One Center's Guide to Outpatient Management of Pediatric Cystic Fibrosis Acute Pulmonary Exacerbation.

Clin Med Insights Pediatr. 2016;10:57-65

Authors: Muirhead CA, Sanford JN, McCullar BG, Nolt D, MacDonald KD

Abstract
Cystic fibrosis (CF) is a chronic disorder characterized by acute pulmonary exacerbations that comprise increased cough, chest congestion, increased mucus production, shortness of breath, weight loss, and fatigue. Typically, severe episodes are treated in the inpatient setting and include intravenous antimicrobials, airway clearance therapy, and nutritional support. Children with less-severe findings can often be managed as outpatients with oral antimicrobials and increased airway clearance therapy at home without visiting the specialty CF center to begin treatment. Selection of specific antimicrobial agents is dependent on pathogens found in surveillance culture, activity of an agent in patients with CF, and the unique physiology of these patients. In this pediatric review, we present our practice for defining acute pulmonary exacerbation, deciding treatment location, initiating treatment either in-person or remotely, determining the frequency of airway clearance, selecting antimicrobial therapy, recommending timing for follow-up visit, and recognizing and managing treatment failures.

PMID: 27429564 [PubMed]

Hypoxic Gene Expression of Donor Bronchi Linked to Airway Complications after Lung Transplantation.

Am J Respir Crit Care Med. 2016 Mar 1;193(5):552-60

Authors: Kraft BD, Suliman HB, Colman EC, Mahmood K, Hartwig MG, Piantadosi CA, Shofer SL

Abstract
RATIONALE: Central airway stenosis (CAS) after lung transplantation has been attributed in part to chronic airway ischemia; however, little is known about the time course or significance of large airway hypoxia early after transplantation.
OBJECTIVES: To evaluate large airway oxygenation and hypoxic gene expression during the first month after lung transplantation and their relation to airway complications.
METHODS: Subjects who underwent lung transplantation underwent endobronchial tissue oximetry of native and donor bronchi at 0, 3, and 30 days after transplantation (n = 11) and/or endobronchial biopsies (n = 14) at 30 days for real-time polymerase chain reaction of hypoxia-inducible genes. Patients were monitored for 6 months for the development of transplant-related complications.
MEASUREMENTS AND MAIN RESULTS: Compared with native endobronchial tissues, donor tissue oxygen saturations (Sto2) were reduced in the upper lobes (74.1 ± 1.8% vs. 68.8 ± 1.7%; P < 0.05) and lower lobes (75.6 ± 1.6% vs. 71.5 ± 1.8%; P = 0.065) at 30 days post-transplantation. Donor upper lobe and subcarina Sto2 levels were also lower than the main carina (difference of -3.9 ± 1.5 and -4.8 ± 2.1, respectively; P < 0.05) at 30 days. Up-regulation of hypoxia-inducible genes VEGFA, FLT1, VEGFC, HMOX1, and TIE2 was significant in donor airways relative to native airways (all P < 0.05). VEGFA, KDR, and HMOX1 were associated with prolonged respiratory failure, prolonged hospitalization, extensive airway necrosis, and CAS (P < 0.05).
CONCLUSIONS: These findings implicate donor bronchial hypoxia as a driving factor for post-transplantation airway complications. Strategies to improve airway oxygenation, such as bronchial artery re-anastomosis and hyperbaric oxygen therapy merit clinical investigation.

PMID: 26488115 [PubMed - indexed for MEDLINE]

9 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

"Cystic Fibrosis"

These pubmed results were generated on 2016/07/19

PubMed comprises more than 24 million citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

Preface: Cystic Fibrosis in Children and Adults: Supplement to Paediatric Respiratory Reviews.

Paediatr Respir Rev. 2016 Jun 18;

Authors: David TJ

PMID: 27424228 [PubMed - as supplied by publisher]

Decreased TGF-β1 and VEGF Release in Cystic Fibrosis Platelets: Further Evidence for Platelet Defects in Cystic Fibrosis.

