[Adults with cystic fibrosis. It's not just about longevity]. / Erwachsene mit Mukoviszidose. Es geht um mehr als die Lebensdauer.

Cystic fibrosis (CF) is one example of serious disorders for which medical progress and the integration of chronic treatment into the patients' daily routines have led to markedly better longevity. Formerly known as a 'killer disease' of childhood, CF is now considered a disorder with childhood onset, but is well known in adult medicine. Since 2009, for the first time CF adults have made up the majority of patients in the German CF registry. The drawbacks of improved longevity are long-term complications (e.g., CFRD, osteoporosis) that were rarely seen before. In particular, unwanted effects of treatments that today are performed for decades rather than years are becoming pressing problems. Unwanted effects as well as the ever-increasing treatment burden must be carefully weighed against the expected benefits of treatment. However, CF medicine has always been aware that it is not just about longevity, but that prolonged life has to have meaning. Therefore, the marked increase in longevity is also a psychosocial challenge. So far, empirical data suggest that the majority of people with CF courageously struggle for a normal life.

Low-dose methotrexate for advanced pulmonary disease in patients with cystic fibrosis.

UNLABELLED: Inflammation is a hallmark in the pathogenesis of pulmonary destruction in cystic fibrosis (CF). There is no proven effective systemic anti-inflammatory treatment for CF patients with advanced pulmonary disease. Methotrexate (MTX) is known as an effective anti-inflammatory treatment in asthma and in juvenile rheumatoid arthritis. The question was: Is an improvement in pulmonary function achievable with low-dose MTX in patients with cystic fibrosis and advanced pulmonary disease.? METHODS: We treated five CF patients with advanced pulmonary disease, who deteriorated in spite of intensive conventional therapy on an individual basis with low-dose MTX. FEV1% and immunoglobulin G (IgG) serum levels were followed from the year before to the year after starting with MTX. RESULTS: In the year before starting with MTX, FEV1% decreased (median: 10% FEV1; range 9-15% FEV1; P<0.005) after starting with MTX, FEV1% increased (median: 9% FEV1; range: 2-15% FEV1; P<0.05). IgG changed (median: -2 g/l; range: 0.2 to -7.3 g/l) in the first year with MTX. CONCLUSION: These preliminary data suggest a beneficial effect of MTX even in advanced pulmonary disease in CF patients and supports the need for a controlled prospective study.

Residual cftr expression varies with age in cftr(tm1Hgu) cystic fibrosis mice: impact on morphology and physiology.

Mouse models for cystic fibrosis (CF) mimic intestinal manifestations of the human disease, but the lung disease phenotypes are lacking in most strains. In this work, the issue was addressed whether aging of the respiratory tract leads to lung pathophysiology in the exon 10 insertional mutant cftr(tm1Hgu) mouse. Weight gain, body weight and life-span of cftr(tm1Hgu) mice were significantly reduced compared with control mice. cftr(tm1Hgu) mice expressed 20, 21 or 37% (median) of wild-type cystic fibrosis conductance transmembrane regulator (cftr) mRNA transcript in lungs, intestine and kidney. Wild-type cftr mRNA in renal and respiratory epithelia varied with age from levels similar to Ztm:MF1 controls at the age of 2 and 4 months to levels seen in patients with CFTR splice mutations beyond the age of 6 months. The morphology of the bronchi and more distal airways was apparently normal in cftr(tm1Hgu) mice during their first year of life. The alveolar surfactant phospholipid pool was increased in cftr(tm1Hgu) mice by 1.5- to 2-fold compared with Ztm:MF1 controls. Alveolar clearance of gamma-labelled scandium oxide - the first report of lung clearance measurement in living mice - was reduced in cftr(tm1Hgu) mice compared with littermate controls. Although no progressive lung pathology was seen in the cftr expression of cftr(tm1Hgu) mice, surfactant phospholipid homeostasis, and alveolar and mucociliary clearance were abnormal. Therefore, the described model is useful for studying the initial CF lung pathophysiology.

Phosphatidylcholine molecular species in lung surfactant: composition in relation to respiratory rate and lung development.

