Co-morbidity In Cystic Fibrosis Research Articles

Chronic hyperglycemia aggravates lung function in a Scnn1b-Tg murine model.

Cystic fibrosis-related diabetes (CFRD), the most common comorbidity in cystic fibrosis (CF), leads to increased mortality by accelerating the decline in lung function. Scnn1b-Tg transgenic mice overexpressing the epithelial sodium channel β subunit exhibit spontaneous CF-like lung disease, including airway mucus obstruction and chronic inflammation. Here, we established a chronic CFRD-like model utilizing Scnn1b-Tg mice made diabetic by injection of streptozotocin. In Ussing chamber recordings of trachea, Scnn1b-Tg mice exhibited larger amiloride-sensitive currents and forskolin-activated currents, without a difference in ATP-activated currents compared to wildtype (WT) littermates. Both diabetic WT (WT-D) and diabetic Scnn1b-Tg (Scnn1b-Tg-D) mice on the same genetic background exhibited substantially elevated blood glucose at 8 weeks; glucose levels also were elevated in bronchoalveolar lavage fluid (BALF) Bulk lung RNA-seq data showed significant differences between WT-D and Scnn1b-Tg-D mice. Neutrophil counts in BALF were substantially increased in Scnn1b-Tg-D lungs compared to controls (Scnn1b-Tg-con) and compared to WT-D lungs. Lung histology data showed enhanced parenchymal destruction, alveolar wall thickening, and neutrophilic infiltration in Scnn1b-Tg-D mice compared to WT-D mice, consistent with development of a spontaneous lung infection. We intranasally administered Pseudomonas aeruginosa to induce lung infection in these mice for 24 hours, which led to severe lung leukocytic infiltration and an increase in pro-inflammatory cytokine levels in the BALF. In summary, we established a chronic CFRD-like lung mouse model using the Scnn1b-Tg mice. The model can be utilized for future studies toward understanding the mechanisms underlying the lung pathophysiology associated with CFRD and developing novel therapeutics.

Abstract #1169814: Insulin for Hypoglycemia?: The Case for Initiating Prandial Insulin First in Cystic Fibrosis Related Diabetes

Cystic fibrosis related diabetes (CFRD) is the most common non-respiratory comorbidity in cystic fibrosis (CF), occurring in 40-50% of adults with CF. CF mediated destruction of the pancreatic tissue from progressive fibrosis and fatty infiltration leads to loss of beta cells and insulin deficiency, but alteration of beta cell function and insulin resistance due to inflammation or infection are also possible mechanisms for diabetes development.

Altered Lipid Metabolism in the Follow Up of Cystic Fibrosis Lung Transplant Patients

<h3>Purpose</h3> This study is aimed at characterizing lipid metabolism alteration in Cystic Fibrosis (CF) patients before and after lung transplant (LuTX), in association with pharmacological therapies, dietary patterns and clinical features, at the aim of elucidating its role in LuTX rejection versus graft tolerance. In spite of reduced body weight, among CF comorbidities, plasma hypertriglyceridemia and low HDL, associated with ectopic lipid accumulation including the airways, liver steatosis and CF related diabetes are reported. An altered ability to oxidize lipids for energy requests was recently suggested in these patients and a high ratio between fat mass and lean mass correlates with clinical worsening, such as reduced FEV and recurrent infections. LuTX causes an increase in fat trunk; it is per se a cause of diabetes insurgence, partially dependent on immunosuppressive therapy. Both reduced and increased weight are considered in the prognosis of rejection and pharmacological reduction of lipid synthesis, by means of statins or activation lipid oxidation by glitazones, may implement survival in LuTX patients. Leptin and adiponectin ratio is altered in CF and in LuTX rejecting patients and CF LuTx exhibit a significantly higher risk to develop hyperlipidemia than non CF. The hypothesis of this study is that CF dyslipidemia and altered ability to use lipids for energy requirement can negatively impact on LuTX, worsening the graft implantation related comorbidities <h3>Methods</h3> The cohort includes adults CF in list for LuTX. Evaluations are performed either before and after LuTX (up to 6 months post). Lipidomic profile is obtained by untargeted LC-MS analyses from plasma, plasma derived microvesicles, explanted lungs and surveillance transbronchial biopsies. Transcriptional profile of lipid metabolism related genes is obtained in lung biopsies by RT-PCR. Lipid metabolism related hormones are evaluated by Luminex multiplex assays from patients' plasma. Clinical biochemistry, lung functional analyses, and nutritional evaluation are routinely performed. <h3>Endpoints</h3> We aim at identifying a lipid metabolism derangement in association with CF LuTX adverse prognosis. The study will provide evidence on the importance of introducing novel nutritional and pharmacological intervention in the follow up of these patients.

