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Aims: To explore whether gender differences in the Scandinavian Cystic Fibrosis (CF) patients exist in the areas of key clinical parameters, complications, and medication. Methods: Cross-sectional data on 890 (416 female) pancreatic insufficient CF patients were evaluated regarding chronic infection, body mass index, lung function, medication, and diabetes, as well as data of Pseudomonas infection status, antibiotic treatment and hospitalization from 1-year follow-up. Results: We found no differences in lung function, body mass index, or frequency of diabetes. The adult group consisted of more males than females (208:168). We found no significant difference in prevalence of chronic Pseudomonas aeruginosa infection, but during the follow-up the incidence of new chronic infection was higher in adult females (10/33 vs. 4/56). Females had higher prevalence of Burkholderia infection (21/416 vs. 11/474). Adult females had more days on intravenous antibiotics (median 39 vs. 26 days/year), and days in hospital (median 2 vs. 0 days/year). More adult females received inhaled and oral steroids. In the pediatric cohort, females were treated more often with macrolides as an anti-inflammatory agent. Conclusion: We found no gender difference in key clinical parameters in our CF population. However, our study showed a higher risk of Pseudomonas and Burkholderia infection among the female patients. Additionally, we found that female patients require more intensified treatment regarding antibiotics, macrolides, steroids and days of hospitalization, indicating a true female disadvantage even with modern aggressive treatment. The finding of more males than females in the adult population suggesting a male advantage, warrants a mortality study. Pediatr Pulmonol. 2010; 45:959-965. (C) 2010 Wiley-Liss, Inc.

Background and aims: The effects of central sleep apnea in Cheyne-Stokes respiration on sleep-related symptoms and quality of life are not very well established. We aimed to investigate whether Ch ...

BACKGROUND: A major problem in clinical lung transplantation is the shortage of donor lungs. Only about 20% of donor lungs are accepted for transplantation. A method to evaluate and recondition lungs ex vivo has been tested on donor lungs that have been rejected for transplantation. METHODS: The donor lungs were reconditioned ex vivo in an extracorporeal membrane oxygenation (ECMO) circuit with STEEN solution (Vitrolife AB, Kungsbacka, Sweden) mixed with erythrocytes. The hyperoncotic solution dehydrates edematous lung tissue. Functional evaluations were performed with deoxygenated perfusate by varying the inspired fraction of oxygen. After the reconditioning, the lungs were kept immersed at 8 degrees C in extracorporeal membrane oxygenation until transplantation was performed. RESULTS: Six of nine initially rejected donor lungs were reconditioned to acceptable function, and in six recipients, double lung transplantation was performed. Three-month survival was 100%. One patient has since died due to sepsis after 95 days, and one due to rejection after 9 months. Four recipients are alive and well without any sign of bronchiolitis obliterans syndrome 24 months after the transplantation. CONCLUSIONS: The result from the present study is promising, and we continue to transplant reconditioned lungs.

Between 1990 and 1995 39 patients were lung transplanted at the University Hospital in Lund. This is a retrospective review of survival and lung function in these patients. There were 17 single-lung transplants (SLT), 21 double-lung transplants (DLT) and 1 heart-lung transplant (HLT). Seven patients died during the period, giving an overall survival of 82%. One-year survival according to Kaplan-Meier survival analysis was 87%, and 2-year survival was 83%. Vital capacity and forced expiratory volume in 1 s (FEV1) 1 year after transplantation were 91% and 100% of predicted, respectively, in the DLT group and 60% and 50% in the SLT group. Bronchiolitis obliterans syndrome (BOS) developed in 11 of the 35 patients (31%) surviving more than 6 months, 2/21 in the DLT group and 8/13 in the SLT group and in the patient with HLT. The median time until detection of BOS was 11 months after the operation (range 6-18 months). Working capacity 1 year after transplantation was 60% of predicted in the DLT group and 47% of predicted in the SLT group. Ventilatory capacity was no longer function limiting. Lung transplantation today is a therapeutic option with a good medium-term survival and good functional results in selected patients with severe lung disease.

