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PubMed2003

Alpha 1-antitrypsin deficiency alleles in cystic fibrosis lung disease.

Cystic fibrosis (CF) transmembrane conductance regulator (CFTR) genotype does not explain the heterogeneity observed in CF pulmonary disease severity. Modifier genes are implicated for this heterogeneity. alpha1-antitrypsin (alpha1-AT) is one of the few antiproteases capable of inactivating neutrophil elastase. We investigated whether alpha1-AT alleles (Z, S deficiency alleles and the 3' G1237-->A mutation) were associated with increased disease severity and the alpha1-AT acute phase response during pulmonary exacerbations. This was a multicenter Canadian study. Seven hundred sixteen patients with CF (age range, 5.0-63.6 yr) were genotyped for the Z, S, and G1237-->A polymorphisms of the alpha1-AT gene. Stable and acute levels of alpha1-AT were measured on 31 adult patients with CF and were correlated to clinical parameters. There were 69, 13, and 18 patients with CF who were MS, SS, and MZ, respectively. There were 95 and 7 patients with CF heterozygous or homozygous for the A1237 allele, respectively. alpha1-AT genotype did not predict pulmonary disease severity, and was not associated with more severe clinical outcome (death or lung transplantation) or age of onset of Pseudomonas aeruginosa infection. Body mass index was a significant predictor of alpha1-AT levels during exacerbations. alpha1-AT genotype is not a major contributor to the variability of pulmonary disease severity in CF.

Acute-Phase Reaction↗

PubMed2005

Effects of montelukast treatment on clinical and inflammatory variables in patients with cystic fibrosis.

BACKGROUND: In cystic fibrosis (CF), the inflammatory process contributes to progressive lung tissue damage. Cysteinyl leukotrienes have been found in the sputum of patients with CF at high concentrations sufficient to cause potent biological effects. OBJECTIVE: To evaluate the effect of anti-inflammatory treatment with montelukast sodium in patients with CF. METHODS: Twenty-six patients aged 6 to 18 years were recruited to this 20-week, randomized, double-blind, placebo-controlled, crossover trial. Patients received montelukast or placebo for 8 weeks in addition to their regular CF treatment. Before and after treatment, findings from spirometry, whole-body plethysmography, and the clinical wheezing and cough scales were evaluated. At the same time, serum and sputum samples were obtained for the measurement of eosinophil cationic protein, interleukin 10 (IL-10), IL-8, and myeloperoxidase levels. RESULTS: Twenty-three patients completed the study. Compared with placebo use, montelukast treatment significantly improved forced expiratory volume in I second, peak expiratory flow, and forced expiratory flow between 25% and 75% and significantly decreased cough and wheezing scale scores (P < .001 for all). There were no significant changes in vital capacity, thoracic gas volume, airway resistance, and residual volume after treatment. Compared with placebo use, montelukast treatment decreased serum and sputum levels of eosinophil cationic protein and IL-8, decreased sputum levels of myeloperoxidase, and increased serum and sputum levels of IL-10 (P < .001 for all). CONCLUSIONS: Montelukast may have measurable anti-inflammatory properties in patients with CF.

Acetates↗

PubMed1987

Absorption of safflower oil and structured lipid preparations in patients with cystic fibrosis.

Patients with cystic fibrosis (CF) and pancreatic insufficiency usually have decreased linoleic and increased oleic, palmitoleic and eicosatrienoic (20:3 omega 9) acids compared to normal values of blood and tissue lipids. These changes are consistent with early essential fatty acid deficiency and are observed despite the regular use of exogenous pancreatic enzyme supplementation. As part of a study to determine the relative role of malabsorption as the etiology for the altered fatty acid status, the change in total plasma fatty acids and in area percent of plasma linoleic acid was determined in CF patients and control subjects following the ingestion of various lipid supplements, including two safflower oil preparations and two structured lipid preparations. Fasting subjects consumed 36 g of lipid in a milkshake containing 15 g of protein and 45 g of carbohydrate. Plasma samples obtained 0, 2, 4, 6 and 8 hr after the meal showed that the CF patients absorbed all preparations when administered with their regular dose of pancreatic enzyme supplement. Comparison of the patterns of increase for total plasma fatty acids and area percent of plasma linoleic acid following the administration of the different lipid supplements in CF patients and control subjects suggests that malabsorption alone is not the cause of the abnormal fatty acid composition in the lipids of CF patients and that increased caloric intake along with consumption of adequate amounts of linoleic acid should improve the linoleic acid status of CF patients; there may be selectively increased metabolism of certain fatty acids from the ingested lipids in the relatively malnourished CF patient compared to control subjects.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗

PubMed1994

Evidence for increased oxidative damage in patients with cystic fibrosis.

