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Biomedical subjects

F Ratjen

Publications and source records attributed to F Ratjen.

At least 19 recordsLinked to original sources
PubMed2005

DNA concentrations in BAL fluid of cystic fibrosis patients with early lung disease: influence of treatment with dornase alpha.

Recombinant DNase (dornase alpha) was shown to improve lung function and reduce pulmonary exacerbations in cystic fibrosis (CF) patients, but its effects on DNA concentrations in the lower airways remain unclear at the present time. As part of the Bronchoalveolar Lavage in the Evaluation of Anti-Inflammatory Treatment (BEAT) Study, a multicenter open study to evaluate the evolution of inflammation in CF patients with early lung disease and its modulation by dornase alpha treatment, we studied DNA concentrations in the bronchoalveolar lavage (BAL) fluid of 48 CF patients with mild lung disease. After the initial BAL, 29 patients received daily treatment with 2.5 mg of dornase alpha; 19 patients served as controls. BAL was repeated after 18 months in all patients. Mean BAL fluid DNA concentrations were not different between groups at baseline (mean +/- SD, 14.1 +/- 6.9 microg/ml for controls, and 17.6 +/- 11.2 microg/ml for the dornase alpha group), but higher than previously reported for infants with CF. A weak but positive correlation (P <0.01) was observed between the percentage of neutrophils in BAL fluid and DNA levels. On reassessment after 18 months, the percentage of neutrophils was not different between the two groups, but DNA had increased in controls, whereas decreased levels were observed in treated patients (P <0.03, t-test). DNA concentrations increased by more than 10 microg/ml in 7 of 19 controls compared to 2 of 29 CF patients treated with rhDNase (P=0.01, Fisher's test). Therefore, treatment with dornase alpha over 18 months reduces DNA load in BAL fluid, which may have a positive effect on the clearance of lower airway secretions.

Adolescent↗
PubMed2005

Prospective evaluation of emerging bacteria in cystic fibrosis.

BACKGROUND: Bacteria contribute considerably to the progression of lung disease in cystic fibrosis. In this prospective, multi-centre study, we aimed to evaluate the occurrence of emerging bacteria and the physicians' assessments of the clinical importance of these findings. METHODS: Twelve CF centres (total number of patients: 1419) reported the detection of any Stenotrophomonas maltophilia, Burkholderia cepacia complex, MRSA, Alcaligenes xylosoxidans, Klebsiella species and Mycobacteria during an observation period of 6 months. RESULTS: 213 specimens with emerging bacteria were reported from 145 different patients. The proportion of patients with emerging bacteria differed between centres (3-38%, mean: 12.6%) and increased with age. The predominant bacterium was S. maltophilia (n=106 positive specimens), followed by Klebsiellae (n=36), B. cepacia complex (n=31), A. xylosoxidans (n=16), Mycobacteria (n=11), MRSA (n=11), and others (n=2). In many instances the same microorganisms had already been reported earlier, indicating intermittent or chronic colonisation. The clinical status was reported to be stable in 70% of patients, and antibiotic treatment was anticipated for 46% of positive specimens. Comparison of clinical data to age matched controls did not reveal any significant differences with regard to pulmonary and nutritional status prior to detection of emerging bacteria. CONCLUSION: These data suggest a high variability between centres regarding the prevalence of emerging bacteria. Most patients maintained a stable clinical condition during the 6-month study period despite being colonised with emerging bacteria.

Adolescent↗
PubMed2005

High-dose corticosteroid therapy for bronchiolitis obliterans after bone marrow transplantation in children.

Bronchiolitis obliterans (BO) is a rare but serious complication of paediatric allogenic bone marrow transplantation (BMT). Currently, there is no clear evidence that therapeutic interventions have a positive impact on the course of the disease. We here report our experience with high-dose pulse methylprednisolone therapy in children after BMT. Nine patients fulfilling clinical and radiologic signs of BO were included in this analysis. The total amount of treatment cycles with pulse methylprednisolone therapy ranged from 1 to 6 cycles (median four cycles). Oxygen saturation increased significantly with normalization of oxygen saturation at the end of therapy in all individuals. Normal oxygen saturation was maintained in all but one patient during follow-up (mean follow-up period 42 {plus/minus} 20 months, range 19-67 months). Forced expiratory volume in 1 s (FEV1) was within the normal range prior BMT and significantly diminished at the time of BO diagnosis. Treatment led to stabilization of lung function, with a significant improvement of FEV1 after 2 months. In all, 7/9 patients remained in clinically stable condition without further deterioration of lung function during follow-up. These data would suggest that anti-inflammatory therapy may be a valuable treatment option in paediatric patients with bronchiolitis obliterans after BMT.