Surfactant reduces surface tension at the air-liquid interface of lung alveoli. While dipalmitoylphosphatidylcholine (PC16:0/ 16:0) is its main component, proteins and other phospholipids contribute to the dynamic properties and homeostasis of alveolar surfactant. Among these components are significant amounts of palmitoylmyristoylphosphatidylcholine (PC16:0/ 14:0) and palmitoylpalmitoleoylphosphatidylcholine (PC16:0/ 16:1), whereas in surfactant from the rigid tubular bird lung, PC16:0/14:0 is absent and PC16:0/16:1 strongly diminished. We therefore hypothesized that the concentrations of PC16:0/14:0 and PC16:0/16:1 in surfactants correlate with differences in the respiratory physiology of mammalian species. In surfactants from newborn and adult mice, rats, and pigs, molar fractions of PC16:0/14:0 and PC16:0/16:1 correlated with respiratory rate. Labeling experiments with [methyl-(3)H]choline in mice and perfused rat lungs demonstrated identical alveolar proportions of total and newly synthesized PC16:0/14:0, PC16:0/16:1, and PC16:0/16:0, which were much higher than those of other phosphatidylcholine species. In surfactant from human term and preterm neonates, fractional concentrations not only of PC16:0/16:0 but also of PC16:0/14:0 and PC16:0/ 16:1 increased with maturation. Our data emphasize that PC16:0/14:0 and PC16:0/16:1 may be important surfactant components in alveolar lungs, and that their concentrations are adapted to respiratory physiology.

Diabetes mellitus and cystic fibrosis: comparison of clinical parameters in patients treated with insulin versus oral glucose-lowering agents.

The prevalence of cystic fibrosis-related diabetes melltitus (CFRD) is increasing as patients with cystic fibrosis (CF) live longer. Because patients with CFRD are insulin-deficient, the standard medical treatment is exogenous insulin. Sulfonylureas enhance insulin secretion by acting on a specific islet beta cell receptor. No data are available about the outcome of sulfonylurea treatment vs. insulin treatment. In this retrospective study, data from 45 patients with CFRD were analyzed regarding their clinical outcome as it related to the treatment protocol. The duration of DM treatment was 7.6 +/- 4.6 years in the insulin-treated group and 3.5 +/- 2.0 years in the sulfonylurea group (n.s.). The age of CFRD diagnosis was significantly earlier in patients treated with insulin (n = 34) than in the patients treated with sulfonylurea (n = 11) (16.4 +/- 3.6 vs. 24.2 +/- 4.8 years, P < 0.001). No statistical differences were found between the two groups in the time of CF diagnosis, the most recent forced expired volume in 1 sec, forced vital capacity, Shwachman score, hemoglobin A(1C) levels, or weight for height index at the end of the study. Our data suggest that a subgroup of CFRD patients can be managed for a number of years with sulfonylurea, and that the clinical outcome was not different in this group compared with the insulin-treated patients.

Diabetes mellitus in patients with cystic fibrosis: the impact of diabetes mellitus on pulmonary function and clinical outcome.

In this multicenter study, the impact of CF-related diabetes mellitus (CFRD) on pulmonary function and clinical outcome has been investigated. To better characterize the relationship between insulin deficiency and clinical outcome we prospectively followed a group of 56 CF patients, 28 with CFRD (group 1) and 28 without diabetes (group 2) for 5 years. The clinical course of the patients was registered at each center. Data included were mortality, pulmonary function, body mass index, in-patient treatment, and CF-typical and diabetes typical complications. At the end of the study nearly twice the number of patients had died in group 1 as compared to group 2, however due to the low patient number this did not reach statistical significance. In patients with diabetes FEV1 and FVC declined significantly over the five year study period, whereas patients without diabetes did not show a significant decline during the study period. Retinopathy, nephropathy, and neuropathy were only observed in diabetic patients. In conclusion, the data presented in this prospective, multicenter study give evidence that insulin deficiency leads to a direct decline in pulmonary function suggesting a cause and effect relationship between insulin deficiency and lung disease.

Metabolism of surfactant phosphatidylcholine molecular species in cftr(tm1HGU/tm1HGU) mice compared to MF-1 mice.