Patients with cystic fibrosis (CF) may be more susceptible to oxidative cell injury than normal healthy children due to both the impaired absorption of antioxidant nutrients and the increased oxidative stress caused by chronic pulmonary infections. The purpose of this study was to examine whether markers of oxidative damage to lipids (malondialdehyde-like substances and lipid hydroperoxides) and proteins (protein carbonyls) were present in the plasma of CF patients. Mean values (+/- SD) of thiobarbituric acid-reactive substances were significantly higher in patients (6.93 +/- 1.47 mumol/L; n = 25) than in controls (5.84 +/- 0.59 mumol/L; n = 10). FFA hydroperoxides were not detected in control subjects (the detection limit of the assay was 0.02 mumol/L), but in 11 of the 33 CF patients studied they were found in a range of 0.03-0.34 mumol/L. Plasma protein carbonyl concentrations did not differ significantly between the two groups (p = 0.076), although a much wider distribution was observed in the CF patients (range 0.17-5.64 nmol/mg protein) than in the control group (range 0.24-1.55 nmol/mg protein). No correlation was found between thiobarbituric acid-reactive substances and FFA hydroperoxides or between either of these markers and protein carbonyl content. Concentrations of plasma vitamin E, vitamin C, and protein sulfhydryls were within the normal ranges in both control subjects and CF patients. The concentration of uric acid was significantly reduced (p < 0.01) in the CF group (204 +/- 96.99 mumol/L) compared with that in control subjects (352 +/- 81.11 mumol/L), but reduction in plasma levels of this antioxidant did not correlate with increased markers of free radical damage.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗

PubMed1989

Activation of an apical Cl- conductance by Ca2+ ionophores in cystic fibrosis airway epithelia.

Cystic fibrosis (CF) airway epithelia express a defect in adenosine 3',5'-cyclic monophosphate (cAMP)-dependent regulation of apical membrane Cl- channels. Recent patch-clamp studies have raised the possibility that Ca2+ -dependent mechanisms for the activation of Cl- secretion may be preserved in CF airway epithelia. To determine 1) whether intact normal (N1) and CF airway epithelia exhibit a Ca2+ -dependent mechanism for activation of Cl- secretion and 2) whether Ca2+ -dependent mechanism for activation of Cl- secretion and 2) whether Ca2+ -dependent mechanisms initiate Cl- secretion via activation of an apical membrane Cl- conductance (GCl-), nasal epithelia from N1 and CF subjects were cultured on collagen membranes, and responses to isoproterenol or Ca2- ionophores [A23187 10(-6) M; ionomycin (10(-5)M)] were measured with transepithelial and intracellular techniques. Isoproterenol induced activation of an apical membrane GCl- in N1 cultures but was ineffective in CF. In contrast, in both N1 and CF amiloride-pretreated cultures, A23187 induced an increase in the equivalent short-circuit current that was associated with an activation of an apical membrane Gc1- and was bumetanide inhibitable. A23187 addition during superfusion of the lumen with a low Cl- (3 mM) solution reduced intracellular Cl- activity of CF cells. A Ca2+ ionophore of different selectivity properties, ionomycin, was also an effective Cl- secretagogue in both N1 and CF cultures. We conclude that 1) the A23187 induced Cl- secretion via activation of an apical GCl- in N1 human nasal epithelium, and 2) in contrast to an isoproterenol-dependent path, a Ca2+ -dependent path for GCl- activation is preserved in CF epithelia.

Adolescent↗

PubMed2004

Comparison of the use of body mass index percentiles and percentage of ideal body weight to screen for malnutrition in children with cystic fibrosis.