Lung. 2016 Jul 16;

Authors: Maloney JP, Narasimhan J, Biller J

Abstract
PURPOSE: Cystic fibrosis (CF) patients suffer from chronic lung inflammation. This inflammation may activate platelets. There are limited data on the role of platelet-secreted cytokines in CF. Platelet cytokines with inflammatory effects include vascular endothelial growth factor (VEGF) and transforming growth factor-β1 (TGF-β1). As levels of these cytokines are tenfold greater in serum than plasma due to platelet release, serum levels may be one index of platelet content, but a more specific index is release during the aggregation of isolated platelets. We postulated that altered release of these platelet cytokines occurs in CF.
METHODS: We obtained sera and plasma from CF outpatients (n = 21) and from healthy controls (n = 20), measured VEGF and TGF-β1, assessed for correlations with platelet number, analyzed cytokine release during platelet aggregation to collagen, and analyzed differences in maximal platelet aggregation.
RESULTS: Platelet number and maximal aggregation levels were higher in CF. Plasma and serum levels of TGF-β1 and VEGF were higher in CF, but these levels were similar after adjusting for platelet number (serum cytokines correlated with platelet count). The release of VEGF and TGF-β1 during aggregation was decreased in CF platelets (by 52 and 29 %, respectively).
CONCLUSION: Platelet release is not a source of the elevated blood proinflammatory cytokines TGF-β1 and VEGF in CF, as platelets from CF patients actually release less of these cytokines. These data provide further evidence for platelet defects in CF.

PMID: 27423781 [PubMed - as supplied by publisher]

Nasal potential difference outcomes support diagnostic decisions in cystic fibrosis.

J Cyst Fibros. 2016 Jul 13;

Authors: Tridello G, Menin L, Pintani E, Bergamini G, Assael BM, Melotti P

Abstract
BACKGROUND: When cystic fibrosis (CF) is suspected Nasal Potential Difference (NPD) measurements are proposed to support controversial diagnosis: we investigated appropriate outcomes at the CF Centre of Verona.
SUBJECTS/METHODS: NPD were measured in 196 subjects: 50 non-CF, 65 classical CF (the reference group) and 81 with uncertain CF (case group). Discriminating power was determined by comparison between several outcomes from the CF reference group versus non-CF: basal, amiloride, 0Cl, isoproterenol, ATP, Delta-amiloride, Delta-0Cl, Delta-isoproterenol, Delta-ATP, Delta-isoproterenol+Delta-0Cl, Wilschanski Index (WI) and Sermet score (SS). The most appropriate cut-off values for variables with the best discriminating power were then applied to the case group. Descriptive statistics, logistic regression models and ROC curve analysis were applied.
RESULTS: WI and SS were the most powerful in discriminating CF from non-CF subjects. In the reference group sensitivity of the 0.82 WI cut-off was 98%, specificity 96%; both sensitivity and specificity of the -0.44 SS cut-off value were 100%. For the case group, WI and SS were, respectively, consistent with CF diagnosis in 94% and 92% of the cases.
CONCLUSIONS: Formulae have the highest discriminating power and can support the diagnosis in uncertain cases; they should be utilized for standardized interpretation of NPD for diagnosis and possibly for clinical research.

PMID: 27423539 [PubMed - as supplied by publisher]

Cystic Fibrosis Liver Disease and Ursodeoxycholic Acid: One Small Step Forward, Miles to Go.

J Pediatr. 2016 Jul 13;

Authors: Narkewicz MR

PMID: 27423176 [PubMed - as supplied by publisher]

Buffering of protons released by mineral formation during amelogenesis in mice.

