Papers by Manfred Ballmann
Pediatric Research, 2004
Cystic fibrosis (CF) disease severity is characterized by a broad variability that has been attri... more Cystic fibrosis (CF) disease severity is characterized by a broad variability that has been attributed, in addition to the CF transmembrane conductance regulator (CFTR) genotype, to modulating factors such as CFTR-mediated residual chloride (Cl Ϫ) secretion. Moreover, CFTR has been suggested to function as a receptor for Pseudomonas aeruginosa (PA). In this study, we investigated whether or not the presence of residual Cl Ϫ secretion protects against early chronic PA colonization of patients' airways. Excluding influences on the phenotype caused by different CFTR mutations, we evaluated a cohort of F508del homozygous individuals with respect to the correlation between residual Cl Ϫ secretion and the age of onset of PA colonization as an important marker of clinical phenotype. A group with early chronic PA colonization before the age of 7 y (n ϭ 14) was compared with a cohort that had no initial PA detection at least until the age of 13 y (n ϭ 10). We determined the Cl Ϫ transport properties by using the intestinal current measurement in rectal suction biopsies. Residual Cl Ϫ secretion, most likely due to the CFTR Cl Ϫ channel, was observed in 63% of subjects, more frequently in early chronically PA colonized than among late or not colonized patients. These results demonstrate the presence of some active F508del-CFTR in the apical cell membrane and imply that factors other than the CFTR-mediated residual Cl Ϫ secretion determine the age of onset of PA colonization. (Pediatr Res 55: 69-75, 2004) Abbreviations Ca 2؉ , calcium cAMP, adenosine 3',5'-cyclic monophosphate CF, cystic fibrosis CFTR, cystic fibrosis transmembrane conductance regulator Cl ؊ , chloride DIDS, 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid FEVPerc, percentiles for predicted forced expiratory volume in 1 s ⌬I sc net , net change in short-circuit current IC, intestinal current K ؉ , potassium PA, Pseudomonas aeruginosa PD, potential difference
Journal of Clinical Medicine, 2020
Alterations in the L-arginine (Arg)/nitric oxide (NO) pathway have been reported in cystic fibros... more Alterations in the L-arginine (Arg)/nitric oxide (NO) pathway have been reported in cystic fibrosis (CF; OMIM 219700) as the result of various factors including systemic and local inflammatory activity in the airways. The aim of the present study was to evaluate the Arg/NO metabolism in pediatric CF patients with special emphasis on lung impairment and antibiotic treatment. Seventy CF patients and 78 healthy controls were included in the study. CF patients (43% male, median age 11.8 years) showed moderately impaired lung functions (FEV1 90.5 ± 19.1% (mean ± SD); 21 (30%) had a chronic Pseudomonas aeruginosa (PSA) infection, and 24 (33%) had an acute exacerbation). Plasma, urinary, and sputum concentrations of the main Arg/NO metabolites, nitrate, nitrite, Arg, homoarginine (hArg), and asymmetric dimethylarginine (ADMA) were determined in pediatric CF patients and in healthy age-matched controls. Clinical parameters in CF patients included lung function and infection with PSA. Additi...
The lancet. Diabetes & endocrinology, Feb 1, 2018
As survival among patients with cystic fibrosis has improved in recent decades, complications hav... more As survival among patients with cystic fibrosis has improved in recent decades, complications have become increasingly relevant. The most frequent complication is cystic-fibrosis-related diabetes. The recommended treatment is injected insulin, but some patients are treated with oral antidiabetic drugs to ease the treatment burden. We assessed the efficacy and safety of oral antidiabetic drugs. We did a multicentre, open-label, comparative, randomised trial in 49 centres in Austria, France, Germany, and Italy. Eligible patients had cystic fibrosis, were older than 10 years, and had newly diagnosed diabetes. We used a central randomisation schedule derived from a Geigy random number table to assign patients 1:1 to receive insulin or repaglinide, stratified by sex and age (10-15 years or >15 years). The primary outcome was glycaemic control assessed by mean change in HbA concentration from baseline after 24 months of treatment. Differences between groups were assessed by linear mode...