BACKGROUND: The Cystic Fibrosis Foundation (CFF) recommends using the percentage of ideal body weight (%IBW(CFF)) and body mass index percentiles (BMIp) to assess weight-for-height status and to screen for malnutrition. OBJECTIVE: The objective was to examine the agreement and discrepancy between the use of %IBW(CFF) and BMIp for screening malnutrition. DESIGN: Data from 13 021 children reported to the 2000 CFF Patient Registry were analyzed. RESULTS: In children of average stature (ie, height-for-age between the 25th and 75th percentiles) and aged <10 y, %IBW(CFF) corresponded closely to BMIp, and the prevalence of underweight estimated by %IBW(CFF) < 90% was similar to that by BMIp < 15th percentile. However, in children with short stature (ie, height-for-age < 25th percentile), %IBW(CFF) reflected significantly better weight-for-height status than did the BMIp, whereas the opposite trend was observed in children with tall stature (ie, height-for-age > 75th percentile). Such discrepancies averaged 8-12 percentage points when BMIp was reexpressed to the same unit and scale as %IBW(CFF). Consequently, the prevalence of underweight estimated by %IBW(CFF) < 90% was significantly lower (7.3%) than that estimated by BMIp < 15th percentile (25.7%) in children with short stature, whereas the opposite trend was found in children with tall stature (47.7% and 14.4%, respectively). Additional analyses showed that BMIp was more sensitive to, and had stronger associations with, the percentage of predicted forced expiratory volume in 1 s. CONCLUSION: Compared with BMIp, %IBW(CFF) underestimated the severity of malnutrition in children with short stature and overestimated the severity of malnutrition in children with tall stature.

Adolescent↗

PubMed1995

Sputum peroxidase activity correlates with the severity of lung disease in cystic fibrosis.

Patients with cystic fibrosis (CF) of the same age differ significantly in their degree of pulmonary disease. Based on preliminary observations, we postulated that the activity of myeloperoxidase would be significantly increased in patients with greater structural lung damage than in those with less lung damage. Acid extracts of weighed sputum samples were assayed for lactoferrin concentrations by ELISA. Activities of peroxidase, cathespsin G, and elastase (with and without proteinase 3) were determined by kinetic analysis using chromogenic substrates. The patients were divided into quartiles based on their Brasfield chest-radiograph score. Patients in the first quartile (least amount of structural lung abnormality) were compared to those in the fourth quartile. The concentration of lactoferrin, a specific (secondary) granule protein of neutrophils, did not differ between the two patient groups. However, the activities of the neutrophil primary granule proteins, peroxidase, elastase, and elastase plus proteinase 3, were significantly elevated in the group with the most structural lung abnormality. Sputum albumin concentration was used to estimate leakages of plasma proteins into the airways. Peroxidase activity, but not the activity of cathepsin G, of elastase, or of elastase plus proteinase 3, correlated significantly with albumin/g sputum in both quartile groups. To confirm the association of sputum peroxidase activity with differences in lung structure and to test its correlation with lung function, spirometry was performed in a second group of patients during the week prior to the time of sputum sampling. In this second group, increased sputum peroxidase activity was associated with worse Brasfield scores and with decreased percent-predicted forced expiratory volume in 1 sec.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed1985

Gastroesophageal reflux in patients with cystic fibrosis.

Children with cystic fibrosis (CF) and their asymptomatic siblings were surveyed to determine the incidence of symptomatic gastroesophageal reflux. A subgroup of patients with CF with poor nutritional status were studied with esophageal manometry, 24-hour esophageal pH recording, and pulmonary function testing before and after initiation of supplemental continuous nighttime nasogastric feeds. Of 68 patients with CF greater than or equal to 5 years of age, 20.6% experienced regurgitation and 26.5% had heartburn. In the control group of 23 asymptomatic siblings greater than or equal to 5 years of age, none experienced regurgitation and 5.6% had heartburn. Among the patients there was no significant association between symptoms of gastroesophageal reflux and bronchodilator therapy. Eight patients had normal lower esophageal sphincter pressure of 24.8 +/- 8.8 mm Hg and thoracoabdominal pressure gradient of 11.4 +/- 4.6 mm Hg; peristalsis and upper esophageal sphincter pressure were normal. There was a significant increase in reflux episodes, episodes greater than 5 minutes, duration of the longest episode, and percent time esophageal pH was less than 4 in patients, compared with published control data, for the entire 24-hour period and during sleep. During sleep, continuous nasogastric feeding significantly increased episodes of reflux, but did not result in an increase in percent time esophageal pH was less than 4, and was not associated with evidence of aspiration or deterioration in pulmonary function. Our findings indicate that symptoms of gastroesophageal reflux, heartburn, and regurgitation are more frequent in patients with CF than in asymptomatic siblings and that gastroesophageal reflux is significantly more common in patients with CF than in controls. Nighttime nasogastric feedings can safely be used as a means of nutritional rehabilitation in patients with CF.

