Felix Ratjen

Effect of inhaled tobramycin on early Pseudomonas aeruginosa colonisation in patients with cystic fibrosis

Early antibiotic treatment of airway colonisation with Pseudomonas aeruginosa can delay onset of chronic lung infection in patients with cystic fibrosis. Whether the pathogen is eradicated by this treatment is unclear. We successfully eradicated the organism in 14 of 15 patients with cystic fibrosis who had been colonised by P aeruginosa. Patients inhaled 80 mg tobramycin twice daily for 12 months. Eradication was confirmed by sequential respiratory cultures and serum antibody titres that were negative for P aeruginosa. Our antibiotic therapy regimen maintained pulmonary function at high levels.

Lipid-laden macrophages in bronchoalveolar lavage fluid as a marker for pulmonary aspiration

An increased lipid content in alveolar macrophages of bronchoalveolar lavage (BAL) fluid is thought to be a useful indicator for recurrent pulmonary aspiration. To assess whether pulmonary diseases unrelated to aspiration can raise the lipid content in alveolar macrophages, we evaluated Oil‐Red‐O‐stained smears of BAL fluid in 18 children aged 3–15 years undergoing elective surgery for nonpulmonary illnesses under general anesthesia and in 18 children aged 1–16 years who had pulmonary diseases without clinical evidence of aspiration (pneumonia, exogenous allergic alveolitis, or cystic fibrosis). A semiquantitative lipid‐laden macrophage (LLM) index was determined for each patient.

Decreased levels of nitrosothiols in the lower airways of patients with cystic fibrosis and normal pulmonary function

Airway S-nitrosothiols (SNOs) are naturally occurring bronchodilators. SNOs, nitrate, and nitrite were measured in bronchoalveolar lavage fluid of 23 patients with cystic fibrosis (CF) and mild pulmonary disease (aged 6-16 years) and 13 healthy children (aged 8-15 years). Concentrations of SNOs were decreased in the lower airways of patients with CF and mild pulmonary disease (median, range: 0, 0-320 nmol/L vs 80, 0-970 nmol/L) despite normal levels of the inert nitric oxide metabolites nitrate and nitrite (mean +/- SEM: 3.7 +/- 0.5 micromol/L vs 4.8 +/- 0.9 micromol/L). S-nitrosolation- mediated bioreactivities may be impaired by depletion of the CF airway SNO reservoir.

Effect of continuous antistaphylococcal therapy on the rate of P. aeruginosa acquisition in patients with cystic fibrosis.

Summary. Continuous therapy with antistaphylococcal antibiotics is advocated by some cystic fibrosis (CF) centers, but it is unclear whether this strategy favors early colonization with P. aeruginosa. We used the data base for the German Centers of the European Registry for Cystic Fibrosis (ERCF) to assess the effect of continuous antistaphyloccocal therapy on the rate of P. aeruginosa acquisition in CF patients. Patients included in this analysis had to be <u200918 years of age, P. aeruginosa‐negative prior to entry in the ERCF, and to have had at least 2 additional P. aeruginosa‐negative respiratory cultures while followed in the ERCF.

Influence of Interleukin-10 on Aspergillus fumigatus Infection in Patients with Cystic Fibrosis

Recent evidence suggests that genetic polymorphisms that affect the production of interleukin (IL)-10 may play a role in the response to pathogens in cystic fibrosis (CF). The present study was designed to investigate a possible association between alleles carried at position -1082 in the promoter region of the IL-10 gene and clinical data on 378 patients with CF. After adjustment for potential confounding variables, a significant relationship was found between the -1082GG genotype and both colonization with Aspergillus fumigatus and allergic bronchopulmonary aspergillosis. In addition, higher serum levels of IL-10 were observed in patients colonized with A. fumigatus. These results suggest that polymorphisms in the promoter region of the IL-10 gene may influence the host response to A. fumigatus in the context of CF.

Cystic fibrosis lung disease: the role of nitric oxide.

This review summarizes current knowledge about the role of nitric oxide (NO) in cystic fibrosis (CF) lung disease. NO is endogenously produced by a group of enzymes, the NO synthases (NOSs). There are three isoforms of NOS, each encoded by different genes: neuronal (nNOS), immune or inducible (iNOS), and endothelial (eNOS) nitric oxide synthase.1 They all form NO and L‐citrulline by enzymatic oxidation of L‐arginine. This reaction requires a number of cosubstrates, including molecular oxygen and tetrahydrobiopterin. It is now known whether all three isoenzymes are constitutively expressed in cells of the respiratory tract and that their gene expression is inducible.2,3 NO production by iNOS, the “high‐output” NOS, is stimulated by bacterial lipopolysaccharide (LPS) as well as proinflammatory cytokines such as interleukin (IL)‐1γ, IL‐2, interferon (IFN)‐γ, and tumor necrosis factor (TNF). In contrast to nNOS and eNOS, activation of iNOS does not require an increase in intracellular Ca2+ concentration. Pediatr Pulmonol. 1999; 28:442–448.