Respiratory Medicine, 2017
Background: High-flow nasal cannula (HFNC) 1 is a technique of oxygen supply, initially being use... more Background: High-flow nasal cannula (HFNC) 1 is a technique of oxygen supply, initially being used as a potentially less-invasive alternative to nasal continuous positive airway pressure (nCPAP) 2 for premature infants/neonates, which nowadays crosses the border of neonatal care. HFNC builds up a positive endexpiratory pressure (PEEP) 3 but lacks the opportunity for continuous monitoring. Therefore, pressuredepending complications are a risk. Our goal was to evaluate the current use of HFNC in Germany regarding indications, techniques of application and complications experienced. Studydesign: We used a questionnaire sent to 226 pediatric clinics. Results: We received responses from 67 pediatric clinics (29.6%). HFNC was applied in the age group of 8 to 14 years in 42% and between 14 and 18 years in 33% of the clinics. 54% of the clinics have been using HFNC for more than 3 years. Applied flow rates varied strongly among the clinics. 70% of the clinics use HFNC outside of the established indications (alternative to nCPAP for premature infants and neonates, bronchiolitis) for pneumonia, support after extubation and non-adherence to nCPAP. Severe complications such as pneumothorax have been seen by 17,9% of the clinics. Conclusion: We reported for the first time a nationwide overview about the expanded use of HFNC in pediatric clinics. Our results emphasize the fact that, even though HFNC is widely accepted as a noninvasive procedure there is still a potential of severe side effects. Therefore the use of HFNC should be monitored continuously and closely within an intensive or intermediate care unit.
Transplant Infectious Disease, 2009
To characterize epidemiology and risk factors for respiratory viral infections (RVI) in pediatric... more To characterize epidemiology and risk factors for respiratory viral infections (RVI) in pediatric lung transplant recipients within the ¢rst post-transplant year, a retrospective multicenter study of pediatric lung transplant recipients from 1988 to 2005 was conducted at 14 centers in the United States and Europe. Data were recorded for 1year post transplant. Associations between RVI and continuous and categorical risk factors were assessed using W|lcoxon's rank-sum and w 2 tests, respectively. Associations between time to RVI and risk factors or survival were assessed by multivariable Cox proportional hazards models. Of 576 subjects, 79 subjects (14%) had 101 RVI in the ¢rst year post transplant. Subjects with RVI were younger than those without RVI (median ages 9.7, 13; Po0.01).V|ruses detected included adenovirus (n 5 25), in£uenza (n 5 9), respiratory syncytial virus (n 5 21), parain£uenza virus (n 5 19), enterovirus (n 5 4), and rhinovirus (n 5 22). In a multivariable model for time to ¢rst RVI, etiology other than cystic ¢brosis (CF), younger age, and no induction therapy were independently associated with risk of RVI. Cytomegalovirus serostatus and acute rejection were not associated with RVI. RVI was independently associated with decreased 12-month survival (hazard ratio 2.6, 95% con¢dence interval 1.6^4.4). RVI commonly occurs after pediatric lung transplantation with risk factors including younger age and non-CF diagnosis. RVI is associated with decreased 1-year survival.
Respiration, 2006
Cystic fibrosis (CF) is a recessive genetic disease caused by defects of the cystic fibrosis tran... more Cystic fibrosis (CF) is a recessive genetic disease caused by defects of the cystic fibrosis trans-membrane regulator (CFTR) gene with a median survival of less than 35 years. This work reports on the oldest living German siblings with CF. Besides clinical history, CF genotype and nasal potential difference (NPD) measurement results, the remarkably high exercise activity of the siblings is discussed as a disease-modifying factor. Both male patients have an overall mild pulmonary manifestation. They have suffered from abdominal symptoms since their early childhood, including recurrent pancreatitis and diffuse symptoms leading to partial gastric resection. They were diagnosed as having CF with positive sweat tests at the advanced ages of 45 and 43 years, respectively. Later on genotyping revealed compound heterozygosity for F508del and 2789+5G→A. Using NPD we demonstrated a CF-typical inhibition of the NPD by the Na channel blocker amiloride, although in both siblings the remaining CF...