Adolescent↗

PubMed2005

Changes in airway dimensions on computed tomography scans of children with cystic fibrosis.

RATIONALE: In cystic fibrosis (CF), chronic bacterial infection and inflammation lead to progressive airway wall thickening and lumen dilatation. OBJECTIVES: To quantify airway wall thickening and lumen dilatation in children with CF over a 2-year interval. METHODS: Children with CF (n = 23) who had two computed tomography (CT) scans (CT(cf1) and CT(cf2)) combined with pulmonary function tests (PFTs), with a 2-year interval between measurements, were compared with control subjects (n = 21) who had one CT (CT(controls)). On cross-sectional cut airway-artery pairs, airway wall area (WA), airway lumen area (LA) and perimeter, and arterial area (AA) were quantified. LA/AA (= marker of bronchiectasis), airway wall thickness (AWT), and WA/AA (= markers of wall thickness) were calculated. CT scans were scored using four different scoring systems. PFTs were expressed as percent predicted. RESULTS: Airway WA-to-AA ratio was 1.45 (p < 0.001) and airway LA-to-AA ratio was 1.92 times higher (p < 0.001) in children with CF compared with age-matched control subjects. LA/AA and WA/AA remained unchanged from CT(cf1) to CT(cf2) and did not increase with age. AWT as a function of airway size increased from CT(cf1) to CT(cf2) by 2% (0.03 mm; p = 0.02). The change in AWT was inversely related to the change in forced expiratory flow between 25 and 75% of expiratory VC (p = 0.002). CONCLUSIONS: In CF, quantitative measurements of airways on CT scans show an increased ratio between airway LA and AA and progressive airway wall thickening. Scoring systems show progression of bronchiectasis but unchanged AWT. PFTs remained stable.

Adolescent↗

PubMed1994

Benefits of nocturnal nasal CPAP in patients with cystic fibrosis.

Patients with cystic fibrosis (CF) often hypoventilate during sleep with marked falls in oxygen saturation (SaO2%). This occurs most commonly during REM sleep, when there is a reduction in rib cage excursion and a fall in end-expiratory lung volume (EELV). The aim of this study was to examine the effect of nocturnal nasal continuous positive airway pressure (nCPAP) on SaO2 and the respiratory disturbance index (RDI) during sleep in patients with CF and severe lung disease. Seven patients (FEV1% pred, 23 +/- 5; range, 14 to 28%) were evaluated during sleep on two nights, control and nCPAP (11 +/- 2 cm H2O; range, 8 to 16 cm H2O), with four patients breathing room air and three patients breathing supplemental oxygen on both nights. Mean awake SaO2 was 91 +/- 1% (range, 89 to 93%). All patients showed significant oxyhemoglobin desaturation and respiratory disturbance in the control study. The maximal falls in SaO2 (15 +/- 10%) were most often associated with phasic eye movements, and a decline in rib cage excursion and the sum signal (Respitrace) during REM sleep. Nasal CPAP resulted in a significant improvement in the mean minimum oxygen saturation (MMOS) during both NREM (nCPAP 91 +/- 3% vs control 88 +/- 2%, p < 0.05) and REM sleep (nCPAP 89 +/- 6% vs control 83 +/- 6%, p < 0.05). Transcutaneous CO2 measurements were not significantly different between the control and the nCPAP studies. The RDI was also significantly reduced with nCPAP especially during REM sleep (9 +/- 7 events per hour vs control 25 +/- 11 events per hour, p < 0.05). Nasal CPAP caused no change in total sleep time or sleep efficiency yet significantly reduced the RDI and improved baseline SaO2 during both NREM and REM sleep.

Adolescent↗

PubMed2005

The relationship between sleep disturbance and pulmonary function in stable pediatric cystic fibrosis patients.