Glucagon like peptide 1 (GLP-1) is an incretin hormone released as a bioactive peptide from intestinal L-cells in response to eating. It acts on target cells and exerts several functions as stimulating insulin and inhibiting glucagon. It is quickly deactivated by the serine protease dipeptidyl peptidase IV (DPP-IV) as an important regulatory mechanism. GLP-1 analogues are used as antidiabetic drugs in patients with type 2 diabetes.We served patients with cystic fibrosis (CF, n=29), cystic fibrosis related diabetes (CFRD, n=19) and healthy controls (n=18) a standardized breakfast (23g protein, 25g fat and 76g carbohydrates) after an overnight fasting. Blood samples were collected before meal as well as 15, 30, 45 and 60min after the meal in tubes prefilled with a DPP-IV inhibitor. The aim of the study was to compare levels of GLP-1 in patients with CF, CFRD and in healthy controls.We found that active GLP-1 was significantly decreased in patients with CF and CFRD compared to in healthy controls (p

Concern regarding recurrence of pre-transplant (Tx) malignancy has disqualified patients from Tx. Because this has been poorly studied in lung and heart Tx recipients our aim was to investigate the influence of pre-Tx malignancy on post-Tx recurrence and long-term survival, focusing on pre-operative cancer-free intervals.From our lung and heart Tx programs (1983 to 2011) we retrospectively identified 111 (lung, 37; heart, 74) of 3,830 recipients with 113 pre-Tx malignancies. The patients were divided into 3 groups by pre-Tx cancer-free interval: Group I,12 months (n = 24); Group II, ≥12 to60 months (n = 18); and Group III, ≥60 months (n = 71).Mean age at pre-Tx malignancy was 35±18 years. Mean post-Tx follow-up time was 70±63 months (range, 0-278 months), and malignancy recurrence was 63% in Group I, 26% in Group II, and 6% in Group III. Kaplan-Meier analysis of freedom from post-Tx recurrence revealed the following differences among the groups: Group I vs II, p = 0.08; II vs III, p = 0.002; and I vs III, p0.001. Overall survival (51 deaths) was significantly poorer in Group I than in Groups II and III (p = 0.044). Survival between Groups II and III did not differ significantly (p = 0.93).Cancer-free survival of ≥5 years pre-Tx is associated with the lowest recurrence. However, recurrence is related to the time the patients were cancer-free, as seen in Groups I and II.

The NOCTET (NOrdic Certican Trial in HEart and lung Transplantation) trial demonstrated that everolimus improves renal function in maintenance thoracic transplant (TTx) recipients. Nevertheless, introduction of everolimus is not recommended for patients with advanced renal failure. We evaluated NOCTET data to assess everolimus introduction amongst TTx recipients with advanced renal failure.This 12-month multicenter Scandinavian study randomized 282 maintenance TTx recipients to everolimus introduction with calcineurin inhibitor (CNI) reduction or standard CNI therapy. The measured glomerular filtration rate (mGFR) was noted at baseline and after 1-year using Cr-ethylenediaminetetraacetic acid clearance.In 21 patients with a baseline mGFR of 20 to 29 ml/min/1.73 m(2), renal function improved in the everolimus group compared with the control group ((ΔmGFR 6.7 ± 9.0 vs -1.6 ± 5.1 ml/min/1.73 m(2); p = 0.03). Amongst 173 patients with moderate renal impairment (mGFR 30-59 ml/min/1.73 m(2)), renal function improvement was also greater amongst everolimus patients than in controls (ΔmGFR 5.1 ± 11.1 vs -0.5 ± 8.7 ml/min/1.73 m(2); p0.01). In 55 patients with mGFR 60 to 89 ml/min/1.73 m(2), mGFR did not change significantly in either group. Improvement in mGFR was limited to patients with a median time since TTx of less than 4.6 years and was also influenced by CNI reduction during the study period.Everolimus introduction and reduced CNI significantly improved renal function amongst maintenance TTx patients with pre-existing advanced renal failure. This beneficial effect was limited to patients undergoing conversion in less than 5 years after TTx, indicating a window of opportunity that is appropriate for pharmacologic intervention with everolimus.