Prepuberal insulin secretory indices are long-term predictors of short adult stature in cystic fibrosis.

ObjectiveDiabetes is a frequent comorbidity in cystic fibrosis (CF), related to multiple unfavorable outcomes. During the progression of β-cell dysfunction to diabetes, insulin deficiency could possibly reduce the anabolic support to grow even in the absence of significant glycemic derangements. To test this hypothesis, we evaluated whether prepuberal insulin secretory indices are independent predictors of adult height.DesignObservational cohort study.Research design and methodsA longitudinal analysis of 66 CF patients (33 females) from an ongoing cohort received at prepuberal age (median age of 12 years) modified 3-h oral glucose tolerance tests with 30-min insulin and C-peptide sampling, modeling of insulin secretory and sensitivity parameters, anthropometric evaluation. The latter was repeated when adults after a median follow-up of 9 years.ResultsIn alternative models, we found a positive association with either basal insulin secretion (mean 0.22, 95% CI 0.01, 0.44 z-scores) or prepuberal β-cell glucose sensitivity (mean 0.23, 95% CI 0.00, 0.46 z-scores) and adult height, while total insulin secretion was negatively related to adult height (mean −0.36, 95% CI −0.57, −0.15 z-scores or mean −0.42, 95% CI −0.69, −0.16 z-scores, respectively). The high total insulin secretion of low adult height patients was mainly due to late (>60 min) secretion and was associated with a worse glucose response during OGTT.ConclusionsAbnormal insulin secretion associated with high glucose response during OGTT predicts a decrease in adult height z-score. Our results suggest that insulin secretory defects in CF affect growth prior to the development of fasting hyperglycemia.

Bone Cells Differentiation: How CFTR Mutations May Rule the Game of Stem Cells Commitment?

Cystic fibrosis (CF)-related bone disease has emerged as a significant comorbidity of CF and is characterized by decreased bone formation and increased bone resorption. Both osteoblast and osteoclast differentiations are impacted by cystic fibrosis transmembrane conductance regulator (CFTR) mutations. The defect of CFTR chloride channel or the loss of CFTRs ability to interact with other proteins affect several signaling pathways involved in stem cell differentiation and the commitment of these cells toward bone lineages. Specifically, TGF-, nuclear factor-kappa B (NF-B), PI3K/AKT, and MAPK/ERK signaling are disturbed by CFTR mutations, thus perturbing stem cell differentiation. High inflammation in patients changes myeloid lineage secretion, affecting both myeloid and mesenchymal differentiation. In osteoblast, Wnt signaling is impacted, resulting in consequences for both bone formation and resorption. Finally, CFTR could also have a direct role in osteoclasts resorptive function. In this review, we summarize the existing literature on the role of CFTR mutations on the commitment of induced pluripotent stem cells to bone cells.

Diabetes and Prediabetes in Children With Cystic Fibrosis: A Systematic Review of the Literature and Recommendations of the Italian Society for Pediatric Endocrinology and Diabetes (ISPED).

Cystic fibrosis related diabetes (CFRD) is a comorbidity of cystic fibrosis (CF) that negatively impacts on its clinical course. Prediabetes is an important predictor of either CFRD development and unfavorable prognosis of CF in both pediatric and adult patients. International guidelines recommend insulin only in case of CFRD diagnosis. Whether early detection and treatment of prediabetes may contribute to improve the clinical course of CF is still debated. A subgroup of pediatric diabetologists of the Italian Society for Pediatric Endocrinology and Diabetology (ISPED) performed a systematic review of the literature based on predefined outcomes: impact of pre-diabetes on clinical outcomes and on the risk of developing CFRD; diagnosis of diabetes and pre-diabetes under 10 years of age; effectiveness of therapy on glycemic control, impact of therapy on pulmonary function and nutritional status. Thirty-one papers were selected for the analysis data presented in these papers were reported in tables sorted by outcomes, including comprehensive evidence grading according to the GRADE approach. Following the grading of the quality of the evidence, the entire ISPED diabetes study group achieved consensus for the Italian recommendations based on both evidence and clinical experience. We concluded that in patients with CF, prediabetes should be carefully considered as it can evolve into CFRD. In patients with CF and prediabetic conditions, after complete evaluation of the OGTT trend, glucometrics, glycemic values measured during pulmonary exacerbations and/or steroid therapy, early initiation of insulin therapy could have beneficial effects on clinical outcomes of patients with CF and prediabetes.