BACKGROUND: Cystic fibrosis (CF) is the most common inherited disease affecting northern European populations. It is characterized by a progressive clinical course that causes diurnal and nocturnal pulmonary and gastrointestinal symptoms. OBJECTIVES: To determine whether clinically stable pediatric patients with CF have lower sleep efficiency than healthy control subjects, and to examine the relationship between sleep efficiency and pulmonary function. METHODS: Forty-four CF patients and 40 control subjects completed 5 days of actigraphy recordings. Additionally, sleep questionnaires were independently completed by all study participants and their parents. Pulmonary function testing was performed in all patients with CF. Multiple regression analysis was used to measure the independent correlation between sleep variables and pulmonary function. RESULTS: CF patients had significantly lower sleep efficiency than control subjects. The FEV1 of these patients correlated positively with sleep duration and efficiency, and negatively with the number and duration of nocturnal awakenings, age, and body mass index (BMI). The independent effect of FEV1 on sleep was first examined. Age and FEV1 were the only variables that predicted sleep duration (R2 = 0.3; p = 0.0007), while FEV1 was the only variable predicting sleep efficiency (R2 = 0.28; p = 0.0002). When the independent effect of sleep on FEV1 was analyzed, sleep efficiency, BMI percentile, and gender predicted FEV1 (R2 = 0.46; p < or = 0.0001). The frequency of nocturnal cough reported by patients and their parents was an independent predictor of FEV1. CONCLUSIONS: Pediatric patients with CF and stable pulmonary function have lower sleep efficiency and more frequent nocturnal awakenings than do healthy control subjects. After adjustment for demographic characteristics, there was an independent and significant correlation between sleep parameters and FEV1, when either sleep variables or FEV1 were used as dependent variables. These findings suggest a bidirectional relationship between sleep disturbance and CF lung disease.

Adolescent↗

PubMed2003

A comparison of the therapeutic effectiveness of and preference for postural drainage and percussion, intrapulmonary percussive ventilation, and high-frequency chest wall compression in hospitalized cystic fibrosis patients.

INTRODUCTION: Cystic fibrosis (CF) patients have abnormally viscid bronchial secretions that cause airway obstruction, inflammation, and infection that leads to lung damage. To enhance airway clearance and reduce airway obstruction, daily bronchopulmonary hygiene therapy is considered essential. OBJECTIVE: Compare the effectiveness of and patient preferences regarding 3 airway clearance methods: postural drainage and percussion (PD&P), intrapulmonary percussive ventilation (IPV), and high-frequency chest wall compression (HFCWC). METHODS: The participants were hospitalized CF patients >or= 12 years old. Effectiveness was evaluated by measuring the wet and dry weights of sputum obtained with each method. In random order, each patient received 2 consecutive days of each therapy, delivered 3 times daily for 30 minutes. Sputum was collected during and for 15 minutes after each treatment, weighed wet, then dried and weighed again. Participants rated their preferences using a Likert-type scale. Mean weights and preferences were compared using analysis of variance with repeated measures. Patient preferences were compared using Freidman's test. RESULTS: Twenty-four patients were studied. The mean +/- SD wet sputum weights were 5.53 +/- 5.69 g with PD&P, 6.84 +/- 5.41 g with IPV, and 4.77 +/- 3.29 g with HFCWC. The mean wet sputum weights differed significantly (p = 0.035). Wet sputum weights from IPV were significantly greater than those from HFCWC (p < 0.05). The mean dry sputum weights were not significantly different. With regard to overall preference and to the subcomponents of preference, none of the 3 methods was preferred over the others. CONCLUSIONS: HFCWC and IPV are at least as effective as vigorous, professionally administered PD&P for hospitalized CF patients, and the 3 modalities were equally acceptable to them. A hospitalized CF patient should try each therapy and choose his or her preferred modality.

Child↗

PubMed2002

Current status of gene therapy for cystic fibrosis pulmonary disease.