In cftr(tmIHGU/m1HGU) mice, an animal model designed to study pathophysiologic alterations due to the CFTR defect found in cysticfibrosis, surfactant phospholipids of bronchoalveolar lavage fluid (BALF) are increased. To study the metabolical basis of such increases, we intraperitoneally injected cft(tm1HGU/tm1HGU) mice [methyl-3H]choline and measured [methyl-3H]choline incorporation into phosphatidylcholine (PC) molecular species of lung tissue and BALF after 1.5 to 24 hours. MF1 and MF1 x cftr(tm1HGU/tm1HGU) hybrid mice served as controls. In tissue [methyl-3H]choline incorporation into total PC was constant for 24 hours and identical in control and cftr(tmIHGU/m1HGU) mice. However, from 7.5 to 24 hours there was a shift of [methyl-3H]choline incorporation from palmitoyloleoyl-PC and palmitoyllinoleoyl-PC towards PC species enriched in surfactant, dipalmitoyl-PC, palmitoylmyristoyl-PC, and palmitoylpalmitoleoyl-PC. The relative and absolute 3H-labels of PC species were identical for cftr(tmIHGU/m1HGU) compared to control mice. In BALF [methyl-3H]choline of total PC increased from 1.5 to 24 hours (R2 > .98), mainly due to [methyl-3H]choline-labelled dipalmitoyl-PC, in all experimental groups. In BALF from cftr(tmIHGU/m1HGU) mice, the [methyl-3H]choline label of total PC and individual PC species was significantly increased over control values after 24 hours, but not after 1.5 to 6 hours. Numbers and composition of BALF cells were not different between controls and cftr(tmIHGU/m1HGU) mice. We, conclude that increased alveolar phospholipid in cftr(tmIHGU/m1HGU) mice is likely due to decreased reuptake of surfactant.

Transition of adult patients with cystic fibrosis from paediatric to adult care--the patients' perspective before and after start-up of an adult clinic.

UNLABELLED: Although most patients with cystic fibrosis (CF) survive into adulthood, many CF centres are still run by paediatricians. A transition programme from the paediatric CF unit to a newly established CF clinic at the Department of Internal Medicine was carried out for the whole group of patients > or =18 years. We aimed to evaluate our patients' opinion of the transition by analysing the results of two surveys performed before and after the transition. Nine months before the transition, we mailed an anonymous questionnaire. Statements regarding the forthcoming transition were to be answered on scales from 1 to 4, and the patients had to check a list of adjectives describing the current treatment in the paediatric CF centre as well as the presumed care in the adult unit. Fifteen months after the transition, a second survey with similar questions was carried out. RESULTS: 44 of 68 patients (65%) aged 18 to 33 years replied to the first and 56% of patients to the second questionnaire. Mean duration of treatment at the paediatric CF centre was 7.5 years (range: 1 to 22 years). Twelve patients each were classified as supporters or opponents of the transition, the remaining patients as intermediates. Older patients and those who had not required hospitalisation during the preceding year had a more positive attitude to the transition (p <0.05). There was a linear relationship between the transition attitude score and the presumed quality of care in the Internal Medicine Department (r = 0.62, p <0.001), but no relation to the quality of present paediatric care (r = -0.09, p = 0.59). In the second survey, patients rated the quality of care in the adult CF unit better than prior to the transition. CONCLUSIONS: The transition from paediatric to a newly established adult CF centre was accepted by most adult CF patients. Thorough training of all staff of the new adult unit and a close co-operation between both departments are pre-requisites to guarantee a smooth transition of all patients.

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

BACKGROUND: 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). PATIENTS AND METHODS: 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. RESULTS: 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). CONCLUSION: 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.

Energy supplements rich in linoleic acid improve body weight and essential fatty acid status of cystic fibrosis patients.

BACKGROUND: Patients with cystic fibrosis who have steatorrhea frequently are underweight and have essential fatty acid (EFA) depletion, which is associated with a poor clinical course. It has been stated that poor EFA status is difficult to correct in patients with cystic fibrosis, and an impaired EFA metabolism with reduced synthesis of long-chain polyunsaturated fatty acids has been proposed. In this study, the effects of an oral energy supplement rich in linoleic acid were investigated in patients with cystic fibrosis who had a body weight below 95% of normal for height. METHODS: Thirty-six patients (16 girls) more than 4 years of age were randomized either to a control group (n = 20, age 13.3 +/- 3.8 years, mean +/- SD) receiving intensive dietary counseling only, or an intervention group (n = 16, age, 10.4 +/- 4.3 years) treated for 3 months with dietary counseling plus 628 +/- 254 mL (= kcal) per day of an energy supplement rich in fat (31% of energy) and linoleic acid (16% of energy). RESULTS: In contrast to the control group, the patients with supplemented diets achieved significant increases of energy intake (2189 +/- 731 kcal/day vs. 2733 +/- 762 kcal/day), weight for height (82.8% +/- 8.6% vs. 84.8% +/- 9.6% of normal), and body fat (5.1 +/- 1.7 kg vs. 5.8 +/- 2.2 kg) as well as the initially low values of plasma phospholipid linoleic acid (11.8% +/- 1.1% vs. 17.6% +/- 1.6% of total phospholipid fatty acids) and its main metabolite arachidonic acid (4.4% +/- 0.4% vs. 5.9% +/- 0.3%). CONCLUSIONS: Patients with cystic fibrosis with low body weight and poor EFA status benefit from EFA-rich energy supplements and can synthesize arachidonic acid from the precursor linoleic acid.