The Changing Face of Lung Transplant Waiting Lists in the Era of CFTR Modulators

Purpose Cystic fibrosis (CF) is a life-limiting genetic condition with which often leads to life-threatening respiratory failure requiring lung transplantation. People with CF (PwCF) account for 16% of adult bilateral lung transplants internationally according to a 2016 report of the ISHLT Registry by Yusen et al. With the advent of effective CFTR (cystic fibrosis transmembrane conductance regulator) modulators becoming widely available in recent years, for many PwCF the clinical response has been transformative, and a significant proportion no longer meet criteria for lung transplantation referral and listing. Methods A retrospective analysis was undertaken of the number of PwCF referred in the last 12 months (i.e. since the CFTR modulators tezacaftor/ivacaftor and elexacaftor/tezacaftor/ivacaftor became widely available in the UK) compared to the previous 3 years, for lung transplantation at Harefield Hospital. The impact of CFTR modulators on the Lung Transplant Waiting List at Harefield Hospital was also assessed. Results As of October 2020, of the 25 PwCF who were assessed for lung transplantation and met criteria for listing at time of assessment, only 7 (28%) remain actively listed. All of the others (n=18; 72%) were suspended after starting a CFTR modulator (of which 12 were suspended in the last 12 months). Median improvement in FEV1(%) after starting a modulator in those who subsequently suspended was 10% (range 0-24%). Referrals of PwCF in the last 12 months was 22 compared with an average of 37 referrals per year over the preceding 3 years. Only 14% (7/49) of the current active waiting list for double lung transplantation are PwCF compared with 26% (19/73) a year ago. Conclusion The improvement in quality of life and lung function in PwCF eligible for CFTR modulators can be transformative. However, those who continue to decline despite this treatment, are likely to be older, have multiple CF-related comorbidities, and may be more complex surgical candidates. Transplant centres face a changing landscape as transplant lists become increasingly populated with other patient groups. Those continuing to transplant PwCF need to become experienced at managing complex CF comorbidities.

Islet Function in the Pathogenesis of Cystic Fibrosis-Related Diabetes Mellitus.

Cystic fibrosis-related diabetes mellitus (CFRD) is the most common non-pulmonary co-morbidity in cystic fibrosis (CF). CF is caused by mutations in the cystic fibrosis transmembrane conductance regulator gene (CFTR), which leads to aberrant luminal fluid secretions in organs such as the lungs and pancreas. How dysfunctional CFTR leads to CFRD is still under debate. Both intrinsic effects of dysfunctional CFTR in hormone secreting cells of the islets and effects of exocrine damage have been proposed. In the current review, we discuss these non-mutually exclusive hypotheses with a special focus on how dysfunctional CFTR in endocrine cells may contribute to an altered glucose homeostasis. We outline the proposed role of CFTR in the molecular pathways of β-cell insulin secretion and α-cell glucagon secretion, and touch upon the importance of the exocrine pancreas and intra-pancreatic crosstalk for proper islet function.

Associations Between Glucose Tolerance, Insulin Secretion, Muscle and Fat Mass in Cystic Fibrosis.