Cystic fibrosis (CF) is a common lethal genetic disorder that affects all ethnic populations; however, it is most prevalent in Caucasians. Intensive basic research over the last 20 years has resulted in a wealth of information regarding the CF gene, its protein product and the mutational basis of disease. This increased understanding has lead to the development of gene therapy for the treatment of CF pulmonary disease. Delivery of the CF gene to the airway requires direct in vivo transfer using vectors encoding for normal CF transmembrane regulator (CFTR) protein. Several vectors are currently available for CF gene transfer and include both viral (adenoviruses, adeno-associated viruses) and non-viral (liposomal) systems. Initial clinical trials with each of these vectors have demonstrated that gene transfer to the CF airway is possible. The efficiency of transfer and duration of expression, however, have been limited. The effects of gene transfer on correction of the basic ion transport defects have also been highly variable and inconsistent, irrespective of the vector. Currently, the risk of severe immunological reactions is the primary factor limiting the clinical advancement of gene therapy. Both the adenoviral and liposomal vectors are associated with significant acute inflammatory reactions. The adenoviruses and adeno-associated viruses also elicit humoral immune responses that significantly reduce the efficiency of transgene expression and increase the risk of readministration. Several strategies are under investigation to improve the efficiency of gene transfer to the CF airway. These include overcoming local barriers in the lung, circumventing the immune response and improving vector internalization and/or uptake. Application of gene transfer in the child and possibly the fetus are also potential future clinical applications of gene therapy. However, despite considerable research with gene therapy, there is little evidence to suggest that a well tolerated and effective gene transfer method is imminent and aggressive use of conventional pharmacological therapies currently offer the greatest promise in the treatment of patients with CF.

Cystic Fibrosis↗

PubMed2003

Longitudinal evaluation of bronchopulmonary disease in children with cystic fibrosis.

Children with cystic fibrosis (CF) develop bronchopulmonary disease at variable ages. Determining the epidemiology of chronic lung disease and quantifying its severity, however, have been difficult in infants and young children. As part of the Wisconsin CF Neonatal Screening Project, we were presented with an ideal opportunity to assess longitudinally the evolution of symptoms, signs, and quantitative measures of CF respiratory disease. After newborn screening test results led to early recognition, 64 patients diagnosed at a median age of 6.71 weeks were enrolled and studied systematically at a median age of 11.3 years to obtain clinical information, chest radiographs, and pulmonary function tests. Our observations revealed that a frequent cough by history is evident by 10.5 months of age in half the patients. Quantitative chest radiology (CXR scoring) demonstrated that potentially irreversible abnormalities are present in half the children by 2 years. The severity of Wisconsin and Brasfield CXR scores increased in association with respiratory infections. Longitudinal progression of Wisconsin CXR scores was related to age (P < 0.001), pancreatic insufficiency (P = 0.005), and respiratory secretion cultures positive for Staphylococus aureas (P = 0.039). In contrast, serial spirometry showed limited sensitivity, as did lung volume determinations; neither was satisfactory as repeated measures with acceptable quality control until after 7 years of age. Time to event analyses revealed that half the patients had % predicted FEF(25-75) and FEV(1)/FVC values greater than 80% until 10.7 and 9.9 years, respectively. We conclude that of the methods evaluated, quantitative chest radiology is currently the best procedure for frequent assessment of bronchopulmonary disease in CF, and that radiographic progression is evident in approximately 85% of patients by 5 years of age. Our results also suggest that bronchiectasis and other radiographic evidence of chronic infection are apparent prior to airways obstruction in young CF patients.

Age of Onset↗

PubMed1997

Insulin resistance is associated with decreased clinical status in cystic fibrosis.

Patients with cystic fibrosis (CF) frequently have impaired glucose tolerance and progression to diabetes (DM) with clinical features of both insulin-dependent and non-insulin-dependent diabetes. One feature of non-insulin-dependent DM is decreased insulin sensitivity, also known as insulin resistance. The goal of this study was to determine whether patients with CF exhibit insulin resistance and to determine the potential effect of insulin resistance on clinical status. We also sought to determine whether insulin resistance is associated with a specific CF genotype. We studied 18 patients with CF (8 with normal glucose tolerance, 5 with impaired glucose tolerance, 5 with DM), and 20 lean control subjects matched for age, weight, and sex. All control subjects had normal glucose tolerance. The clinical status for each CF patients was determined according to a modified National Institutes of Health scoring system. Each subject underwent a three-step hyperinsulinemic euglycemic clamp (insulin doses of 10, 40, 120 mU/m2 per minute). Results from the 120 mU/m2 per minute infusion defined maximal glucose disposal rate (defined in milligrams per kilogram body weight per minute) at steady state with peripheral insulin levels 195 +/- 20 mU/ml. Subjects with CF demonstrated insulin resistance (control subjects = 13.6 +/- 1.1, patients with CF = 10.2 +/- 1.6 mg/kg per minute; p = 0.003). When each subgroup was compared separately with control subjects, all subgroups were statistically insulin resistant (glucose disposal rate, patients with CF and normal glucose tolerance = 10.8; those with impaired glucose tolerance = 8.4; those with DM = 10.1 mg/kg per minute), and the patients with CF with impaired glucose tolerance were the most insulin resistant. When plotted versus glucose disposal rate, a striking positive correlation between worsened clinical status and insulin resistance (r = 0.85) is demonstrated. Furthermore, there is no correlation between insulin resistance and fasting blood glucose, subject age, or percent ideal body weight (all r values not significant). In conclusion, patients with CF exhibit insulin resistance that is associated with worsened clinical status. We believe it is the combination of insulin resistance and decreased insulin secretion that is responsible for the high incidence of CF-related diabetes.