Pediatric Research, 1989
Idiopathic juvemle osteoporosis 1s a rare bone disease of unknown pathomechanisin. Results of bon... more Idiopathic juvemle osteoporosis 1s a rare bone disease of unknown pathomechanisin. Results of bone histomorphometry are scant and controversial. Knowledne of bone resomtion and formation values could allow to choose ap ropriate-treatment. A Transiliac bone biopsy was done afPer double tetracycline labeling in 25 osteoporotic children aged 4-16.5 years before treatment.
Journal of the Neurological Sciences, 1989
Plasma membrane fluidity of intact nonmuscle cells from patients with myotonic dystrophy (MyD) wa... more Plasma membrane fluidity of intact nonmuscle cells from patients with myotonic dystrophy (MyD) was determined by fluorescence anisotropy measurements. Anisotropy values of the probe diphenylhexatriene were decreased in patient mononuclear cells (0.163 + 0.017, n = 13) versus controls (0.181 + 0.013, n = 13, P < 0.01) and in patient platelets (0.087 + 0.017, n = 9) versus controls (0.137 + 0.015, n = 9, P < 0.001) indicating increased plasma membrane fluidity in patient nonmuscle cells. Vasopressin plasma concentrations were increased in patients (7.4 + 2.1 pg/ml, n = 12) versus controls (4.5 + 1.4 pg/ml, n = 22, P < 0.0005), whereas serum osmolality was normal. These data are compatible with a decreased vasopressin sensitivity in MyD patients. Specific binding of ~25I-labelled vasoactive intestinal peptide (VIP) was decreased in patient mononuclear cells (2.9 + 0.9~o/106 cells, n = 8) versus controls (5.2 ___ 1.6~o/106 cells, n = 9, P < 0.005) and receptor affinity for VIP was decreased in patient mononuclear cells (K d = 0.26 + 0.05nM, n = 8) versus controls (Kd=0.19+0.02nM, n=9, P<0.005). In nonmuscle cells of MyD patients, increased membrane fluidity correlated with decreased receptor availability. This might explain the various endocrine defects described in MyD patients.
The Journal of Heart and Lung Transplantation, 2005
Pediatric lung or heart-lung transplantation (pL/HLTx) represents a challenge for an extraordinar... more Pediatric lung or heart-lung transplantation (pL/HLTx) represents a challenge for an extraordinary patient population. The requirements in immunosuppressive therapy and the associated risks result in disappointing long term results, especially when the life expectancy of this age group is taken into account. Also, due to the size of these patients, the donor pool for the individual recipient is significantly smaller, compared to that of adult patients. We performed a retrospective analysis of our patient cohort and compared the results of pediatric to adult patients. Methods: Out of a total of more than 660 L/HLTx recipients at our institution, 65 patients (pts.) belong to the pediatric group (Ͻ 20 years), with 46 pts. between 16 and 20 years of age, 15 pts. between 11 and 15, 2 between 5 and 10, and 2 between 0 and 5. 13 underwent transplantation in 2003, 7 up to Sept. in 2004. Due to the severe organ shortage, we have begun to routinely transplant reduced size (RS) organs in the pediatric LTx group since 2003. Main underlying disease was CF (45%). 1 year survival was 66Ϯ 7% vs. 77Ϯ2% in the adult group, 3 year survival was 56Ϯ8 %, compared to 69Ϯ2% survival in adults. Comparison of survival of RS size to non-RS size LTx shows no difference in outcome. As with all pediatric pts. undergoing solid organ transplants, we noted a significantly increased rate of rejections. Our data corroborate that pL/HLTx is associated with a differing scope of complications and therapeutic requirements. Since survival does not differ between RS LTx and non-RS LTx, RS LTx offers means to enlarge the donor pool for pediatric recipients. Due to the specific requirements pL/HLTx should be performed by specialized programs, and adapted treatment and monitoring regimes have to be developed, to increase the long term results following pL/HLTx.