Fractional analysis of bronchoalveolar lavage fluid cytology in cystic fibrosis patients with normal lung function

Cystic fibrosis (CF) is associated with a neutrophil dominated airway inflammation. So far bronchoalveolar lavage (BAL) studies in CF have used pooled BAL samples which may be more representative of the alveolar compartment rather than the airways. To assess whether the first sample of a BAL is more sensitive in the evaluation of airway inflammation, the authors have studied 105 stable CF patients aged 5-37 yrs with a mean forced expiratory volume in one second (FEV1) of 96+/-15% (mean+/-SD). BAL cytology of the first and pooled samples were compared to reference values obtained in children without respiratory disease. Absolute cell counts and the percentage of neutrophils were significantly increased in CF patients. If the 95% confidence interval was used as a cut-off point, 17/105 CF patients had a normal percentage of neutrophils in pooled BAL samples, but only three also had a normal percentage of neutrophils in the first BAL aliquot. Therefore, neutrophil dominated airway inflammation is more pronounced in the first, mainly bronchial, bronchoalveolar lavage sample suggesting that sequential analysis of bronchoalveolar lavage fluid may have a higher sensitivity to detect early inflammatory changes in CF patients.

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 6–15u2005yrs (n=9) with acute HP were studied. BAL was performed before initiation of antiinflammatory treatment via a flexible bronchoscope in the middle lobe with 3u2005mL·kg body weight−1 normal saline warmed to body temperature; BAL cytology and lymphocyte surface markers were compared with agematched 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 antigenDR 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 antigenDR expression appears to be a helpful adjunct in the diagnosis of paediatric patients with this disorder.

Anti-inflammatory cytokines in cystic fibrosis lung disease

Lung inflammation plays a pivotal role in the pathogenesis of airway disease in cystic fibrosis (CF). An imbalance between pro- and anti-inflammatory mediators has been observed and a deficiency in the anti-inflammatory response has been proposed, but this concept remains controversial. In the present study, the concentrations of two anti-inflammatory mediators, lipoxin A (LxA4) and Clara cell protein 10 (CC-10), were assessed in bronchoalveolar lavage fluid (BALF) of CF patients with a wide range of endobronchial inflammation and disease controls with neutrophilic inflammation unrelated to CF. No differences were observed in LxA4 BALF concentrations between CF patients and controls with a similar degree of neutrophilic airway inflammation. Concentrations were also similar in CF patients with mild versus more severe airway inflammation. In contrast, CC-10 concentrations were lower in CF patients, but this decrease was limited to patients with more intense airway inflammation. The present data do not support the concept of a primary defect in anti-inflammatory mediators in cystic fibrosis lung disease. Although Clara cell protein concentrations were found to be reduced, these alterations appear to be secondary to neutrophilic airway inflammation rather than due to a primary deficiency.

Airway nitric oxide in infants with acute wheezy bronchitis.

Concentrations of nitric oxide (NO) in exhaled air are increased in children and adults with asthma, and NO measurements are used as a non‐invasive marker to monitor airway inflammation in these patients. To define the role of NO in infants with acute wheezy bronchitis, we measured nasal and end‐tidal NO concentrations in 17 infants with acute virus‐associated wheezy bronchitis, in 22 term infants without respiratory disease, and in nine premature infants. Nasal NO measurements were performed with an olive placed in the infants nose; end‐tidal NO concentrations were assessed during tidal breathing through a snugly fitting face mask. Both end‐tidal NO concentrations and nasal NO concentrations were reduced in infants with acute wheezy bronchitis. There were no differences in NO concentrations between term infants and premature infants. Measurements by both techniques were highly reproducible, as assessed by repeated measurements three times daily on three consecutive days in eight premature infants. Reduced airway NO concentrations in infants with virus‐associated acute wheezy bronchitis are in contrast to findings in adults where both upper and lower airway NO levels are increased in patients with asthma. Whether this reflects a different inflammatory reaction to upper airway infections in acutely wheezy infants or pathophysiologic differences in airway response remains to be determined.