Adult↗

PubMed2004

Ultrase MT12 and Ultrase MT20 in the treatment of exocrine pancreatic insufficiency in cystic fibrosis: safety and efficacy.

BACKGROUND: Cystic fibrosis causes exocrine pancreatic insufficiency, leading to malabsorption. Supplemental pancreatic enzyme therapy alleviates the concomitant malnutrition experienced by cystic fibrosis patients. It is recognized that patients experience variations in clinical response to different brands of enzymes. This has prompted the US Food and Drug Administration to require that enzyme supplements be subjected to New Drug Applications. AIM: To investigate the safety and efficacy of supplemental pancreatic enzyme therapy in cystic fibrosis subjects. METHODS: We compared two doses of one formulation of enteric-coated pancreatic enzymes: Ultrase MT12 (12,000 lipase units per capsule) and Ultrase MT20 (20,000 lipase units per capsule), to placebo in two separate safety and efficacy studies. RESULTS: Mean total fat, protein and carbohydrate intake did not differ significantly between the groups. A significant difference in both fat and protein absorption occurred with the enzyme therapy groups. The Ultrase MT12 and Ultrase MT20 groups experienced a mean fat and protein absorption 79.4% and 83.8%, and 87.3% and 88.6%, respectively. No adverse events related to study drug were reported. CONCLUSIONS: This study further supports the use of enzymes to treat pancreatic insufficiency in cystic fibrosis. Excellent fat and protein absorption was achieved with minimal adverse events and safe doses.

Adolescent↗

PubMed2005

Use of lung transplantation survival models to refine patient selection in cystic fibrosis.

Lung transplantation in cystic fibrosis may improve survival for patients with low 5-year predicted survival. Identifying characteristics that affect post-transplantation survival may improve patient selection and survival benefit. Using Cystic Fibrosis Foundation Patient Registry and United Network for Organ Sharing data, we identified 845 lung transplant recipients from 1991-2001, and 12,826 control patients from 1997. We used Cox proportional hazards models to identify variables that influence post-transplantation survival. To estimate the survival benefit of transplantation for patients affected by identified variables, we compared Kaplan-Meier survival curves of transplanted and control patients stratified by 5-year predicted survival. Post-transplantation survival improved annually. Youth, Burkholderia cepacia, and cystic fibrosis-related arthropathy increased the post-transplantation hazard of death. Compared with control subjects, transplanted adults with a 5-year predicted survival of less than 50% without B. cepacia or arthropathy have improved survival. Transplanted adults with B. cepacia, arthropathy, or a 5-year predicted survival of greater than 50% have decreased survival. Transplantation never improves survivorship for pediatric patients. Patients with arthropathy, B. cepacia infection, or younger age derive no aggregate survival benefit and must appraise carefully the high risk of decreased post-transplantation survival. Adult patients with low 5-year predicted survival without B. cepacia infection should receive priority for lung transplantation.

Adult↗

PubMed2000

Pathogenesis of lung disease in cystic fibrosis.

Lung disease in cystic fibrosis is primarily due to a defect in the cystic fibrosis transmembrane regulating protein (CFTR). This results in abnormal chloride transfer across epithelial membranes causing an excessively viscid mucus lining of the airways. Bacterial invasion particularly with Staphylococcus aureus, Haemophilus influenzae and Pseudomonas aeruginosa stimulates a vigorous and excessive primarily neutrophil-driven inflammatory response throughout the lungs. Products of this inflammation not only damage incoming bacteria but also the host tissue itself. Over a period of years this chronic suppurative process results in permanent ongoing lung destruction principally manifested as bilateral bronchiectasis.

Cystic Fibrosis↗