BACKGROUND: Lung transplantation (LTx) is established as a life-saving treatment in end-stage lung disease. However, long-term survival is hampered by the development of chronic rejection, almost synonymous with bronchiolitis obliterans syndrome (BOS). The rejection is characterized by deposition of extracellular matrix in small airways. Fibroblasts/myofibroblasts are the main producers of extracellular matrix molecules such as proteoglycans. This study compared fibroblast phenotype and activity in the wound healing process at different points after LTx in patients who later did, or did not, develop BOS. METHODS: Distally derived fibroblasts from patients 6 and 12 months after LTx and from healthy controls were analyzed for production of the proteoglycans versican, perlecan, biglycan, and decorin, with and without transforming growth factor (TGF)-I²(1). Fibroblast migration and proliferation were also studied. RESULTS: At 6 and 12 months after LTx, versican production was higher in fibroblasts from LTx patients (p < 0.01 p < 0.01) than from controls. Fibroblasts from patients who later developed BOS were more responsive to TGF-I²(1)-induced synthesis of versican and biglycan than patients without signs of rejection (p < 0.05). Production of perlecan and decorin was negatively correlated with fibroblast proliferation in fibroblasts at 6 months after LTx. In a more detailed case study of 2 patients, one with and one without BOS, the altered proteoglycan profile was associated with impaired lung function. CONCLUSIONS: LTx changes the phenotype of fibroblasts to a non-proliferative but extracellular matrix-producing cell due to wound healing involving TGF-I²(1). If not controlled, this may lead to development of BOS. (Less)

Many cystic fibrosis patients are vitamin D-insufficient. Cystic fibrosis-related diabetes is a major complication of cystic fibrosis. The literature suggests that vitamin D might possess certain glucose-lowering properties. We aimed to assess the relationship between vitamin D and cystic fibrosis-related glucose intolerance.We enrolled 898 cystic fibrosis patients from Sweden, Norway and Denmark. Vitamin D intake was assessed using a seven-day food record. Serum 25-hydroxyvitamin D (s25OHD) and HbA(1c) were measured, and an OGTT was carried out. Multiple linear and logistic regressions were used for HbA(1c) and cystic fibrosis-related diabetes/OGTT result as outcome variables, respectively. Each model was controlled for country, and for known cystic fibrosis-related diabetes risk factors: age, sex, genotype, liver dysfunction, long-term corticosteroid treatment, and lung and pancreatic function.Degree of vitamin D insufficiency (OR 1.36; p = 0.032) and s25OHD 30 nmol/l (OR 1.79; p = 0.042) were significant risk factors for cystic fibrosis-related diabetes. Accordingly, HbA(1c) value was positively associated with s25OHD 30 nmol/l and 50 nmol/l, as well as with degree of vitamin D insufficiency (adjusted R (2) = 20.5% and p 0.05 in all). In subgroup analyses, s25OHD 30 nmol/l determined the HbA(1c) value in paediatric patients (adjusted R (2) = 20.2%; p = 0.017), but not in adults.Vitamin D status is associated with HbA(1c) and diabetes in cystic fibrosis, particularly in children. The study justifies prospective studies on the proposed role of vitamin D deficiency in the pathophysiology of diabetes mellitus.

Use of the mammalian target of rapamycin inhibitor everolimus with an accompanying reduction in calcineurin inhibitor (CNI) exposure has shown promise in preserving renal function in maintenance thoracic transplant patients, but robust, long-term data are required.In a prospective, open-label, multicenter study, thoracic transplant recipients more than or equal to 1 year posttransplant with mild-to-moderate renal insufficiency were randomized to continue their current CNI-based immunosuppression or convert to everolimus with predefined CNI exposure reduction. After a 12-month core trial, patients were followed up to month 24 after randomization.Of 245 patients who completed the month 12 visit, 235 patients (108 everolimus and 127 controls) entered the 12-month extension phase. At month 24, mean measured glomerular filtration rate had increased by 3.2±12.3 mL/min from the point of randomization in everolimus-treated patients and decreased by 2.4±9.0 mL/min in controls (P0.001), a difference that was significant within both the heart and lung transplant subpopulations. During months 12 to 24, 5.6% of everolimus patients and 3.1% of controls experienced biopsy-proven acute rejection (P=0.76). There were no significant differences in the rate of adverse events or serious adverse events (including pneumonia) between groups during months 12 to 24.Converting maintenance thoracic transplant recipients to everolimus with low-exposure CNI results in a renal benefit that is sustained to 2 years postconversion, with significantly improved measured glomerular filtration rate in both heart and lung transplant patients. Despite reductions of more than 50% in CNI exposure, there was no marked loss of efficacy. The safety profile of the everolimus-based regimen was acceptable.