Adolescent↗
PubMed2005

[Cystic fibrosis modifying genes].

Cystic fibrosis is a common autosomal recessive disease that is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. The CFTR gene encodes a membrane-bound chloride ion channel. CFTR gene mutations cause alterations in fluid and salt secretion of various tissues. The CF phenotype is highly variable even in siblings and twins carrying the same CFTR mutations. The course of CF pulmonary disease is modulated by both environmental and genetic factors independent of CFTR. This review summarises association studies that focused on disease modifier genes in CF. Understanding the molecular and cellular basis of the genotype-phenotype associations will help to better understand the disease and to identify new targets for therapeutic interventions in CF.

Cystic Fibrosis↗
PubMed2005

Oral L-arginine supplementation in cystic fibrosis patients: a placebo-controlled study.

Exhaled nitric oxide (eNO) is decreased in cystic fibrosis (CF). The effect of oral L-arginine, the precursor of enzymatic nitric oxide (NO) formation, on airway NO in patients with CF was studied. In a pilot study, oral L-arginine was given in a single dose of 200 mg x kg(-1) body weight to eight healthy controls and eight CF patients. Subsequently, the same L-arginine dose was given to 10 patients with CF (five females) t.i.d. for 6 weeks in a randomised double-blind placebo-controlled crossover study. A single dose of oral L-arginine resulted in a 5.5-fold increase of L-arginine in plasma and a 1.3-fold increase of L-arginine in sputum after 2 h. Maximum eNO, within 3 h of L-arginine intake, increased significantly in both CF patients (5.4+/-2.1 ppb versus 8.3+/-3.5 ppb) and controls (18.0+/-8.1 ppb versus 26.4+/-12.3 ppb). Supplementation of L-arginine for 6 weeks resulted in a sustained increase in eNO compared to placebo (9.7+/-5.7 ppb versus 6.3+/-3.1 ppb). An effect of L-arginine supplementation on forced expiratory volume in one second was not observed. These data indicate that airway nitric oxide formation in cystic fibrosis patients can be augmented with oral L-arginine supplementation.

Adolescent↗
PubMed2004

Nodular pulmonary vasculitis in a twelve-year-old boy.

A 12-year-old boy presented with left shoulder pain during physical exercise and complained of uncommon sweating and fatigue. Diagnostic evaluation revealed a solitary pulmonary nodule in the left upper lobe. All laboratory values were within normal limits, except for an elevated level of antineutrophil cytoplasmic antibodies directed against myeloperoxidase (p-ANCA). Surgery was performed, and pathological examination showed a localized granulomatous vasculitis. Antineutrophil cytoplasmic antibodies directed against affinity purified proteinase 3 (p-ANCA) concentrations returned to baseline within 6 months, and the patient has done well during a follow-up period of 2 years. While nodular vasculitis is known to occur in Wegener's granulomatosis, to the best of our knowledge, this case represents the first c-ANCA negative primary pulmonary vasculitis in childhood.

Antibodies, Antineutrophil Cytoplasmic↗
PubMed2003

High prevalence of human metapneumovirus infection in young children and genetic heterogeneity of the viral isolates.

RNA of the newly identified human metapneumovirus (HMPV) was detected in nasopharyngeal aspirates of 11 of 63 (17.5%) young children with respiratory tract disease. Markers of infection caused by another member of the Pneumovirinae subfamily of the family Paramyxoviridae, respiratory syncytial virus (RSV), were identified in 15 of these patients (23.8%). Three patients were simultaneously infected with HMPV and RSV. Studies of the clinical characteristics of HMPV-infected children did not reveal any difference between HMPV-infected patients and a control population of RSV-infected patients with regard to disease severity, but the duration of symptoms was significantly shorter for HMPV-infected patients. Phylogenetic analysis of the amplified viral genome fragments confirmed the existence and simultaneous circulation within one epidemic season of HMPV isolates belonging to two genetic lineages.

Genetic Variation↗
PubMed2003

Flexible endoscopy of paediatric airways.

Paediatric fibreoptic bronchoscopy is used for ever wider indications, and increasingly used in many contexts, including paediatric and neonatal intensive care. The report of this Task Force contains an overview on the current applications of paediatric bronchoscopy. The report discusses the facilities and equipment needed for the procedure, including the newly developed bronchoscopes which are allowing intervention even in very small children. The indications of both flexible and rigid bronchoscopes in the context of newer and smaller flexible endoscopic equipment are also considered. The care of the instruments, including disinfection and sterilisation, is fully documented. Patient management is described, including the relative merits of conscious sedation and general anaesthesia, as well as special settings for the procedure, including the needs in intensive care. Special procedures, increasingly performed bronchoscopically are described. These include bronchoalveolar lavage, endobronchial and transbronchial biopsy, laser therapy, bronchography, and endoscopic intubation and drug therapy. Finally, neonatal bronchoscopy is discussed, and the ethics of bronchoscopic procedures, including bronchoscopic research in children. Advances in instrumentation, and also improved anaesthetic techniques, allow fibreoptic bronchoscopy to be safely performed in even very small, sick infants, provided proper precautions are taken.

