Function In Cystic Fibrosis Patients Research Articles

Beta 2 adrenergic receptor polymorphisms in cystic fibrosis

There has been a recent emphasis on identifying modifier genes that influence the severity of cystic fibrosis (CF) lung disease. The beta-2-adrenergic receptor is expressed on airway smooth muscle, is the target for inhaled beta agonists, and has several common polymorphisms in its gene, ADRB2. Polymorphisms changing glycine to arginine or glutamate to glutamine in codons 16 and 27, respectively, were associated with differences in clinical response to inhaled beta agonists in individuals with asthma. We compared acute airway responsiveness and 5-year decline in pulmonary function in CF patients with different ADRB2 genotypes. One hundred and six subjects performed spirometry before and after the administration of an inhaled bronchodilator, and had ADRB2 genotype determined for codons 16 and 27. Comparing the percent change in FEV(1) and FEF(25-75) continuously revealed differences in the degree of airway responsiveness to bronchodilator between ADRB2-genotyped groups. However, there was no significant relationship between the ADRB2 genotype at positions 16 and 27 and bronchodilator response when defined as 12% improvement in FEV(1). Five-year decline in percent predicted FEV(1) showed no association with ADRB2 genotype. These data are consistent with variants of the ADRB2 gene having different responses to bronchodilator, but the long-term effects, if any, are not apparent over a 5-year period.

Early Decline of Pancreatic Function in Cystic Fibrosis Patients with Class 1 or 2 CFTR Mutations

Most cystic fibrosis (CF) patients develop steatorrhea and require pancreatic enzyme replacement therapy. However, there are few data regarding the decline of exocrine pancreatic function within the first years of life in relation to CF genotype. We assessed the decline of pancreatic function in CF infants carrying class 1 or 2 CFTR mutations who were diagnosed in a neonatal screening program. Twenty-eight CF patients were included in the study and 27 completed the study. In all subjects, fecal pancreatic elastase-1 concentrations and fecal fat excretion were scheduled to be determined at diagnosis, at 6 months of age and subsequently at 6-month intervals. In all CF patients, fecal pancreatic elastase-1 concentrations of the first assay after diagnosis (3 to 4 months of age) were lower than the cut-off level for normals of <200 microg/g stool. Steatorrhea was found in 81.5% of these subjects. At the age of 6 months, all screened CF subjects had fecal pancreatic elastase-1 concentrations <100 microg/g and at the age of 12 months all were pancreatic insufficient. At that time, having proved pancreatic insufficiency in all studied subjects, we stopped the scheduled further assessment. CF patients require careful monitoring of pancreatic status from diagnosis onwards. In patients carrying class 1 or 2 CFTR mutations, pancreatic insufficiency develops in the first months of life. The proper assessment of pancreatic insufficiency and intestinal malabsorption is crucial for the early introduction of pancreatic enzymes.

Early Decline of Pancreatic Function in Cystic Fibrosis Patients with Class 1 or 2 CFTR Mutations

ABSTRACTBackground:Most cystic fibrosis (CF) patients develop steatorrhea and require pancreatic enzyme replacement therapy. However, there are few data regarding the decline of exocrine pancreatic function within the first years of life in relation to CF genotype. We assessed the decline of pancreatic function in CF infants carrying class 1 or 2 CFTR mutations who were diagnosed in a neonatal screening program.Materials and Methods:Twenty‐eight CF patients were included in the study and 27 completed the study. In all subjects, fecal pancreatic elastase‐1 concentrations and fecal fat excretion were scheduled to be determined at diagnosis, at 6 months of age and subsequently at 6‐month intervals.Results:In all CF patients, fecal pancreatic elastase‐1 concentrations of the first assay after diagnosis (3 to 4 months of age) were lower than the cut‐off level for normals of &lt;200 μg/g stool. Steatorrhea was found in 81.5% of these subjects. At the age of 6 months, all screened CF subjects had fecal pancreatic elastase‐1 concentrations &lt;100 μg/g and at the age of 12 months all were pancreatic insufficient. At that time, having proved pancreatic insufficiency in all studied subjects, we stopped the scheduled further assessment.Conclusion:CF patients require careful monitoring of pancreatic status from diagnosis onwards. In patients carrying class 1 or 2 CFTR mutations, pancreatic insufficiency develops in the first months of life. The proper assessment of pancreatic insufficiency and intestinal malabsorption is crucial for the early introduction of pancreatic enzymes.