To explore whether gender differences in the Scandinavian Cystic Fibrosis (CF) patients exist in the areas of key clinical parameters, complications, and medication.Cross-sectional data on 890 (416 female) pancreatic insufficient CF patients were evaluated regarding chronic infection, body mass index, lung function, medication, and diabetes, as well as data of Pseudomonas infection status, antibiotic treatment and hospitalization from 1-year follow-up.We found no differences in lung function, body mass index, or frequency of diabetes. The adult group consisted of more males than females (208:168). We found no significant difference in prevalence of chronic Pseudomonas aeruginosa infection, but during the follow-up the incidence of new chronic infection was higher in adult females (10/33 vs. 4/56). Females had higher prevalence of Burkholderia infection (21/416 vs. 11/474). Adult females had more days on intravenous antibiotics (median 39 vs. 26 days/year), and days in hospital (median 2 vs. 0 days/year). More adult females received inhaled and oral steroids. In the pediatric cohort, females were treated more often with macrolides as an anti-inflammatory agent.We found no gender difference in key clinical parameters in our CF population. However, our study showed a higher risk of Pseudomonas and Burkholderia infection among the female patients. Additionally, we found that female patients require more intensified treatment regarding antibiotics, macrolides, steroids and days of hospitalization, indicating a true female disadvantage even with modern aggressive treatment. The finding of more males than females in the adult population suggesting a male advantage, warrants a mortality study.

The effects of central sleep apnea in Cheyne-Stokes respiration on sleep-related symptoms and quality of life are not very well established. We aimed to investigate whether Cheyne-Stokes respiration is related to health-related quality of life. We also studied the impact on daytime sleepiness and nocturnal dyspnea.Included were 203 consecutive patients, stabilized following in-hospital treatment for decompensated congestive heart failure. They underwent overnight cardiorespiratory sleep apnea recordings in hospital and answered a set of questions on symptoms and health-related quality of life questionnaires in the form of the Nottingham Health Profile and the Minnesota Living with Heart Failure Questionnaire. After excluding seven patients with predominantly obstructive apneas and 14 with insufficient recordings, 182 patients were included in the final analysis.One third of the patients had an apnea-hypopnea index (AHI) of30. Falling asleep in front of the television was the only symptom related to (AHI). Nocturnal dyspnea, daytime sleepiness, generic quality of life or disease-specific quality of life were not related to AHI.Cheyne-Stokes respiration was not associated with health-related quality of life, daytime sleepiness or nocturnal dyspnea among patients stabilized following treatment for congestive heart failure.

BACKGROUND.: The proliferation signal inhibitor everolimus offers the potential to reduce calcineurin inhibitor (CNI) exposure and alleviate CNI-related nephrotoxicity. Randomized trials in maintenance thoracic transplant patients are lacking. METHODS.: In a 12-month, open-labeled, multicenter study, maintenance thoracic transplant patients (glomerular filtration rate >/=20 mL/min/1.73m and 1 year posttransplant were randomized to continue their current CNI-based immunosuppression or start everolimus with predefined CNI exposure reduction. RESULTS.: Two hundred eighty-two patients were randomized (140 everolimus, 142 controls; 190 heart, 92 lung transplants). From baseline to month 12, mean cyclosporine and tacrolimus trough levels in the everolimus cohort decreased by 57% and 56%, respectively. The primary endpoint, mean change in measured glomerular filtration rate from baseline to month 12, was 4.6 mL/min with everolimus and -0.5 mL/min in controls (P