Background:A frequent comorbidity in cystic fibrosis (CF) is CF related diabetes (CFRD) caused by a gradual decline in insulin secretion. The reduction in the anabolic hormone, insulin, might explain the weight loss that precedes onset of CFRD. We investigated the association between muscle and fat mass in relation to glucose tolerance and insulin function.Methods:In a cross-sectional study with CF patients (⩾18 years), we conducted an oral glucose tolerance test and dual energy X-ray absorptiometry scan (DXA). Based on plasma glucose, glucose tolerance was defined as normal (NGT): 1-hour <11.1 mmol/L and 2-hour <7.8 mmol/L, impaired (IGT): 2-hour ⩾7.8 and <11.1 mmol/L or CFRD: 2-hour ⩾11.1 mmol/L. Insulin resistance (HOMA-IR) was derived from fasting levels of plasma glucose and plasma insulin, and fat-free and fat mass index (kg/m2) from DXA. Associations were evaluated using linear regression models adjusted for age, sex, and pancreas insufficiency.Results:Among 79 CF patients with exocrine pancreas insufficiency, impairment of glucose tolerance corresponded to reduced insulin secretion. In the IGT group the fat-free mass index (FFMI) was 1.2 kg/m2 (95% CI: [−2.3, −0.03] kg/m2, P = .044) lower compared to the NGT group. FFMI increased insignificantly by 0.4 kg/m2 (95% CI: [−0.6, 1.5] kg/m2, P = .422) among the insulin-treated CFRD group compared to IGT. Fat mass index (FMI) was not different between groups but tended to decrease with glucose tolerance impairment. For each 100 pmol/L increase in fasting insulin FFMI increased by 1.77 kg/m2 (95% CI: [0.21, 3.33] kg/m2/pmol/L/100) and FMI increased by 6.15 kg/m2 (95% CI: [3.87, 8.44] kg/m2/pmol/L/100). In multivariate analyses, HOMA-IR was positively associated with FFMI (β = 0.5 kg/m2/HOMA-IR, 95% CI: [0.08, 0.92] kg/m2/HOMA-IR, P = .021) and FMI (β = 1.5 kg/m2/HOMA-IR, 95% CI: [0.87, 2.15] kg/m2/HOMA-IR, P < .001).Conclusions:Muscle mass was significantly lower among participants with impaired glucose tolerance (IGT), while muscle mass was normalized among those treated with insulin.

Cystic fibrosis: Physiopathology and the latest pharmacological treatments

Cystic fibrosis (CF) is a lethal autosomal recessive genetic disease, caused by a mutation in the cystic fibrosis transmembrane conductance regulator gene (CFTR), which primarily affects the lungs and digestive system. This gene encodes the CFTR protein, a distinctive membrane transporter of the ATP-binding cassette (ABC) superfamily. It functions as a chloride channel, allowing the balance and transport of chloride through the apical membrane of epithelial cells. Due to its ubiquitous location, mutations in the CFTR gene trigger multiple changes in ion transport and metabolic pathways, affecting various organs, as it will be herein explained. Pulmonary impairment is the most characteristic comorbidity of CF and respiratory failure is the main cause of death.This review presents the importance of an early diagnosis of CF to establish, as soon as possible, a primary therapy for symptomatic prevention and relief. It also mentions new therapeutic approaches that include CFTR modulators. They are correctors and/or potentiators of the deficient CFTR channel. In an attempt to overcome the disadvantages of CFTR modulators, the application of biotechnology techniques is addressed, such as gene therapy, gene editing, RNA therapy and therapeutic microRNAs. The potential of the intranasal administration route is another presented aspect.

Abnormal glucose tolerance and the 50-gram glucose challenge test in Cystic fibrosis

Diabetes has emerged as a major co-morbidity in cystic fibrosis (CF). The 75 g oral glucose tolerance test (OGTT) is used to screen for CF-related diabetes (CFRD) but is inconvenient, and adherence to screening is poor. The 50 g glucose challenge test (GCT) is shorter, performed non-fasting, and may serve to pre-screen the subset of individuals requiring confirmatory OGTT. We performed a pilot study in twenty-seven CF individuals across the glucose tolerance spectrum to test whether the GCT could identify subjects with abnormal glucose tolerance defined as 2-h OGTT glucose ≥7.8 mmol/L (2 h-AGT) or 1-h defined as 1-hr OGTT glucose ≥11.1 mmol/L (1 h-AGT). A GCT threshold of 8.1 mmol/L was 73% sensitive and 63% specific for 2hr-AGT and 80% sensitive and 65% specific for 1hr-AGT. Therefore, a screening GCT may reduce need for confirmatory OGTT for identifying AGT but a larger study is warranted to identify a robust cutoff for CFRD.