Airway Obstruction↗
PubMed2003

Bronchoalveolar lavage fluid findings in children with hypersensitivity pneumonitis.

Bronchoalveolar lavage (BAL) has been shown to be useful in the diagnosis of hypersensitivity pneumonitis (HP) in adults, the typical constellation being lymphocytosis with a decrease in the CD4/CD8 ratio. Only limited data exist for the diagnostic value of BAL cytology in paediatric patients with this disorder. Children aged 6-15 yrs (n=9) with acute HP were studied. BAL was performed before initiation of anti-inflammatory treatment via a flexible bronchoscope in the middle lobe with 3 mL x kg body weight(-1) normal saline warmed to body temperature; BAL cytology and lymphocyte surface markers were compared with age-matched controls. The percentage of lymphocytes was significantly increased in all patients with HP. No significant differences were observed in the CD4/CD8 ratio between children without lung disease and those with HP. Increased expression of human leukocyte antigen-DR was found in seven of eight children with HP, whereas natural killer cells were elevated in five of eight children. Every patient had at least one of these two alterations in BAL fluid in addition to lymphocytosis. It was concluded that while lymphocytosis is generally present in children with hypersensitivity pneumonitis, the CD4/CD8 ratio is not increased in these patients. Assessing natural killer cells and human leukocyte antigen-DR expression appears to be a helpful adjunct in the diagnosis of paediatric patients with this disorder.

Alveolitis, Extrinsic Allergic↗
PubMed2002

Nasal nitric oxide levels in cystic fibrosis patients are associated with a neuronal NO synthase (NOS1) gene polymorphism.

Nitric oxide (NO) plays an important role in a number of physiological processes in the airways, including host defense. Although the exact cellular and molecular source of the NO formation in airways is unknown, there is recent evidence that neuronal NO synthase (NOS1) contributes significantly to NO in the lower airways of cystic fibrosis (CF) patients. NOS1 protein has been shown to be expressed in nasal epithelium, suggesting an involvement of NOS1-derived NO in upper airway biology. We here hypothesized that nasal NO concentrations in CF patients are related to genotype variants in the NOS1 gene. Measurements of nasal NO concentration and pulmonary function were performed in 40 clinically stable CF patients. Genomic DNA from all patients was screened for an intronic AAT-repeat polymorphism in the NOS1 gene using polymerase chain reaction and simple sequence length polymorphism (SSLP) analysis. The allele size at that locus was significantly (P = 0.001) associated with upper airway NO. Mean (+/- SD) nasal NO concentrations were 40.5 +/- 5.2 ppb in CF patients (n = 12) with high repeat numbers (i.e., both alleles > or =12 repeats) and 72.6 +/- 7.4 ppb in patients (n = 28) with low repeat numbers (i.e., at least one allele <12 repeats). Furthermore, in the group of CF patients harboring NOS1 genotypes associated with low nasal NO, colonization of airways with P. aeruginosa was significantly more frequent than in patients with NOS1 genotypes associated high nasal NO concentrations (P = 0.0022). We conclude that (1) the variability in CF nasal NO levels are related to naturally occurring variants in the NOS1 gene, and (2) that nasal NOS1-derived NO affects the susceptibility of CF airways to infection with P. aeruginosa.

Adolescent↗
PubMed2002

[Pulmonary metabolism of nitric oxide (NO) in patients with cystic fibrosis].

Airway nitric oxide (NO) and its metabolites are involved in a number of physiological and pathophysiological processes. For instance, NO relaxes airway smooth muscle, improves airway ciliary motility, has antimicrobial effects, and increases expression of the CFTR (cystic fibrosis transmembrane regulator) protein in airway epithelial cells. Of interest, concentrations of NO and of bioactive S-nitrosothiols (SNOs) are decreased in the airways of patients with cystic fibrosis (CF). When compared to patients with relatively normal pulmonary NO formation, CF patients with low NO-concentrations have a significantly reduced pulmonary function and a higher frequency of bacterial colonisation of the airways with pathogens such as P. aeruginosa. As a consequence of these observations clinical trails have now been initiated to study possible effects of an augmented bronchial NO-concentration in CF-patients.