Eur J Oral Sci. 2016 Jul 16;

Authors: Bronckers AL, Lyaruu DM, Jalali R, DenBesten PK

Abstract
Regulation of pH by ameloblasts during amelogenesis is critical for enamel mineralization. We examined the effects of reduced bicarbonate secretion and the presence or absence of amelogenins on ameloblast modulation and enamel mineralization. To that end, the composition of fluorotic and non-fluorotic enamel of several different mouse mutants, including enamel of cystic fibrosis transmembrane conductance regulator-deficient (Cftr null), anion exchanger-2-deficient (Ae2a,b null), and amelogenin-deficient (Amelx null) mice, was determined by quantitative X-ray microanalysis. Correlation analysis was carried out to compare the effects of changes in the levels of sulfated-matrix (S) and chlorine (Cl; for bicarbonate secretion) on mineralization and modulation. The chloride (Cl(-) ) levels in forming enamel determined the ability of ameloblasts to modulate, remove matrix, and mineralize enamel. In general, the lower the Cl(-) content, the stronger the negative effects. In Amelx-null mice, modulation was essentially normal and the calcium content was reduced least. Retention of amelogenins in enamel of kallikrein-4-deficient (Klk4-null) mice resulted in decreased mineralization and reduced the length of the first acid modulation band without changing the total length of all acidic bands. These data suggest that buffering by bicarbonates is critical for modulation, matrix removal and enamel mineralization. Amelogenins also act as a buffer but are not critical for modulation.

PMID: 27422589 [PubMed - as supplied by publisher]

UDP-glucose promotes neutrophil recruitment in the lung.

Purinergic Signal. 2016 Jul 15;

Authors: Sesma JI, Weitzer CD, Livraghi-Butrico A, Dang H, Donaldson S, Alexis NE, Jacobson KA, Harden TK, Lazarowski ER

Abstract
In addition to their role in glycosylation reactions, UDP-sugars are released from cells and activate widely distributed cell surface P2Y14 receptors (P2Y14R). However, the physiological/pathophysiological consequences of UDP-sugar release are incompletely defined. Here, we report that UDP-glucose levels are abnormally elevated in lung secretions from patients with cystic fibrosis (CF) as well as in a mouse model of CF-like disease, the βENaC transgenic (Tg) mouse. Instillation of UDP-glucose into wild-type mouse tracheas resulted in enhanced neutrophil lung recruitment, and this effect was nearly abolished when UDP-glucose was co-instilled with the P2Y14R antagonist PPTN [4-(piperidin-4-yl)-phenyl)-7-(4-(trifluoromethyl)-phenyl-2-naphthoic acid]. Importantly, administration of PPTN to βENaC-Tg mice reduced neutrophil lung inflammation. These results suggest that UDP-glucose released into the airways acts as a local mediator of neutrophil inflammation.

PMID: 27421735 [PubMed - as supplied by publisher]

Sleep and Pain in Pediatric Illness: A Conceptual Review.

CNS Neurosci Ther. 2016 Jul 15;

Authors: Allen JM, Graef DM, Ehrentraut JH, Tynes BL, Crabtree VM

Abstract
BACKGROUND: Sleep disruption is a common comorbidity of pediatric pain. Consequences of pain and disrupted sleep, evidence for the pain-sleep relation, and how aspects of illness, treatment, and pharmacological pain management may contribute to or exacerbate these issues are presented.
AIMS: This conceptual review explored the relation between pain and sleep in children diagnosed with chronic medical or developmental conditions. The goal of this review is to expand upon the literature by examining common themes in sleep disturbances associated with painful conditions across multiple pediatric illnesses. Populations reviewed include youth with intellectual and developmental disabilities (IDD), migraines, cystic fibrosis (CF), sickle cell disease (SCD), cancer, juvenile idiopathic arthritis (JIA), juvenile fibromyalgia (JFM), and functional gastrointestinal disorders (FGIDs).
RESULTS: Consistent evidence demonstrates that children with medical or developmental conditions are more vulnerable to experiencing pain and subjective sleep complaints than healthy peers. Objective sleep concerns are common but often under-studied. Evidence of the pain-sleep relationship exists, particularly in pediatric SCD, IDD, and JIA, with a dearth of studies directly examining this relation in pediatric cancer, JFM, CF, and FGIDs. Findings suggest that assessing and treating pain and sleep disruption is important when optimizing functional outcomes.
CONCLUSION: It is essential that research further examine objective sleep, elucidate the pain-sleep relationship, consider physiological and psychosocial mechanisms of this relationship, and investigate nonpharmacological interventions aimed at improving pain and sleep in vulnerable pediatric populations.