Lutein, zeaxanthin, macular pigment, and visual function in adult cystic fibrosis patients

The macular pigment, thought to be a postmortem artifact less than 100 years ago by Gullstrand, has been the subject of intense research in recent years. The macular pigment is derived from dietary carotinoids, lutein, and zeaxanthin, which endow it with a yellow-orange color that absorbs short-wavelength light en route to the photoreceptors. This filtering of high-energy photons, together with scavenging of free radicals, is thought to be a mechanism of major health significance for the human retina. Decreased plasma concentrations of the pigments from which macular pigment has been derived have been associated with an increased incidence of macular degeneration, although it is unclear that levels of these carotinoids in the eye directly relate to the risk of retinal disease. More subtle than frank macular degeneration are the losses in sensitivity of cone photoreceptors associated with normal aging. A high amount of macular pigment might protect the retina from age-related loss in cone sensitivity, but other interpretations are plausible. If macular pigment does forestall the effects of normal aging, one might expect that patients with cystic fibrosis (CF) may display accelerated retinal aging. This hypothesis is based on the pancreatic insufficiency in CF, even with replacement pancreatic enzyme therapy, that results in decreased carotenoid uptake. While a few reports indicate some compromised visual function in CF patients (that may be because of nutritional deficiencies other than carotinoids), the hypothesis that CF patients may display accelerated retinal aging due to reduced macular pigment levels has not been tested. This study investigated CF patients and age-matched controls for: (1) plasma carotenoid levels; (2) optical density and distribution of macular pigment in the retina; and (3) visual performance including photopic contrast sensitivity, color discrimination and multifocal electroretinograms. Compared to age-matched controls, both serum levels of lutein and zeaxanthin and macular pigment in the retina were significantly reduced in CF patients. Despite dramatic low levels in serum and macular carotinoids (lutein and zeaxanthin) that are likely to have affected the study group for decades, CF patients did not have deficits of vision as might be expected from the hypothesis that macular pigment protects the retina against factors contributing to normal aging.—John L. Keltner The macular pigment, thought to be a postmortem artifact less than 100 years ago by Gullstrand, has been the subject of intense research in recent years. The macular pigment is derived from dietary carotinoids, lutein, and zeaxanthin, which endow it with a yellow-orange color that absorbs short-wavelength light en route to the photoreceptors. This filtering of high-energy photons, together with scavenging of free radicals, is thought to be a mechanism of major health significance for the human retina. Decreased plasma concentrations of the pigments from which macular pigment has been derived have been associated with an increased incidence of macular degeneration, although it is unclear that levels of these carotinoids in the eye directly relate to the risk of retinal disease. More subtle than frank macular degeneration are the losses in sensitivity of cone photoreceptors associated with normal aging. A high amount of macular pigment might protect the retina from age-related loss in cone sensitivity, but other interpretations are plausible. If macular pigment does forestall the effects of normal aging, one might expect that patients with cystic fibrosis (CF) may display accelerated retinal aging. This hypothesis is based on the pancreatic insufficiency in CF, even with replacement pancreatic enzyme therapy, that results in decreased carotenoid uptake. While a few reports indicate some compromised visual function in CF patients (that may be because of nutritional deficiencies other than carotinoids), the hypothesis that CF patients may display accelerated retinal aging due to reduced macular pigment levels has not been tested. This study investigated CF patients and age-matched controls for: (1) plasma carotenoid levels; (2) optical density and distribution of macular pigment in the retina; and (3) visual performance including photopic contrast sensitivity, color discrimination and multifocal electroretinograms. Compared to age-matched controls, both serum levels of lutein and zeaxanthin and macular pigment in the retina were significantly reduced in CF patients. Despite dramatic low levels in serum and macular carotinoids (lutein and zeaxanthin) that are likely to have affected the study group for decades, CF patients did not have deficits of vision as might be expected from the hypothesis that macular pigment protects the retina against factors contributing to normal aging.—John L. Keltner

Lutein, zeaxanthin, macular pigment, and visual function in adult cystic fibrosis patients