Commercial versus native surfactants. Surface activity, molecular components, and the effect of calcium.

Despite their broad clinical use, there is no standardized comparative study on the functional, biochemical, and morphologic differences of the various commercial surfactants in relation to native surfactant. We investigated these parameters in Alveofact, Curosurf, Exosurf, and Survanta, and compared them with native bovine (NBS) and porcine (NPS) surfactant. For Curosurf and Alveofact the concentrations necessary for minimal surface tensions < 5 mN/m were six to 12 times higher (1.5 and 3 mg/ml, respectively) than with NPS and NBS. Exosurf and Survanta only reached 22 and 8 mN/m, respectively. Increasing calcium to nonphysiologic concentrations artificially improved the function of Alveofact and Curosurf, but it had little effect on Exosurf and Survanta. Impaired surface activity of commercial versus native surfactants corresponded with their lack in surfactant protein SP-A and decreased SP-B/C. The higher surface activity of Curosurf compared with Alveofact corresponded with its higher concentration of dipalmitoylphosphatidylcholine (DPPC). Despite their enrichment in DPPC Survanta and Exosurf exhibited poor surface activity because of low or absent SP-B/C. Ultrastructurally, Curosurf and Alveofact consisted mainly of lamellar and vesicular structures, which were also present in NPS and NBS. Exosurf contained crystalline structures only, whereas the DPPC-enriched Survanta contained separate lamellar/vesicular and crystalline structures. We conclude that in vitro surface activity of commercial surfactants is impaired compared with native surfactants at physiologic calcium concentrations. In the presence of SP-B/C, surface activity corresponds to the concentration of DPPC. Our data underscore the importance of a standardized protocol at physiologic calcium concentrations for the in vitro assessment of commercial surfactants.

[Surgery of acquired laryngotracheal stenoses in childhood. Experiences and results from 1988-1998. II: The cricotracheal resection]. / Die Chirurgie der erworbenen laryngotrachealen Stenosen im Kindesalter. Erfahrungen und Ergebnisse von 1988-1998. Teil II: Die cricotracheale Resektion.

Approximately 90% of infants and children with severe acquired laryngotracheal stenoses are tracheotomy dependent and therefore impaired in their physical and speech developments. In addition, tracheotomized infants can be endangered by the cannula due to the possible crusting of secretions or its dislocation. Thus, early repair of a stenosis is mandatory. Within the last 10 years, we successfully operated on 18 children with severe laryngotracheal stenoses. Ten children were treated with a modified Cotton technique. This paper reports our results of cricotracheal resection performed in 8 children since 1994 (age distribution: 7 months through age 15 years). Four children had Cotton grade II stenoses, three had grade III stenoses and one grade IV stenoses. In 3 patients a tracheotomy had been performed at another institution. Since their tracheostomas were too far caudal, they could not be included in the primary resection. All 8 children have been successfully decannulated. Five children without tracheotomies could be extubated uneventfully on the 5th postoperative day. All three primarily tracheotomized children needed further endotracheal stenting with T-tubes because of stomal and suprastomal collapse. Two of these latter children additionally required a tracheoplasty with rib cartilage grafts in order to stabilize the suprastomal trachea prior to decannulation. No patient experienced injuries to the recurrent laryngeal nerves or insufficiencies of the anastomosis. All children's voices were not impaired. This is the third report in literature of cricotracheal resections in infants and children, indicating that this effective, one-stage procedure is superior to laryngotracheal reconstruction with rib cartilage.

[Surgery of acquired laryngotracheal stenoses in childhood. Experiences and results from 1988 to 1998. I: Laryngotracheal reconstruction]. / Die Chirurgie der erworbenen laryngotrachealen Stenosen im Kindesalter. Erfahrungen und Ergebnisse von 1988 bis 1998. Teil I: Die Laryngotracheale Rekonstruktion.