Background: Cyclosporine (CsA) absorption varies early after transplantation and can be accurately assessed by the area under the absorption curve (AUC). The 2-hour post-dose (C2) level of CsA in whole blood is reported to be a useful surrogate marker of CsA AUC in kidney and liver transplant monitoring, but should be further explored in thoracic organ recipients. Methods: In a 12-month study we included de novo lung (n = 95) and heart (n = 96) recipients. All participants received cyclosporine (Sandimmun Neoral) monitored by CO and blood was collected for analysis of C2 retrospectively. Abbreviated AUC (AUC(0-4)) was measured at 7 days and 3 months. Primary outcome was C2 relation to the frequency of acute cellular rejection (ACR) needing treatment and possible decline in measured glomerular filtration rate (mGFR). Recipients were divided into lower, middle and upper third C2 groups based on 2-week post-operative values (tertiles T1 to T3). Results: C2 was the most robust substitute for AUC(0-4) in the group of patients studied. For lung, but not heart, recipients there were differences in mean number of ACRs (p = 0.05), incidence of any rejections (p = 0.04), mean number of any rejections (p = 0.001) and time to first rejection (p = 0.03) between T1 and T3. C2 did not predict reduction in mGFR. Conclusions: C2 is a sensitive predictor for ACR in lung, but not heart, recipients, C2 was not predictive of a decline in mGFR. This study suggests that management of lung recipients by C2 may diminish the number of ACRs. J Heart Lung Transplant 2009; 28:919-26. Copyright (C) 2009 by the International Society for Heart and Lung Transplantation. (Less)

on post transplant survival of patients (pts) bridged to transplant. Methods and Materials: 490 pts were implanted with HeartMate II LVAD in the multicenter BTT clinical trial. 416/490 (85%) had TPG data available for analysis. TPG was calculated as the difference between mean pulmonary arterial pressure and pulmonary capillary wedge. Pts were divided into two groups based on the median TPG value. Results: The median TPG of all pts was 10 mmHg. Pts age (50 13 vs. 51 12), sex, co morbidities, renal and hepatic function, and pre-HTX LVAD support times (239 264 days vs. 262 264 days) did not differ between groups. Overall, there were no differences in LVAD outcomes (Recovery, HTX, or ongoing support) for pts below median TPG ( 10 mmHg) and those above median TPG ( 10 mmHg). However, one year post HTX survival for pts with TPG below the median value ( 10 mmHg) was significantly higher (94%) than for those patients with TPG 10 mmHg (82%) (p 0.006). Analysis based on median PVR of 2.69 or upper quartile PVR of 3.8 did not reveal any differences between LVAD outcome of the groups or their post HTX survival. (91% vs 86% p 0.308, and 90% vs 84% p 0.3 respectively). Conclusions: Elevated TPG prior to LVAD implantation rather than high PVR, is associated with worse 1-year survival in HTX recipients. Elevated TPG appears as an important risk factor for post HTX mortality and therefore should be taken into consideration when contemplating heart transplant versus LVAD destination therapy in patients with advanced CHF.

169* Bactericidal activity of human cystic fibrosis macrophages against Pseudomonas aeruginosa N. Cifani1, S. Guarnieri2, M.A. Mariggio2, F. Spadaro3, S. Guglietta4, M. Anile5, F. Venuta5, S. Quattrucci6, F. Ascenzioni1, P. Del Porto1. 1Sapienza University, Dept. Biology and Biotechnology, Rome, Italy; 2G. d’Annunzio University ChietiPescara, Dept. Neurosciences and Imaging, Pescara, Italy; 3Istituto Superiore Sanita, Dept. Cell Biology and Neurosciences, Rome, Italy; 4European Institute of Oncology, Dept. Exp. Oncology, Milan, Italy; 5Sapienza University, Dept. Thoracic Surgery, Rome, Italy; 6Sapienza University, Dept. Pediatrics, Rome, Italy