PMID: 27421251 [PubMed - as supplied by publisher]

Human Immunodeficiency Virus and Allergic Bronchopulmonary Aspergillosis: Case Report and Review of Literature.

Open Forum Infect Dis. 2016 Apr;3(2):ofw116

Authors: Galiatsatos P, Melia MT, Silhan LL

Abstract
Allergic bronchopulmonary aspergillosis (ABPA) results from a hypersensitivity response to airways colonization with Aspergillus fumigatus, and it occurs most often in individuals with asthma or cystic fibrosis. Allergic bronchopulmonary aspergillosis is an indolent, but potentially progressive, disease in patients. In patients infected with human immunodeficiency virus (HIV), ABPA is rare, and its description in the literature is limited to case reports. We describe the occurrence of ABPA in a 37-year-old woman with well controlled HIV infection. This represents the first documented case of ABPA in an HIV-infected patient whose only pulmonary comorbidity included the ramifications of prior acute respiratory distress syndrome due to Pneumocystis jirovecii pneumonia. We also review prior case reports of ABPA in HIV-infected patients and consider risk factors for its development.

PMID: 27419184 [PubMed]

Is it feasible to radiologically monitor the evolution of non-CF bronchiectasis?

Respirology. 2016 Aug;21(6):1137

Authors: Crivelli P, Sverzellati N, Sotgiu G, Aliberti S

PMID: 27416880 [PubMed - in process]

6 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

"Cystic Fibrosis"

These pubmed results were generated on 2016/07/15

PubMed comprises more than 24 million citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

8 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

"Cystic Fibrosis"

These pubmed results were generated on 2016/07/14

PubMed comprises more than 24 million citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

7 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

"Cystic Fibrosis"

These pubmed results were generated on 2016/07/13

PubMed comprises more than 24 million citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

Glucose Fluctuations are Not Modulated by the Proportion of Calories from Macronutrients or Spontaneous Total Energy Expenditure in Adults with Cystic Fibrosis.

Can J Diabetes. 2016 Jul 7;

Authors: Ziai S, Coriati A, St-Pierre D, Chabot K, Desjardins K, Leroux C, Richter MV, Rabasa-Lhoret R

Abstract
OBJECTIVES: To determine the modifiable factors affecting glucose variability in people with cystic fibrosis (CF). CF-related diabetes (CFRD) is the most common complication of CF, and its presence increases morbidity and mortality in patients. Patients with CF (with and without CFRD) have potentially harmful glucose fluctuations and glucose excursions when compared to healthy adults. Carbohydrate intake and exercise have been shown to affect glycemia. Therefore, our hypothesis was that the proportion of energy from carbohydrates and total energy expenditure (TEE) would influence glucose fluctuations in adults with CF.
METHODS: A cross-sectional study involved 36 patients with CF, in whom continuous glucose monitoring systems were installed. Glucose fluctuations were then quantified using 3 indexes: mean amplitude of glucose excursions, standard deviation and coefficient of variation. Patients filled out a 3-day food diary to quantify energy intake and the proportions of calories from carbohydrates, fats and proteins, and they wore Sensewear Armbands to estimate spontaneous TEE and footsteps walked. Glucose tolerance status was determined using oral glucose tolerance tests.
RESULTS: Patients with CF with normal and impaired glucose tolerance had fewer glucose fluctuations than patients with CFRD (p<0.05). However, linear regression models used to determine whether nutrition or energy expenditure affects glucose fluctuations demonstrated that energy, the proportion of carbohydrates, of fat and of protein, TEE or the number of footsteps walked did not affect glucose fluctuation indexes (p>0.05).
CONCLUSIONS: TEE and the proportion of energy from carbohydrates did not affect glucose fluctuations in adults with CF.

PMID: 27397678 [PubMed - as supplied by publisher]

Changes in lipid raft proteome upon TNF-α stimulation of cystic fibrosis cells.