Exposure to Bile Leads to the Emergence of Adaptive Signaling Variants in the Opportunistic Pathogen Pseudomonas aeruginosa.

The chronic colonization of the respiratory tract by the opportunistic pathogen Pseudomonas aeruginosa is the primary cause of morbidity and mortality in cystic fibrosis (CF) patients. P. aeruginosa has been shown to undergo extensive genomic adaptation facilitating its persistence within the CF lung allowing it to evade the host immune response and outcompete co-colonizing residents of the lung microbiota. However, whilst several studies have described the various mutations that frequently arise in clinical isolates of P. aeruginosa, the environmental factors governing the emergence of these genetic variants is less well characterized. Gastro-oesophageal reflux has recently emerged as a major co-morbidity in CF and is often associated with the presence of bile acids in the lungs most likely by (micro) aspiration. In order to investigate whether bile may select for genetic variants, P. aeruginosa was experimentally evolved in artificial sputum medium, a synthetic media resembling environmental conditions found within the CF lung. Pigmented derivatives of P. aeruginosa emerged exclusively in the presence of bile. Genome sequencing analysis identified single nucleotide polymorphisms (SNPs) in quorum sensing (lasR) and both the pyocyanin (phzS) and pyomelanin (hmgA) biosynthetic pathways. Phenotypic analysis revealed an altered bile response when compared to the ancestral P. aeruginosa progenitor strain. While the recovered pigmented derivatives retained the bile mediated suppression of swarming motility and enhanced antibiotic tolerance, the biofilm, and redox responses to bile were abolished in the adapted mutants. Though loss of pseudomonas quinolone signal (PQS) production in the pigmented isolates was not linked to the altered biofilm response, the loss of redox repression could be explained by defective alkyl-quinolone (AQ) production in the presence of bile. Collectively, these findings suggest that the adaptive variants of P. aeruginosa that arise following long term bile exposure enables the emergence of ecologically competitive sub-populations. Altered pigmentation and AQ signaling may contribute to an enhancement in fitness facilitating population survival within a bile positive environment.

Extra-respiratory comorbidities and transplantation in the French cystic fibrosis registry

ABSTRACTBackground: To better understand the potential role of lung transplantation (LT) in accelerating or slowing down extrarespiratory cystic fibrosis (CF) complications, we compare the respective prevalence of extrapulmonary CF comorbidities in transplanted and nontransplanted adult CF patients.Methods: About 20% of the adult CF patients included in the French CF registry have undergone transplantation. We analyzed all adults included in the French CF registry in 2014 and compared them according to their transplant status, irrespective of the year of transplantation, to describe the prevalence of CF-related diabetes (CFRD), end-stage renal disease and osteoporosis (Chi-squared and Fisher’s exact tests).Results: A total of 3339 adult CF patients were included in the French CF Registry and 673 (20.2%) were transplanted. Prevalence of CFRD was significantly higher in transplanted patients compared to nontransplanted patients irrespective of the age group; the prevalence of end-stage renal disease and osteoporosis was also significantly higher in transplanted patients.Conclusion: These results demonstrate the high prevalence of extrapulmonary comorbidities in transplanted CF adult patients particularly CFRD. We highlight the need for specific surveillance and prevention for transplanted CF patients who were already treated for extra espiratory comorbidities before lung transplantation, due to the potential aggravation of their comorbidities after transplantation.

Микробиологическая диагностика сопутствующей микобактериальной инфекции при фиброзном кистозе (муковисцидозе)

Diseases caused by mycobacteria, leprosy and tuberculosis, are widely known for many centuries. However, interest in mycobacteriosis, as an infectious disease of human organs caused by other mycobacteria, was only apparent from the late 50s of the 20th century. Over the years of observation, the number of cases of mycobacteriosis in various regions of the world has increased significantly, including in patients with cystic fibrosis. A key sign of comorbidity in cystic fibrosis is a chronic microbial infection that determines the severity of the course and the prognosis of the disease. In order to identify and identify mycobacteria isolated from patients with cystic fibrosis from 2011 to 2018, sputum was examined from 160 patients with cystic fibrosis and suspected mycobacterial infection. Mycobacteria were secreted in 17 (10.6%) patients with cystic fibrosis, of which non-tuberculous mycobacteria predominated. Thirteen patients were infected with M. abscessus (76.4%), two with M.avium (11.7%), one with M.xenopi (5.8%), one with M. tuberculosis (5.8%). Determination of drug sensitivity of mycobacteria showed that the culture of M.tuberculosis was sensitive to all antituberculosis drugs, and strains of nontuberculous mycobacteria had a different spectrum of drug susceptibility to drugs used for the therapy of mycobacteriosis. Identification of infectious agents will help ensure the timely initiation of adequate treatment, proper monitoring and prevention of the spread of non-tuberculosis mycobacteria among patients with cystic fibrosis .