Subglottic laryngotracheal stenosis represents the most severe intubation injury and is increasingly encountered in children due to long-term ventilation during intensive care treatment. Since more than 90% of these children have tracheostomies their physical, psychosocial and speech development can be greatly impaired. A tracheostomy in infants can also be a potentially life-threatening condition, making necessary resolution of the laryngotracheal stenosis and removal of the tracheostoma as soon as possible. During the past 10 years, we have treated 46 children with laryngotracheal problems, including 18 children with severe laryngotracheal stenosis. Ten children (3 with grade II stenosis and 7 with grade III stenosis) were treated by laryngotracheal reconstruction using an anterior rib cartilage graft as described by Cotton. One child with posterior glottic stenosis required a posterior laminotomy with a second rib cartilage graft. Differing from the original method, we stabilized the enlarged endotracheal lumen postoperatively with a Montgomery t-tube. This was kept in place for 10 months on average (shortest period, 6 months; longest period, 12 months). All 10 children could be decannulated, and the tracheostoma closed. Three of the children were operated in other institutions and had a different technique prior to our intervention. Two of our operations failed initially. However, both patients were treated successfully by a second intervention (which was the fourth operation for one of the patients). The reasons for our modification, the operative technique and tips for postoperative management, as well as possible pitfalls and complications, are discussed.

Necrotising enterocolitis: is there a relationship to specific pathogens?

UNLABELLED: Outbreaks of necrotising enterocolitis (NEC) have often been related to specific pathogens such as Enterobacteriaceae. This relationship, however, remains uncertain because of the retrospective nature of the studies addressing this issue. We performed a prospective study to investigate whether there is indeed an association between NEC and specific pathogens. Between April 1993 and March 1997, stools of neonates of < 36 weeks admitted to our neonatal unit were investigated for bacteria in weekly intervals. Clinical and bacteriological data from each infant who developed NEC were compared with those from two control infants matched for gestational age and date of admission. Eighteen infants developed 19 episodes of NEC (clinical signs + air in portal vein); 8 of these had laparotomy; two died. Occurrences of NEC were homogeneously distributed over the 4-year study period. The only significant differences in the clinical course prior to NEC were a more severe stage of respiratory distress syndrome [median 2 (0-4) vs. 0 (0-3), P < 0.05] and a higher proportion of infants who had only been formula fed (63 vs. 32%, P < 0.05) in the cases. Within the last week prior to NEC, potentially pathogenic bacteria were identified in stools of all cases and 79% of controls (P < 0.05). However, there was no significant difference in the occurrence of specific pathogens or groups of pathogens in cases compared with controls. CONCLUSION: Although gut colonisation with potential pathogens appeared to be a prerequisite for the development of NEC, there were no specific bacteria associated with this disease if data from infants with NEC were compared with those from time- and gestational age-matched controls.

Multicenter, open-label study of recombinant human DNase in cystic fibrosis patients with moderate lung disease. DNase International Study Group.

Cystic fibrosis is characterized by the accumulation of thick viscous purulent secretions. Recombinant human deoxyribonuclease I (rhDNase) breaks down extracellular DNA, which contributes to the increased viscosity of sputum. A multinational, open-label study was conducted in 974 cystic fibrosis patients with moderate lung disease [forced vital capacity (FVC) 40-70% of predicted values] to examine the safety and efficacy of aerosolized rhDNase, 2.5 mg, once daily over a period of at least 12 weeks. Patients were assessed under conditions reflecting routine clinical practice. During rhDNase therapy, at least one respiratory tract infection (RTI) requiring intravenous antibiotics was experienced by 29.5% of patients. Forced expiratory volume in 1 second (FEV1) and FVC were significantly improved from baseline by a mean of 10.5% and 7.2%, respectively. Voice alteration and pharyngitis were the most frequent rhDNase-related adverse events, but only 2% of all patients discontinued treatment due to adverse events. The results obtained were similar to a subanalysis of data from the first 3 months of a placebo-controlled U.S. study. The patients in the present study had a similar frequency of RTIs and improvement in pulmonary function, and reported fewer rhDNase-related and cystic fibrosis-related adverse events than patients in the U.S. study. We conclude that administration of rhDNase is safe, well tolerated, and effective under conditions reflecting routine clinical practice in patients with cystic fibrosis and moderate lung disease.

Placebo-controlled, double-blind, randomized study of aerosolized tobramycin for early treatment of Pseudomonas aeruginosa colonization in cystic fibrosis.