Pancreatic insufficiency in cystic fibrosis (CF), even with replacement pancreatic enzyme therapy, is often associated with decreased carotenoid absorption. Because the macular pigment of the retina is largely derived from 2 carotenoids, lutein and zeaxanthin, the decreased serum concentrations seen in CF may have consequences for ocular and retinal health Our aims were to determine plasma carotenoid concentrations, determine absorption and distribution of macular pigment, and assess retinal health and visual function in CF patients. In 10 adult CF patients (ages 21-47 y) and 10 age- and sex-matched healthy control subjects, we measured macular pigment density in vivo, measured serum lutein and zeaxanthin concentrations, and comprehensively assessed visual performance (including contrast sensitivity, color discrimination, and retinal function) under conditions of daylight illumination. Serum lutein and zeaxanthin were significantly reduced (P < 0.005) in CF patients ( +/- SD: 87 +/- 36.1 and 27 +/- 15.8 nmol/L, respectively) compared with control subjects (190 +/- 72.1 and 75 +/- 23.6 nmol/L, respectively). Although macular pigment optical density was significantly lower (P < 0.0001) in the CF group (0.24 +/- 0.11) than in the control group (0.53 +/- 0.12), no significant differences in visual function were observed. Adults with CF have dramatically low serum and macular concentrations of carotenoids (lutein and zeaxanthin), but their ocular status and visual function are surprisingly good. The clinical implications of low plasma concentrations of carotenoids in CF are yet to be clarified.

Abnormal glucose tolerance in cystic fibrosis: Why should patients be screened?

Abnormal glucose tolerance in cystic fibrosis: Why should patients be screened?

Epithelial Cell Chloride Channel Activity Correlates with Improved Airway Function in Cystic Fibrosis Patients with the Major Mutant: Delta F508

Epithelial Cell Chloride Channel Activity Correlates with Improved Airway Function in Cystic Fibrosis Patients with the Major Mutant: Delta F508

Jointly modelling the relationship between survival and pulmonary function in cystic fibrosis patients.

Modelling the relationship between pulmonary function and survival in cystic fibrosis (CF) is complicated by the fact that measures of pulmonary function commonly used such as the forced expiratory volume in one second (FEV(1)) are measured with error, and patients with the poorest lung function are increasingly censored by death, that is, data are available only for the patients who have survived to the current age. We assume a linear random effects model for FEV1 per cent predicted, where the random intercept and slope of FEV(1) per cent predicted, along with a specified transformation of the age at death follow a trivariate normal distribution. We illustrate how this model can be used to describe the relationship between age at death and parameters of the individual patient's regression of FEV(1) per cent predicted versus age, such as the slope and the intercept or true value of FEV(1) per cent predicted at a given age. We also illustrate how the model provides empirical Bayes estimates of these individual parameters. In particular, we explore how the predicted value of the age at death might be used as a prognostic or severity index. The model and methods are illustrated on a cohort of 188 cystic fibrosis patients with a common genotype (homozygous for the DeltaF508 mutation), born on or after 1965 and followed at the CF Center at the Rainbow Babies and Children's Hospital, Cleveland, OH, U.S.A.

Effect of choice of reference equation on analysis of pulmonary function in cystic fibrosis patients.

Pulmonary function is an important measure of disease severity and prognosis in cystic fibrosis (CF). It is generally expressed as a percentage of a predicted value, calculated using regression equations derived from a reference population. A number of reference equations are in widespread use. The purposes of this study were to determine: 1) the extent to which, for a given absolute FEV(1) value, percent of predicted (PPFEV(1)) values vary when derived by different reference equations; and 2) whether these differences affect conclusions of longitudinal and cross-sectional analyses. Subjects were all Caucasians 6-18 years old in the 1990 Cystic Fibrosis Foundation Registry. We found clinically important discrepancies in PPFEV(1) when calculated by the methods of Dockery et al. [Am Rev Respir Dis 1983;128:405-412] and Wang et al. [Pediatr Pulmonol 1993;15:75-78] as compared to Knudson et al. [Am Rev Respir Dis 1983;127:725-734] or Polgar and Promadhat [Pulmonary Function Testing in Children 1971; Philadelphia: W.B. Saunders]. In longitudinal analyses, the choice of reference equation resulted in varying apparent rates of decline in FEV(1). For example, among subjects ages 12-14 years in 1990, the decline in PPFEV(1) from 1990-1995 varied between 2-11%, depending on the choice of reference equation. In cross-sectional analyses, the choice of reference equation affected the distribution of subjects classified as having mild, moderate, or severe lung disease. CF physicians should be aware of the impact of choice of reference equation in both clinical care and research.

Buccal adherence of Pseudomonas aeruginosa in patients with cystic fibrosis under long-term therapy with azithromycin.