Long-Term Follow-Up in a Girl with Cystic Fibrosis and Diabetes Since the First Year of Life.

Diabetes mellitus is the most common comorbidity in cystic fibrosis (CF). Recently, more attention has been paid to early glucose metabolism derangements (GMDs). The subject of this report is a female patient, affected by CF since 3 months of age. She presented with intermittent diabetes during early childhood. At the age of 10 years, oral glucose tolerance test (OGTT) was performed and showed glucose intolerance (IGT) status; glargine insulin therapy was started. At the age of 13 years, CF-related diabetes with fasting hyperglycemia occurred, so rapid insulin at meals was added. During the following year, clinical and nutritional status improved. Stable clinical conditions were observed in the following 3 years. This is the first case of very long-term follow-up concerning a CF patient with GMDs. Our case confirms the importance of paying attention to early GMDs in very young CF patients and seems to suggest that earlier therapy could ameliorate CF natural history.

Cystic Fibrosis Revisited – a Review Study

Cystic fibrosis (CF) is an incurable, chronic disease, which causes severe damages to respiratory and digestive tracts. It is the most common genetically inherited disease among caucasians. This disease is caused by defects in CF genes, the so-called mutations in cystic fibrosis transmembrane conductance regulator (CFTR) gene population. At present over 100,000 people suffer from this disease worldwide. The purpose of this review study is to describe the pathophysiology of CF and provide the latest information on its diagnosis and treatment therapies with respect to the improvement of patient's quality of life and emphasis on targeted specialized care. The methodological approaches include a method of literature review of available sources exploring the issue of cystic fibrosis both from a global and specific perspective point of view. A search was performed in the databases PubMed, MEDLINE, Web of Science, Scopus, Springer and ScienceDirect. Furthermore, other sources cited in the analyzed studies were also examined. On the basis of evaluation of these literature sources, the research issue was explored. The main benefits (e.g., specialized centres for the treatment of CF exist or a new breakthrough in the gene therapy of CF has been made) and limitations (e.g., comorbidity of CF, lifelong and costly treatment, or adverse impact on patient's and caregiver's quality of life) in the treatment of narcolepsy are highlighted. CF requires an integrated treatment approach in specialized CF centers, involving various factors contributing to a better patient's state of health in the form of relevant and well-balanced non-pharmacological and pharmacological therapies. In addition, further large scale clinical trials are needed in order to develop compounds that are aimed at the most common classes of CFTR.

