel abnormalities in gastrointestinal diseases. We aimed to assess the rate of predefined bowel ultrasound signs and their relationship with gastrointestinal symptoms and the cystic fibrosis transmembrane conductance regulator (CFTR) genotype in cystic fibrosis patients in regular follow-up. METHODS: Prospective study of 70 consecutive patients with cystic fibrosis and 45 controls who underwent abdominal ultrasound; pertinent findings were related to gastrointestinal symptoms and, in cystic fibrosis patients, to pancreatic status, malabsorption degree, lipase intake, CFTR genotype (classified as severe or mild against functional class of CFTR mutations). RESULTS: 96% patients showed at least one abnormal bowel ultrasound sign. Most frequent signs were lymph node enlargement (64%), bowel loop dilatation (55%), thick corpuscular intraluminal content (49%), bowel wall hypervascularization (26%), thickened bowel wall (22%) and intussusception (17%). Patients with recurrent abdominal pain showed more bowel wall hypervascularization than patients without recurrent pain (47% vs. 19%, respectively; p = 0.02) and intussusception (58% vs. 17%, respectively; p < 0.01). Genotype was not associated to specific bowel ultrasound signs. Patients with bowel loop intussusception showed greater lipase intake than those without intussusception (8.118 ± 2.083 vs. 5.994 ± 4.187, respectively; p < 0.01). CONCLUSION: Cystic fibrosis patients present a higher rate of bowel ultrasound abnormalities than controls. Bowel ultrasound abnormalities are associated with abdominal symptoms.

Efficacy and tolerability of Creon for Children in infants and toddlers with pancreatic exocrine insufficiency caused by cystic fibrosis: an open-label, single-arm, multicenter study.

OBJECTIVES: To evaluate the efficacy and safety of a pancreatic enzyme preparation specifically developed for infants and small children with cystic fibrosis (CF). METHODS: Twelve patients with CF younger than 24 months with pancreatic exocrine insufficiency and a coefficient of fat absorption (CFA) less than 70% were treated with Creon for Children (Solvay Pharmaceuticals GmbH, Hannover, Germany) minimicrospheres for 8 weeks. The primary end point was the mean change from baseline in the CFA after 2 weeks of treatment, based on 72-hour fat balance assessments. RESULTS: Two weeks' treatment with Creon for Children resulted in a significant increase in the mean CFA from 58.0% at baseline to 84.7% (P=0.0013) in the full analysis sample. There was a significant reduction of mean stool fat (from 13.3 to 5.3 g/d; P=0.001) and mean fecal energy loss (from 238.5 to 137.9 kJ/d; P=0.018) at 2 weeks. Dietary fat intake did not change, whereas an improvement was observed in stool frequency and characteristics. Patient weight and height increased over 8 weeks of treatment. No serious adverse event was reported. CONCLUSIONS: Creon for Children was well tolerated and significantly decreased fat malabsorption in infants with pancreatic exocrine insufficiency due to CF.

Benefits of breastfeeding in cystic fibrosis: a single-centre follow-up survey.

AIM: To study the effect of breastfeeding (BF) on growth, lung function and number of infections during the first 3 years of life in children with cystic fibrosis (CF). MATERIAL AND METHODS: One hundred forty-six CF patients, 5-18 years old, were recruited at their annual care visit. Information about infant feeding, psychosocial and socioeconomic conditions and smoking exposure was obtained by interviews. Anthropometric parameters at 1 year of age and the number of infections and hospitalisations during the first 3 years of life were obtained from clinical charts. Anthropometrics and pulmonary function parameters were obtained at enrollment. RESULTS: In CF patients, particularly those with pancreatic insufficiency, the prevalence of BF was lower than the general Italian population. After multivariate analysis patients with prolonged BF showed higher values of CED expiratory volume in 1 sec (FEV-1) (p = 0.001) and a lower number of infections during the first 3 years of life (p = 0.098). CONCLUSION: Prolonged BF is beneficial in children with CF and may protect them against decline of pulmonary function. Particular attention should be paid to promote BF in infants with CF.

Liver disease in cystic fibrosis.

Liver involvement in Cystic Fibrosis (CF) is much less frequent than both pulmonary and pancreatic diseases that are present in 80-90% of CF patients; liver disease (LD) affects only one third of CF patients, however, because of the decreasing mortality from extrahepatic causes, its recognition and management is becoming a relevant clinical issue. Recent observations suggest that clinical expression of LD in CF may be influenced by genetic modifiers; their identification is an important issue because it may allow recognition of patients at risk for the development of LD at the time of diagnosis of CF and early institution of prophylactic strategies. Oral bile acid therapy, aimed at improving biliary secretion in terms of bile viscosity and bile acid composition, is currently the only available therapeutic approach for CF-associated LD. However, the impact of this therapy on the natural history of LD remains to be defined and long-term effectiveness on clinically relevant outcomes should be further investigated. Liver transplantation should be offered to CF patients with progressive liver failure and/or with life-threatening sequelae of portal hypertension, who also have mild pulmonary involvement that is expected to support long-term survival. The 1-year survival rate after transplantation in CF patients is approximately 80%, with beneficial effects on lung function, nutritional status, body composition and quality of life in most cases.