The Journal of Heart and Lung Transplantation, 2009
hospital discharge. Adverse events using standardized definitions were analyzed as reported to EL... more hospital discharge. Adverse events using standardized definitions were analyzed as reported to ELSO. Results: Of 334 children who met the study inclusion criteria, the median age was 2.3 years (IQR 0.5 to 9.7); 162 (48.8%) were female, 209 (62.6%) were white, 135 (40.4%) had cardiomyopathy (CMP), and 111 (33.2%) received CPR prior to ECMO support. Overall 108 (32.3%) died on ECMO; 175 (52.4%) survived to hospital discharge including 76/135 (56.3%) with CMP and 99/199 (49.7%) with CHD (Pϭ0.27). Overall, the median duration of support was 22 days (95% CI 19 to 25). The following serious adverse events were reported: CNS injury (16.7%), infection (21.4%) and renal failure (8.4%). Survival to ECMO decannulation (PϽ0.01) and survival to hospital discharge (PϽ0.01) decreased significantly after 14 days on ECMO. Conclusions: ECMO is effective for short-term circulatory support but is not reliable for long-term circulatory support which is often necessary for children awaiting heart transplant. Half of all subjects bridged with ECMO failed to survive to hospital discharge with in-hospital mortality increasing significantly after 14 days of ECMO support. CNS injury, infection and renal failure were reported in a minority of patients on ECMO.
The Journal of Heart and Lung Transplantation, 2009
Background: Pediatric lung transplantation (LTx) remains a challenge for a highly selected group ... more Background: Pediatric lung transplantation (LTx) remains a challenge for a highly selected group of patients. The requirements for immunosuppressive therapy and the associated risks must be weighed against the long-term prognosis of this operation. Therefore, we retrospectively analyzed our experience after 53 lung and heart-lung transplantations (HLTx) in children. Methods: All pediatric patients Ͻ18 years of age who underwent LTx (n ϭ 37) and HLTx (n ϭ 16) at our institution were included in this study. We analyzed indications for transplantation, survival rates and causes of death. Herein we assess pediatric-specific challenges in comparison to adults. Results: Thirty-day mortality was 13.2%. Kaplan-Meier survival rates at 1, 3, 5 and 10 years were 69%, 64%, 44% and 39%, respectively. Main indications for transplantation were cystic fibrosis and congenital heart disease with Eisenmenger syndrome. Other diagnoses were retransplantation, primary pulmonary hypertension and pulmonary fibrosis. The main causes of death were infection and chronic graft failure. Reduced-size transplantation was performed in 42% of double-lung transplantation (DLTx) patients without negatively impacting survival. Six patients received pulmonary retransplantation, 1 of whom died early. Conclusions: Pediatric transplantation is a feasible therapeutic option when undertaken by an experienced team. It should be offered to the small patient population suffering from end-stage pulmonary disease. The limited number of pediatric donor organs can be overcome by using reduced-size organs. However, the management of pediatric-specific complications and therapeutic requirements is essential for positive long-term results after LTx in these patients.
Journal of Cystic Fibrosis, 2006
Infection, 2009
Purpose: We hypothesized that a single intravenous (iv) tobramycine infusion (treatment B) would ... more Purpose: We hypothesized that a single intravenous (iv) tobramycine infusion (treatment B) would have equivalent anti-infectious efficacy in chronic Pseudomonas aeruginosa (PA) infection in cystic fibrosis (CF) as the commonly performed treatment of three doses (treatment A). Toxicity and practicability may even be improved in the single-dose regimen. Methods: This was a randomized crossover study comparing outcome after 14 and 35 days. The primary end-point was a decrease in the leukocyte count, and the secondary end-points were clinical and lung function parameters, Pseudomonas quantification in sputum, and inflammation markers (immunoglobulin G, C-reactive protein) in serum. 30 patients (20 female, mean age 11.2 years, mean age range 1.7-18.1 years) received elective 14-day courses of treatments A or B, followed by the alternative treatment after a mean interval of 37 (± 21) weeks. Results: With the exception of PA density, there were no significant differences between both treatment strategies after 14 days of treatment. After 35 days of treatment, there were no significant changes in the leukocyte count and inflammation markers. Both treatment strategies reduced the bacterial load in the airways, as reflected by a decreased PA density in sputum. Nephrotoxicity was equal in both groups, with a transient slight elevation of urinary N-acetyl-b-glucosaminidase concentrations. Standard audiometry tests revealed no evidence of a hearing impairment in any patient following therapy. Mean body weight increased during the study period by 0.5 kg. Forced expiratory volume increased by approximately 5% of the predicted volume, forced vital capacity increased by 2% of predicted capacity, and forced mid expiratory flow rate increased by 7% (A) or 4% (B) of the predicted normal value, although these changes were not statistically significant. Conclusion: We conclude that tobramycin given in a daily single dose (with the advantage of being more practical in a home environment) has an efficacy equal to that of three daily doses in terms of elective antipseudomonal therapy in clinically stable patients with CF.