Venous Thromboembolism in Pediatric Cystic Fibrosis

Background: Pediatric venous thromboembolism (VTE) is a rare but serious medical condition resulting in significant morbidity, mortality and healthcare costs. In the recent decade, the rate of general pediatric VTE has dramatically increased across all age ranges, from neonates to adolescents. This increase is likely multi-factorial, including more aggressive management of critically ill patients, improved survival of children with chronic disease and the increased use of central venous catheters (CVCs). Cystic fibrosis (CF) is a chronic, inflammatory disease process often managed with courses of intravenous antibiotics administered through CVCs, both peripherally inserted central catheters (PICC) and implantable venous ports. There are limited data documenting an increased risk of VTE in CF patients with ports. However, there are no published data on PICC line-associated VTE or overall VTE incidence specifically in the pediatric CF population.Methods: A retrospective cohort study was conducted in CF patients, ages 0 to 21 years, followed at the CF Care Center at Children's Hospital Colorado between 2003 and 2016, who were enrolled in the national CF Foundation Patient Registry. VTE cases were identified by informatics, including anticoagulation administration, documentation of VTE in radiographic reports and nursing flowsheets, and use of VTE ICD-9 and ICD-10 codes. All identified cases were confirmed by manual chart review and data including personal and family history of VTE, use of prophylaxis and VTE type, diagnosis date, diagnostic modality and line-association were entered into a secured REDCap longitudinal database. Data including CF mutation, CF co-morbidities, microbiology history, pulmonary function testing, disease modifying medications, thrombophilia testing and central line specifications and duration were collected for every admission on all study participants to allow for future risk factor analysis.Results: The cohort consisted of 488 participants with a total of 2,590 admissions (mean 5.34 per participant, range 1-56). Two hundred and forty-nine individuals were male (51%) and the majority were Caucasian (463, 95.3%) with a normal BMI (average 19.7, range 14.8-25.4). A total of 1,157 CVCs were placed over the study period including 981 PICCs (84.8%), 93 ports (8%) and 83 unspecified (7.2%). Thirty-one VTEs were diagnosed in 23 participants (4.3%) on 29 admissions (1.12%). Twelve of the 23 participants with VTE were male (52%) and the average age of those with VTE was 15.3 years (range 4-21). Twenty-two of the VTEs were deep vein thromboses, including 4 pulmonary emboli, and 9 were in superficial veins. The average day of VTE diagnosis was hospital day 4.9 (range 0-14). At the time of diagnosis, 11 had ports, 15 had PICCs and 5 had no CVC. The majority of VTEs were associated with the CVC (19, 61.3%) and of those CVC-associated VTEs, the majority were seen with PICCs (14, 73.7%). On average, PICC-associated VTE occurred on line day 5.2 (range 2-14) and port-associated VTE occurred on line day 897.5 (range 37-1496). Of the 23 participants with VTE, 14 were tested for Factor V Leiden mutation and 2 were heterozygous. Similarly, for the prothrombin mutation, 13 were tested and two were heterozygous. While the majority of participants had minimal to no thrombophilia evaluation, notably, an elevated factor VIII was associated with 11 of 12 VTE diagnoses (91.7%, average 215.47, range 61-341.3).Conclusion: In this large pediatric cohort of patients with CF, there was an increased number of VTE when compared to previously published general pediatric populations. Consistent with known risk factors, the average participant with VTE was in their teenage years and had a CVC, although 16% occurred without a line in place. Gender and obesity did not appear to contribute dramatically as the male/female distribution was roughly equal and the average BMI was within normal range. If a CVC was placed, the vast majority of CF patients received PICCs. PICCs also made up the majority of CVC-associated VTE with the average thrombosis occurring on day 5 following line placement. Few participants with VTE had complete thrombophilia evaluations but of those that did, factor VIII was elevated in all but one individual. DisclosuresWang:HEMA Biologics: Membership on an entity's Board of Directors or advisory committees; CSL Behring: Membership on an entity's Board of Directors or advisory committees; Baxalta: Membership on an entity's Board of Directors or advisory committees; LFB: Membership on an entity's Board of Directors or advisory committees; Biogen: Membership on an entity's Board of Directors or advisory committees; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees.

MiR-146a, miR-155, miR-370, and miR-708 Are CFTR-Dependent, Predicted FOXO1 Regulators and Change at Onset of CFRDs.

Cystic fibrosis-related diabetes (CFRD) is the most frequent and severe co-morbidity in cystic fibrosis (CF). Presentation and severity are quite variable. To investigate changes in microRNAs (miRNAs) due to CF transmembrane conductance regulator malfunctioning in vitro, to study the circulating levels of selected miRNAs in serum samples from patients, and to assess their relationships in different age groups with genotype, glucose tolerance state, and at onset of CFRD. Design/Setting/Patients/Interventions: Transcriptional profiling of all known miRNAs in CFBE41o- cells, in their normal counterparts (16HBE14o- cells), and in IB3 cells was performed. A set of miRNAs was differentially expressed in the CF cells. By in silico analysis, four miRNAs (miR-146a, miR-155, miR-370, and miR-708) were selected as potential regulators of the FOXO1 gene. Seventy-four CF patients and 50 healthy subjects whose glucose tolerance was characterized by an oral glucose tolerance test were enrolled in the study, and the identified miRNAs were quantified in serum by quantitative RT-PCR. Main Outcome Measurements/Results: A total of 111 miRNAs were differentially expressed in the two CF cell lines. miR-155, miR-370, and miR-708 were up-regulated and miR-146a was down-regulated in vitro, whereas in vivo, miR-146a, miR-155, and miR-370 were up-regulated, and miR-708 was down-regulated. These changes showed relationships with genotype, glucose tolerance state, and onset of CFRD. The data showed significant changes in miRNAs dependent on genotype and glucose tolerance state in CF patients and highlighted some miRNAs of importance in CFRD at onset. miRNAs could explain some of the variability observed in CF.