Cystic Fibrosis↗
PubMed2002

Matrix metalloproteases in BAL fluid of patients with cystic fibrosis and their modulation by treatment with dornase alpha.

BACKGROUND: Matrix metalloproteinases (MMPs) are involved in the remodelling and degradation of extracellular matrix and may play a role in pulmonary tissue destruction in cystic fibrosis (CF). METHODS: Bronchoalveolar lavage (BAL) fluid levels of MMP-8, MMP-9, and their natural inhibitor TIMP-1 were measured on two occasions within 18 months in 23 children with mild CF, 13 of whom were treated with DNase. RESULTS: MMP-8 (39.3 (6.8) v 0.12 (0.01) ng/ml), MMP-9 (58.0 (11.4) v 0.5 (0.02) ng/ml), and the molar ratio of MMP-9/TIMP-1 (0.36 (0.05) v 0.048 (0.01)) were significantly higher in patients with CF than in control children without lung disease. Gelatine zymography showed the typical banding pattern of neutrophil derived MMP-9, including 130 kDa NGAL-MMP-9 complex and 92 kDa latent MMP-9 bands; 85 kDa bands (corresponding to active MMP-9) were seen in all patients. There was a close correlation between BAL fluid concentrations of MMPs and alpha(2)-macroglobulin, a marker of alveolocapillary leakage. After 18 months MMP levels were increased in untreated patients and decreased in patients treated with DNase. CONCLUSIONS: Uninhibited MMPs may contribute to pulmonary tissue destruction even in CF patients with mild lung disease that may be positively affected by treatment with DNase.

Adolescent↗
PubMed2002

Surfactant in children with malignancies, immunosuppression, fever and pulmonary infiltrates.

In children with malignancies and immunosuppression, significant morbidity and mortality result from respiratory complications. The aim of the present study was to investigate whether or not this is associated with altered surfactant components or functions. Bronchoalveolar lavage fluid from 24 children with malignancies, immunosuppression, pulmonary infiltrates and fever unresponsive to empirical antibiotic treatment were compared to that from 24 healthy children. Levels of surfactant protein (SP) A and D and their binding capacity for Pseudomonas aeruginosa, as well as levels of SP-B and SP-C, were assessed by enzyme-linked immunosorbent assay. The large and small surfactant aggregate forms were separated and the biophysical activity of large surfactant aggregates was determined using a pulsating bubble surfactometer. Compared to healthy controls, SP-A levels were increased four-fold, the increase being most pronounced in those children with pathogens recovered from their bronchoalveolar lavage fluid. In children with malignancies, levels of SP-C were increased two-fold and of small surfactant aggregates five-fold. No differences were observed in levels of SP-B or SP-D, binding capacity of SP-A or SP-D or the surface activity of large surfactant aggregates. The increased levels of surfactant protein A, particularly in children with recovered microorganisms, and unchanged binding capacity of surfactant protein A are consistent with upregulated local host defence mechanisms. Increased surfactant protein A and C may also be responsible for the conserved biophysical activity of surfactant in children with malignancies, immunosuppression, pulmonary infiltrates and fever.

Adolescent↗
PubMed2002

Bronchial reactions to the inhalation of high-dose tobramycin in cystic fibrosis.

It has been established that inhaled tobramycin has a positive effect on respiratory function in Pseudomonas-aeruginosa positive patients with cystic fibrosis (CF). In a previous study the authors reported that low-dose tobramycin preparations containing the preservative phenol caused significant bronchial obstruction. Recently, high-dose tobramycin preparations with and without preservatives/phenol have become available. To assess the airway response to these preparations flow/volume curves in 12 patients with CF (four males, eight females, mean age+/-SD=19.0+/-7.4 yrs) were measured. The tobramycin preparations: Nebicina 2.0 mL (150 mg, containing the preservative phenol), Distobram 3.0 mL (150 mg, containing preservatives), Tobi 5.0 mL (300 mg), Tobi 2.5 mL (150 mg), and Tobi 5.0 mL, were used after bronchodilator application. Immediately and/or 5 min after the tobramycin inhalations there was a significant fall in lung function with the different preparations. There was no significant difference between preparations with and without preservatives/phenol. The bronchial obstruction was comparable to that observed after the inhalation of low-dose tobramycin and after saline. After 10 min of inhalation, the lung function returned to baseline values. Most patients preferred the Tobi 2.5 mL and disliked the Nebicina preparation due to the unpleasant taste. Preceding treatment with bronchodilators prevented the decline in lung function. Assessment of bronchial response at the first nebulisation of high-dose tobramycin and, in case of significant obstruction, beta-agonists in combination with the antibiotic inhalation are recommended.

Administration, Inhalation↗