The oropharyngeal barrier is an innate host defence mechanism to prevent bacterial Lung infection. A compromised barrier function is observed in patients with cystic fibrosis (CF) who are chronically infected with Pseudomonas aeruginosa. Macrolides are assumed to modify host defence. We investigated the oropharyngeaL barrier function in CF patients treated with azithromycin (AZM). In a prospective study, eleven chronically infected children with CF were treated with longterm low-dose AZM. The oropharyngeal barrier function was assessed by adherence of P. aeruginosa (strain PACF 12-1) to buccal epithelial cells of the patients before and after therapy. The mean (standard deviation, SD) buccaL adherence before therapy was markedly high with 8.0 (4.8) bacteria/cell. Following therapy with AZM adherence decreased in all patients by 70% or 5.6 to 2.4 (1.1) bacteria/cell (p = 0.007), representing close to normal LeveLs (1.2 +/- 0.6). Long-term low-dose AZM therapy may improve the compromised oropharyngeaL barrier function in patients with CF, opening new perspectives for early treatment of P. aeruginosa infection in CF.

Nutrition and lung function in cystic fibrosis patients: review

Complex interactions between nutrition, skeletal and respiratory muscle function and energy expenditure in cystic fibrosis patients exist. Malnutrition significantly contributes to muscle weakness in patients with chronic obstructive pulmonary disease of the adult or in cystic fibrosis in childhood. Together with a measurable increase in resting energy expenditure the malnutrition, as a consequence of pancreatic insufficiency, leads to pulmonary deterioration. Whether pulmonary disease, pancreatic insufficiency, increased energy expenditure or insufficient intake of nutrition are the starters for the destructive circle or whether the basic defect is responsible for some of the components interacting with each other remains to be determined.

Lundh meal: a single non-invasive challenge test for evaluation of exocrine and endocrine pancreatic function in cystic fibrosis patients.

The determination of endocrine and exocrine pancreatic function in cystic fibrosis patients is clinically important. Recently, a new non-invasive test, in which pancreatic stimulation by a Lundh meal is followed by sequential serum lipase measurements, was found to be a good indicator of exocrine pancreatic status. Since the Lundh meal also contains glucose, the present study assessed whether it also might be suitable for evaluation of the pancreatic endocrine axis. After an overnight fast, 10 healthy non-diabetic subjects and 14 cystic fibrosis patients ingested a Lundh meal. Glucose, insulin, and C peptide levels were measured at various time intervals following the meal. For purposes of comparison, the oral glucose tolerance test was also performed on the cystic fibrosis patients. All healthy subjects demonstrated an increase in glucose levels post Lundh meal, peaking at 45 min (mean 140+/-21 mg/dl) and then gradually declining and reaching the normal range at 120 min. Concordant peaks of insulin (46.3+/-20 IU/ml) and C peptide (5.8+/-1. 5 ng/ml) levels were noted at 60 min. All 14 cystic fibrosis patients had normal basal glucose levels: in 8, the pattern of glucose, insulin, and C peptide post Lundh meal was similar to that of the healthy controls. These 8 patients also had a normal oral glucose tolerance test, and their hemoglobin A(1C) levels were within the normal range. The other 6 cystic fibrosis patients demonstrated glucose levels above 200 mg/dl 30-60 min post Lundh meal, and all also had an impaired oral glucose tolerance test. Of these 6, 4 had high levels of hemoglobin A(1C). This study demonstrates that the Lundh meal challenges the endocrine pancreas as well as the oral glucose tolerance test. Thus, determination of both exocrine and endocrine pancreatic status can be achieved by a single non-invasive test.

Pulmonary dysfunction in cystic fibrosis is associated with oxidative stress

The aim of this study was to determine whether a relationship exists between the circulating concentration of antioxidants, or markers of oxidative stress, and pulmonary function in cystic fibrosis patients. Plasma was obtained from 34 patients attending a cystic fibrosis clinic. Oxidative stress was investigated by measuring the concentrations of circulating lipid hydroperoxides and malondialdehyde (lipid peroxidation) and protein carbonyls (protein oxidation). Antioxidant status was determined from the plasma concentrations of alpha-tocopherol, ascorbic acid, uric acid and total sulphydryls. Forced vital capacity (FVC), forced expiratory volume in one second (FEV1) and forced mid-expiratory flow (FEF25-75) were measured in 25 of the subjects by spirometry, and expressed as percentage predicted for normal height, weight and age. Lung function decreased significantly with age and was associated with decreased plasma alpha-tocopherol, ascorbic acid and sulphydryl concentrations. The reduction in pulmonary function correlated with elevated plasma malondialdehyde, but not with lipid hydroperoxide or protein carbonyl concentrations. Patients with severe lung dysfunction (FEV1 < 50% predicted) had higher plasma concentrations of lipid hydroperoxides than those with mild-to-moderate lung dysfunction (FEV1 > 50% pred). This study provides evidence that cystic fibrosis patients have inadequate antioxidant defences to cope with the elevated oxidative stress that they regularly experience. We believe that recurring oxidative lung injury contributes to the decline in pulmonary function in these patients.