Purpose The NOCTET (NOrdic Certican Trial in HEart and lung Transplantation) trial demonstrated that everolimus improves renal function in maintenance thoracic transplant recipients. Nevertheless, switch to everolimus is not recommended for patients with advanced renal failure. We evaluated NOCTET data to assess everolimus introduction amongst thoracic transplant recipients with advanced renal failure. Methods and Materials In this 12-month multicenter Scandinavian study 282 maintenance thoracic transplant recipients were randomized to everolimus with calcineurin inhibitor (CNI) reduction (56% reduction in CNI exposure achieved) or standard CNI therapy. GFR was measured at baseline and 1-year using Cr-EDTA clearance. Results In patients with baseline GFR 60 ml/min the effect was more modest. Time since transplant was a mediating factor as GFR improvement was limited to patients with time since transplant Conclusions Conversion to everolimus and reduced CNI significantly improves renal function amongst maintenance thoracic transplant patients with pre-existing advanced renal failure. This beneficial effect is limited to patients undergoing conversion less than 5 years after transplant indicating a "window of opportunity" that is appropriate for pharmacological intervention with everolimus.

Background: Malnutrition is a well-known complication in cystic fibrosis (CF). There is good evidence that maintaining a normal body-weight correlates well with improved survival in CF. Energy intake in excess of 120% of the estimated average requirement (EAR) has been advised since 1980s. Objectives: To investigate the nutritional intake and status in the adult Scandinavian CF-population. Subjects/Methods: A cross-sectional multi-centre study was used to investigate the nutritional status of 456 adult CF-patients (2003-2006). Height and weight were measured and body mass index (BMI) and z-scores were calculated. Pulmonary function was examined by dynamic spirometry. A 7-day pre-coded food record (FR) obtained energy and nutrient intake data in 180 patients. Results: The mean energy intake was 114 (SD 30.0)% of EAR and thus significantly lower than the target of 120% EAR (p

Background Previous studies showing a strong relationship between Cheyne-Stokes respiration and the severity of left ventricular systolic dysfunction have usually been done in selected patient populations with lower age and a higher proportion of males than the "typical" in-hospital patient with heart failure. The purpose of the present study was test the strength of this relationship in unselected patients admitted to hospital due to decompensated chronic heart failure. Methods We evaluated 191 patients (32% women), mean age 73 years, ready for discharge from the heart failure unit in the University Hospital of Malmö, Sweden. The patients underwent echocardiography for determination of left ventricular ejection fraction and left ventricular inner diastolic diameter. A respiratory investigation during sleep was performed the last night before discharge. Results We found that 66% of the patients had Cheyne-Stokes respiration more than 10% of the total recording time. Only 7 (3.6%) of the patients had predominantly obstructive apnoeas. There was a significant but very weak relationship between left ventricular ejection fraction and left ventricular inner diastolic diameter on one hand and Cheyne-Stokes respiration on the other. Age was a stronger determinant of Cheyne-Stokes respiration than any of the cardiac or other clinical variables. Conclusion Although presence of Cheyne-Stokes respiration indicates left ventricular dysfunction, its severity seems only weakly related to the severity of heart failure. Age was found to be a stronger determinant, which may reflect the underlying age-dependency found also in healthy subjects. Due to age restrictions or other selection criteria, the importance of age may have been underestimated in many previous studies on factors associated with Cheyne-Stokes respiration.

Background: Autoantibodies against bactericidal permeability increasing protein (BPI-ANCA) are frequently present in cystic fibrosis patients and have been reported to be associated to colonization with Pseudomonas (P) aeruginosa and lung damage. In the present study, we investigated BPI-ANCA as a prognostic marker and its relation to P. aeruginosa colonization and lung function. Methods: BPI-ANCA, measured by ELISA, was examined relative to lung function and microbiological findings. The prognostic value of BPI-ANCA was assessed in 46 adult patients followed for 1.2–8.9 years. The cross-sectional investigation was performed in 366 patients (age 0.5–55). Results: The presence of BPI-ANCA predicted poor prognosis. An adverse outcome occurred in 15/28 BPI-ANCA positive patients and in 2/18 BPI-ANCA negative patients ( p =0.01). This result remained valid when the patients were stratified according to lung function ( p =0.03). Findings of BPI-ANCA were correlated to P. aeruginosa colonization and lung damage. Development of BPI-ANCA occurred after colonization with P. aeruginosa . All colonized patients did not develop BPI-ANCA. The BPI-ANCA levels were fairly stable during the disease course, but decreased significantly following lung transplantation. Conclusion: BPI-ANCA responses follow colonization with P. aeruginosa and may be predictive for lung damage.