In chronic Pseudomonas aeruginosa pulmonary infection of patients with cystic fibrosis (CF), antibiotic therapy generally fails to eradicate the bacterial pathogen. The mucoid bacterial phenotype, high sputum production by the host, and low airway levels of antibiotics seem to be responsible for the observed decrease in antibiotic efficacy. We hypothesized that early antibiotic treatment by inhalation in CF patients may be able to prevent or at least delay airway infection. In a prospective placebo-controlled, double-blind, randomized multicenter study, 22 CF patients received either 80 mg b.i.d. of aerosolized tobramycin or placebo for a period of 12 months shortly after the onset of P. aeruginosa pulmonary colonization. Two patients in the tobramycin and six patients in the placebo group stopped inhalation before the 12 month treatment period. Using life table analysis, the time to conversion from a P. aeruginosa-positive to a P. aeruginosa-negative respiratory culture was significantly shorter in the tobramycin-treated group than in the placebo group (P < 0.05, log rank test). Lung function parameters and markers of inflammation did not change in either group during treatment. The results of this study suggest that early tobramycin inhalation may prevent and/or delay P. aeruginosa pulmonary infection in CF patients.

Long-term follow up of changes in FEV1 and treatment intensity during Pseudomonas aeruginosa colonisation in patients with cystic fibrosis.

BACKGROUND: Colonisation with Pseudomonas aeruginosa (PA) is a striking feature of lung involvement in cystic fibrosis. To identify the clinical consequences of the different steps of colonisation with PA under a defined therapeutic regime (no prophylactic antibiotic treatment as long as patients had no severe pulmonary disease), their influence on pulmonary function and on therapeutic intensity was examined. METHODS: Forty patients with cystic fibrosis were followed from first detection of PA (PA1), chronic PA colonisation (PAc), first mucoid PA detection (PAm), to chronic mucoid PA colonisation (PAcm). Percentage predicted forced expiratory volume in one second (FEV1), the number of intravenous antibiotic treatment courses, and the percentage of patients on inhaled antibiotics were followed retrospectively and longitudinally in relation to the different steps of PA colonisation. The annual changes in FEV1 and therapeutic intensity in the two years preceding each step were compared with the two years following each step. Changes in FEV1 were related to therapeutic intensity. RESULTS: The mean (SD) annual changes in FEV1 (% predicted) worsened significantly only with the transition to the mucoid stages (PAm: 4.6 (13.2) versus -4.3 (8.1); PAcm: 7.3 (12.0) versus -4.8 (7.4)) with a mean difference (95% CI) between before and after the transition of 8.9 (2.6 to 15.2) for PAm and 12.1 (6.4 to 17.6) for PAcm. With non-mucoid PA stages the therapeutic intensity increased in the year of transition and with mucoid PA stages it increased in the years following transition. Therapeutic intensity was unrelated to changes in FEV1. CONCLUSION: With the treatment regime used an accelerated decrease in FEV1 was successfully prevented in the non-mucoid stages but not in the mucoid stages of PA colonisation.

Insulin resistance with altered secretory kinetics and reduced proinsulin in cystic fibrosis patients.

BACKGROUND: Impaired glucose tolerance and secondary diabetes are frequent in older patients with cystic fibrosis (CF), associated with increased frequency of infections and reduced life expectancy. Studies on the pathophysiology of islet cell secretion in CF are a prerequisite for a scientifically based therapeutic approach. METHODS: Oral glucose tolerance tests were performed in 71 patients (14.2 +/- 0.5 years; mean +/- SE) and 56 control subjects (16.5 +/- 0.9 years). Glucose, insulin, C-peptide, and proinsulin were measured every 30 min. RESULTS: Glucose tolerance in CF patients was classified as normal (NGT, n = 48), impaired (IGT, n = 14), or diabetic (DM, n = 9). Even in CF patients with NGT, blood glucose was significantly elevated at 30, 60, and 90 min of the test. Surprisingly, the secretory responses of insulin and C-peptide were not reduced in CF patients with IGT or DM compared with both healthy controls or CF patients with normal glucose tolerance. However, peak insulin concentration was reached at 90 min in CF-IGT or CF-DM patients compared with 30 min in controls. The ratio of glucose to insulin, an indicator of insulin resistance, increased in CF patients with progression of carbohydrate intolerance. Proinsulin was significantly reduced in all CF patients compared with controls (p < 0.001; Wilcoxon's rank sum test). CONCLUSIONS: In CF patients with impaired glucose tolerance or diabetes, integrated insulin release is not diminished, indicating that insulin resistance is likely to contribute to hyperglycemia in CF patients with IGT or DM. Reduced proinsulin levels in CF patients are compatible either with enhanced conversion of proinsulin to insulin in compensation for reduced beta-cell mass, or enhanced clearance of proinsulin.