Islet-intrinsic effects of CFTR mutation.

Cystic fibrosis-related diabetes (CFRD) is the most significant extra-pulmonary comorbidity in cystic fibrosis (CF) patients, and accelerates lung decline. In addition to the traditional view that CFRD is a consequence of fibrotic destruction of the pancreas as a whole, emerging evidence may implicate a role for cystic fibrosis transmembrane-conductance regulator (CFTR) in the regulation of insulin secretion from the pancreatic islet. Impaired first-phase insulin responses and glucose homeostasis have also been reported in CF patients. CFTR expression in both human and mouse beta cells has been confirmed, and recent studies have shown differences in endocrine pancreatic morphology from birth in CF. Recent experimental evidence suggests that functional CFTR channels are required for insulin exocytosis and the regulation of membrane potential in the pancreatic beta cell, which may account for the impairments in insulin secretion observed in many CF patients. These novel insights suggest that the pathogenesis of CFRD is more complicated than originally thought, with implications for diabetes treatment and screening in the CF population. This review summarises recent emerging evidence in support of a primary role for endocrine pancreatic dysfunction in the development of CFRD.Summary• CF is an autosomal recessive disorder caused by mutations in the CFTR gene• The vast majority of morbidity and mortality in CF results from lung disease. However CFRD is the largest extra-pulmonary co-morbidity and rapidly accelerates lung decline• Recent experimental evidence shows that functional CFTR channels are required for normal patterns of first phase insulin secretion from the pancreatic beta cell• Current clinical recommendations suggest that insulin is more effective than oral glucose-lowering drugs for the treatment of CFRD. However, the emergence of CFTR corrector and potentiator drugs may offer a personalised approach to treating diabetes in the CF population

ESPEN-ESPGHAN-ECFS guidelines on nutrition care for infants, children, and adults with cystic fibrosis

Malnutrition is both a frequent feature and a comorbidity of cystic fibrosis (CF), with nutritional status strongly associated with pulmonary function and survival. Nutritional management is therefore standard of care in CF patients. ESPEN, ESPGHAN and ECFS recommended guidelines to cover nutritional management of patients with CF. The guidelines were developed by an international multidisciplinary working group in accordance with officially accepted standards. The GRADE system was used for determining grades of evidence and strength of recommendation. Statements were discussed, submitted to Delphi rounds, reviewed by ESPGHAN and ECFS and accepted in an online survey among ESPEN members. The Working Group recommends that initiation of nutritional management should begin as early as possible after diagnosis, with subsequent regular follow up and patient/family education. Exclusive breast feeding is recommended but if not possible a regular formula is to be used. Energy intake should be adapted to achieve normal weight and height for age. When indicated, pancreatic enzyme and fat soluble vitamin treatment should be introduced early and monitored regularly. Pancreatic sufficient patients should have an annual assessment including fecal pancreatic elastase measurement. Sodium supplementation is recommended and a urinary sodium:creatinine ratio should be measured, corresponding to the fractional excretion of sodium. If iron deficiency is suspected, the underlying inflammation should be addressed. Glucose tolerance testing should be introduced at 10 years of age. Bone mineral density examination should be performed from age 8-10 years. Oral nutritional supplements followed by polymeric enteral tube feeding are recommended when growth or nutritional status is impaired. Zinc supplementation may be considered according to the clinical situation. Further studies are required before essential fatty acids, anti-osteoporotic agents, growth hormone, appetite stimulants and probiotics can be recommended. Nutritional care and support should be an integral part of management of CF. Obtaining a normal growth pattern in children and maintaining an adequate nutritional status in adults are major goals of multidisciplinary cystic fibrosis centers.