Anti-Pseudomonas aeruginosa IgG subclass titers in patients with cystic fibrosis: correlations with pulmonary function, neutrophil chemotaxis, and phagocytosis.

To explore possible mechanisms for the association between elevated immunoglobulin levels and lower pulmonary function in cystic fibrosis patients, we measured serum IgG subclass levels and anti-P. aeruginosa IgG subclass titers and correlated levels with neutrophil phagocytosis and chemotaxis. Serum was obtained from 13 cystic fibrosis patients colonized with the same serotype of P. aeruginosa, 12 noncolonized patients, and 12 normal volunteers. All anti-P. aeruginosa IgG subclass titers were elevated in serum from colonized patients. IgG3 level and anti-P. aeruginosa IgG3 titer were inversely correlated with pulmonary function. Phagocytosis of P. aeruginosa by neutrophils correlated with serum IgG3 level and was increased by opsonization with serum from colonized patients. Chemotactic index was increased in serum from colonized patients and inversely correlated with pulmonary function chest roentgenogram score. Chemotactic index directly correlated with anti-P. aeruginosa IgG3 titer and serum IgG3. These data demonstrate that cystic fibrosis patients with increased IgG3 levels are in poorer clinical condition and that their serum enhances neutrophil function. Such patients may have increased pulmonary inflammation with subsequent lung damage.

Proinsulin, proinsulin intermediate and insulin in cystic fibrosis

We determined the changes in insulin, intact proinsulin and 32-33 split proinsulin as markers of beta cell damage in assessing the state of carbohydrate intolerance in patients with cystic fibrosis. Measurements of insulin, proinsulin and 32-33 proinsulin concentrations in cystic fibrosis following oral glucose tolerance test (OGTT). Sixteen cystic fibrosis patients attending the chest outpatient clinic for follow-up, age range 14-42 years, and 14 healthy controls matched for age and body mass index. Insulin, intact proinsulin and 32-33 split proinsulin were measured immunoradiometrically at 0, 30, 60, 90 and 120 minutes after an OGTT. Glucose and HbA1 were also measured. Cystic fibrosis patients were divided into two groups according to their OGTT results: those with diabetes mellitus or impaired glucose tolerance and those with normal glucose tolerance. Insulin concentrations and insulin/glucose ratios at 30 minutes were lower in both cystic fibrosis groups in comparison with the control. There was also a significant increase in the time to reach peak insulin levels in both cystic fibrosis groups. Fasting intact proinsulin concentrations and the proportion of proinsulin-like molecules were significantly higher in cystic fibrosis with diabetes mellitus or impaired glucose tolerance than in the control group, but not in the normal glucose tolerance cystic fibrosis group. There was no significant difference in the plasma concentrations of 32-33 split proinsulin amongst the three groups. Abnormal beta cell function in cystic fibrosis patients was reflected initially in a diminished 30-minute insulin response to oral glucose. A significant rise in fasting intact proinsulin and the proportion of proinsulin-like molecules was seen only in cystic fibrosis patients who had progressed to impaired glucose tolerance or diabetes mellitus. Cystic fibrosis patients with normal glucose tolerance showed changes intermediate between the control and the other group.

Decline of exocrine pancreatic function in cystic fibrosis patients with pancreatic sufficiency.

Patients with cystic fibrosis and pancreatic sufficiency were investigated for evidence of progressive pancreatic disease. From a cohort of 630 patients, 20 pancreatic-sufficient patients became pancreatic insufficient after an average duration of 5.6 y (range 0.6-20.6 y) from diagnosis. Among 54 patients documented to be pancreatic sufficient by direct pancreatic stimulation test, 47 remained pancreatic sufficient and seven developed pancreatic insufficiency. The patients who ultimately developed pancreatic insufficiency were younger and had greatly reduced outputs of enzyme, fluid, and electrolytes. Those who remained pancreatic sufficient showed enzyme secretion close to or within the non-cystic fibrosis control range. Twenty of these patients underwent a second pancreatic stimulation test after an average interval of 4 y (range 1.3-6.2 y). No significant alteration in enzyme, fluid, or electrolyte output was seen in the patients who remained pancreatic sufficient, but there was further reduction in enzyme and fluid output in the patients who developed pancreatic failure. In conclusion, the majority of pancreatic-sufficient patients with pancreatic enzyme secretion within the control range showed no deterioration of function over an extended time period. However, a small number of pancreatic-sufficient patients with reduced enzyme and fluid secretion are at risk of pancreatic failure.