Journal of Cystic Fibrosis, 2006
Most of the studies on the psychological impact of cystic fibrosis (CF) were confined to the narr... more Most of the studies on the psychological impact of cystic fibrosis (CF) were confined to the narrow focus on whether or not CF is associated with psychopathology. Studies on coping as well as on quality of life have broadened this scope, so that aspects beyond clinical significance get more attention, today. A new German scale (FESUK) to assess social inhibition and anxiety not fulfilling criteria of anxiety disorder allowed to study another aspect of psychological functioning in that broadened scope. Methods: multi-centre investigation using FESUK as well as clinical measures (SASC-R, anxiety scale; SDQ, psychopathology scale; SSR, stress perception and coping scale; a disease-impact scale designed for the purpose of this study) crosssectional case-control design. Sample: N 68 eligible; N 47 CF youngsters (x 11.9y; 26 female) from 3 German CF centres; n 27 controls (not randomised) allowing to analyse 25 complete pairs. Results: Whilst the sick role as well as the widespread (moderate) parental overprotection may imply a greater shyness and social anxiety in CF children our results rather showed the opposite. CF youngsters scored lower than their casecontrols (n 25) as well as compared to the age-related references of the FESUK (n 47). This was true for the global score on social inhibition (p 0.036) as well as regarding social anxiety (p 0.016). FESUK scores significantly corresponded to SASC-R scores (rtt 0.44 0.67; all p <0.01). Conclusions: Our findings support previous reports indicating high resilience in CF patients.
European Respiratory Journal, 2005
Cystic fibrosis-related diabetes mellitus (CFRD) is the most frequent comorbidity in cystic fibro... more Cystic fibrosis-related diabetes mellitus (CFRD) is the most frequent comorbidity in cystic fibrosis. Its clinical relevance is stressed by the association with increased mortality, and decreased pulmonary and nutritional status. An annual oral glucose tolerance test (OGTT) is recommended as a screening test for CFRD, but this is often not realised because of its time-and resource-consuming nature. Therefore, alternative approaches are welcome. In 2003, the American Diabetes Association (ADA) lowered the cutoff point separating normal from elevated fasting plasma glucose from ,6.1 mmol?L-1 to ,5.6 mmol?L-1 , suggesting the performance of an OGTT only in those with impaired fasting glucose (IFG; range 5.6-6.0 mmol?L-1). The current authors tested whether this approach was reliable for the early identification of patients with CFRD. OGTTs from 1,128 patients (53% males; 47% females; median age 17.1 yrs) were available for analysis. A total of 101 (8.9%) OGTTs were classified as diabetic. The new ADA criteria for IFG increased the sensitivity to 82% (versus 65%) and decreased the specificity to 70% (versus 94%) compared with the old criteria used to identify patients with diabetic OGTTs. In conclusion, the American Diabetes Association approach of using impaired fasting glucose as an indication for performing selective oral glucose tolerance tests is definitely unsuitable when aiming at the early identification of patients with cystic fibrosis-related diabetes mellitus, and it cannot replace annual oral glucose tolerance tests.
Environmental Microbiology, 2012
Ex vivo transcriptional profiling reveals a common set of genes important for the adaptation of P... more Ex vivo transcriptional profiling reveals a common set of genes important for the adaptation of Pseudomonas aeruginosa to chronically infected host sites (2013) Environmental Microbiology, 15 (2), pp. 570-587. Ex vivo transcriptional profiling reveals a common set of genes important for the adaptation of Pseudomonas aeruginosa to chronically infected host sites
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Papers by Manfred Ballmann