J Proteomics. 2016 Jul 7;

Authors: Chhuon C, Pranke I, Borot F, Tondelier D, Lipecka J, Fritsch J, Chanson M, Edelman A, Ollero M, Guerrera IC

Abstract
We have previously shown (i) that the cystic fibrosis transmembrane regulator (CFTR) locates to lipid raft-like microdomains of epithelial cells upon TNF-α proinflammatory stimulation; and (ii) that TNF-α increases the membrane localization and the channel function of F508del-mutated CFTR. In the present work, we hypothesized that CFTR mutations modify the proteome of lipid rafts in the same proinflammatory conditions. We prepared lipid rafts from HeLa cells transfected with either wild-type or F508del-CFTR and incubated for 10min with 100U/mL of TNF-α. Proteins were extracted, trypsin digested, and peptides analyzed by high resolution MS. Proteins were quantified by a stable isotope labeling with aminoacids in cell culture approach. Out of the 22 proteins differentially recruited in lipid rafts after proinflammatory exposure, 17 were increased in F508del cells with respect to wild-type, including two G-protein coupled receptors, three anion transporters, and one cell surface mucin. In both HeLa and bronchial epithelial cells we confirmed that G-protein coupled receptor 5A relocates to lipid rafts along with F508del-CFTR after TNF-α treatment. These results could enlighten the cross-talk between CFTR and TNF-α and its impact on the cell response to proinflammatory challenge.
BIOLOGICAL SIGNIFICANCE: CFTR mutations are at the origin of cystic fibrosis. The latter disease is characterized, among other symptoms, by a defective management of infection and inflammation in the airways. Short exposure to the proinflammatory cytokine TNF-α targets mutated CFTR to the plasma membrane and increases its chloride channel activity. The results hereby presented show a substantial modification of the lipid raft proteome in the same conditions, and may enlighten the effect of this cytokine and the role of CFTR in the cell response to inflammation.

PMID: 27397611 [PubMed - as supplied by publisher]

Mortality on the Waiting List for Lung Transplantation in Patients with Idiopathic Pulmonary Fibrosis: A Single-Centre Experience.

Lung. 2015 Oct;193(5):677-81

Authors: Bennett D, Fossi A, Bargagli E, Refini RM, Pieroni M, Luzzi L, Ghiribelli C, Paladini P, Voltolini L, Rottoli P

Abstract
PURPOSE: Lung transplantation (LTX) is nowadays accepted as a treatment option for selected patients with end-stage pulmonary disease. Idiopathic pulmonary fibrosis (IPF) is characterized by the radiological and histologic appearance of usual interstitial pneumonia. It is associated with a poor prognosis, and LTX is considered an effective treatment to significantly modify the natural history of this disease. The aim of the present study was to analyse mortality during the waiting list in IPF patients at a single institution.
METHODS: A retrospective analysis on IPF patients (n = 90) referred to our Lung Transplant Program in the period 2001-2014 was performed focusing on patients' characteristics and associated risk factors.
RESULTS: Diagnosis of IPF was associated with high mortality on the waiting list with respect to other diagnosis (p < 0.05). No differences in demographic, clinical, radiological data and time spent on the waiting list were observed between IPF patients who underwent to LTX or lost on the waiting list. Patients who died showed significant higher levels of pCO2 and needed higher flows of O2-therapy on effort (p < 0.05). Pulmonary function tests failed to predict mortality and no other medical conditions were associated with survival.
CONCLUSIONS: Patients newly diagnosed with IPF, especially in small to medium lung transplant volume centres and in Countries where a long waiting list is expected, should be immediately referred to transplantation, delay results in increased mortality. Early identification of IPF patients with a rapid progressive phenotype is strongly needed.

PMID: 26216722 [PubMed - indexed for MEDLINE]

Lung clearance index in adults and children with cystic fibrosis.

Chest. 2016 Jul 6;

Authors: O'Neill K, Tunney MM, Johnston E, Rowan S, Downey DG, Rendall J, Reid A, Bradbury I, Elborn JS, Bradley JM

Abstract
BACKGROUND: Lung clearance index (LCI) has good clinimetric properties and an acceptable feasibility profile as a surrogate endpoint in Cystic Fibrosis (CF). Although most studies to date have been in children, increasing numbers of adults with CF also have normal spirometry. Further study of LCI as an endpoint in CF adults is required. Therefore, the purpose of this study was to determine the clinimetric properties of LCI over the complete age range of people with CF.
METHODS: Clinically stable adults and children with CF and age matched healthy controls were recruited.
RESULTS: LCI and spirometry data for 110 CF subjects and 61 controls were collected at a stable visit. CF Questionnaire-Revised (CFQ-R) was completed by 80/110 CF subjects. Fifty-six CF subjects completed a second stable visit. The LCI CV% was 4.1% in adults and 6.3% in children with CF. The coefficient of repeatability of LCI was 1.2 in adults and 1.3 in children. In both adults and children, LCI (AUC(ROC)=0.93 and 0.84) had greater combined sensitivity and specificity to discriminate between people with CF and controls compared to FEV1 (AUC(ROC)=0.88 and 0.60) and FEF25-75 (AUC(ROC)=0.87 and 0.68). LCI correlated significantly with the CFQ-R treatment burden in adults (r=-0.37; p<0.01) and children (r=-0.50; p<0.01). Washout tests were successful in 90% of CF subjects and were perceived as comfortable and easy to perform in both adults and children.
CONCLUSIONS: These data support the use of LCI as a surrogate outcome measure in CF clinical trials in adults as well as children.

PMID: 27395423 [PubMed - as supplied by publisher]

Long-Term Pulmonal Therapy of Cystic Fibrosis-Patients with Amitriptyline.

Cell Physiol Biochem. 2016 Jul 11;39(2):565-572

Authors: Adams C, Icheva V, Deppisch C, Lauer J, Herrmann G, Graepler-Mainka U, Heyder S, Gulbins E, Riethmueller J

Abstract
BACKGROUND/AIMS: Several recent clinical studies revealed an accumulation of ceramide in bronchial epithelial cells of patients with cystic fibrosis (CF). Degradation of ceramide concentrations in lungs of CF patients employing the functional acid sphingomyelinase inhibitor amitriptyline revealed a benefit in lung function, weight and exacerbation rates.
METHODS: To test for a beneficial effect of amitriptyline in vivo, we performed two phase II randomised, double-blind, placebo-controlled studies. CF patients were treated with 25 mg amitriptyline twice daily, i.e. a total dose of 50 mg/d. After those two studies part of the patients used amitriptyline in an off-lable-use for routine treatment. These patients were observed after one, two and three years after continuous use of amitriptyline and were matched with those patients who were not treated. These patients were used as a control group.
RESULTS: After one year of treatment, forced expiratory volume in 1 sec predicted (FEV1) increased significantly by 7.6±7.0%, p=<0.001, and weight increased by 2.1±2.3kg, p=<0.001 in the amitriptyline population (n=20), whereas FEV1 decreased significantly in the control group by 1.8±3.3%, p=0.010, and weight increased by 1.1±2.7kg, p=0.010 (n=14). After two years of treatment, FEV1 increased significantly by 5.6±10.3%, p=0.009, and weight increased by 3.6±2.9kg, p=<0.001 in the amitriptyline population (n=12). In contrast, FEV1 decreased in the control group by 2.1±3.7%, p=0.051 and weight increased by only 0.4±2.9kg, p=0.31 (n=10). After three years of treatment, FEV1 increased significantly by 7.7±8%, p=0.050, and weight increased by 7.3±3.8kg, p=0.016, in the amitriptyline population (n=5), whereas FEV1 decreased in the control group by 1.0±1.3%, p=0.075 and weight increased by 0.4±1.5kg, p=0.29 (n=5).
CONCLUSION: Amitriptyline significantly increases FEV1, reduces ceramide in lung cells and increases weight of CF patients.

PMID: 27395380 [PubMed - as supplied by publisher]