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.

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.

Effect of 3 weeks' rehabilitation on neutrophil surface antigens and lung function in cystic fibrosis.

Neutrophil leukocytes have been shown to be the predominant cells in inflammatory airway infiltrates of cystic fibrosis (CF) patients. The aim of this study was to investigate the effect of rehabilitation on neutrophil surface antigen expression and lung function in healthy controls and stable CF patients with moderately severe disease. The absolute number of neutrophils and the level of surface marker expression on neutrophils were elevated in 12 CF patients compared with eight healthy controls. The level of neutrophil surface marker expression was similar in bronchoalveolar lavage fluid from CF patients who underwent bronchoscopy for diagnostic or therapeutic reasons. After 3 weeks' rehabilitation, there was a significant reduction in the expression of CD11b (complement receptor type 3), CD13 (aminopeptidase N), CD32 (low-affinity Fc gamma chain receptor II), and CD35 (complement receptor type 1) in only the CF patients. At the same time, lung function improved significantly. The increase in forced vital capacity correlated significantly with the decrease in CD32 level. These results demonstrate that rehabilitation in a specialized clinic can reduce the neutrophil-dominated inflammation and improve the lung function of stable CF patients with moderately severe disease even without changing any medications.

Cytokine-mediated Bax deficiency and consequent delayed neutrophil apoptosis: a general mechanism to accumulate effector cells in inflammation.

Neutrophils are important effector cells in immunity to microorganisms, particularly bacteria. Here, we show that the process of neutrophil apoptosis is delayed in several inflammatory diseases, suggesting that this phenomenon may represent a general feature contributing to the development of neutrophilia, and, therefore, in many cases to host defense against infection. The delay of neutrophil apoptosis was associated with markedly reduced levels of Bax, a pro-apoptotic member of the Bcl-2 family. Such Bax-deficient cells were also observed upon stimulation of normal neutrophils with cytokines present at sites of neutrophilic inflammation, such as granulocyte and granulocyte-macrophage colony-stimulating factors, in vitro. Moreover, Bax-deficient neutrophils generated by using Bax antisense oligodeoxynucleotides demonstrated delayed apoptosis, providing direct evidence for a role of Bax as a pro-apoptotic molecule in these cells. Interestingly, the Bax gene was reexpressed in Bax-deficient neutrophils under conditions of cytokine withdrawal. Thus, both granulocyte expansion and the resolution of inflammation appear to be regulated by the expression of the Bax gene in neutrophils.

A childhood asthma death in a clinical trial: potential indicators of risk.

A 9 yr old girl with a history of eczema and asthma was admitted to our specialist asthma service and recruited into a trial designed to investigate systemic as well as therapeutic benefits of inhaled corticosteroids. Eight months after referral the patient died from an acute asthma attack. This childhood asthma death during an inhaled steroid trial has facilitated identification of risk factors. Despite good clinical response to inhaled corticosteroids, the patient was distinguishable from the other patients by: increased variability of the morning and evening peak flow rates; increased reactivity, though not sensitivity, to histamine; and an unprecedented rise in serum soluble interleukin-2 receptor levels immediately after commencing inhaled steroids. The immunological basis for corticosteroid resistance and immunohistochemical studies on postmortem specimens from asthma deaths suggest that T-cell activation markers may be indicators of the fatality prone asthmatic.

Differential IgE recognition of recombinant Aspergillus fumigatus allergens by cystic fibrosis patients with allergic bronchopulmonary aspergillosis or Aspergillus allergy.

Allergic bronchopulmonary aspergillosis (ABPA), an intense inflammatory reaction to Aspergillus in the lung, is recognized as a severe complication in patients with cystic fibrosis (CF). The diagnosis of ABPA in CF patients sensitized to Aspergillus fumigatus is complicated by interfering laboratory and clinical findings shared by the diseases. We have used cDNA encoding A. fumigatus allergens which were cloned from a cDNA library displayed on phage surface to produce recombinant proteins in Escherichia coli. Differential IgE responses to the allergens in A. fumigatus-sensitized CF patients with or without ABPA and CF controls without sensitization to A. fumigatus were demonstrated. A secreted ribotoxin (rAsp f 1) and a peroxisomal protein (rAsp f 3) were recognized by sera from A. fumigatus-sensitized CF-patients with or without ABPA. An intracellular manganese superoxide dismutase (rAsp f 6) and rAsp f 4, a protein with unknown function, were recognized exclusively by IgE from sera of CF patients with ABPA. Therefore, Asp f 4 and Asp f 6 represent specific markers for ABPA and allow a sensitive, fully specific diagnosis of the disease. The data suggest distinct IgE responses to colonization of the bronchial tree in CF patients with ABPA or A. fumigatus allergy and therefore a differential recognition of the pathogen in the two IgE-related inflammatory diseases.

The anaerobic threshold in cystic fibrosis: comparison of V-slope method, lactate turn points, and Conconi test.

Physical exercise can improve sputum clearance in patients with cystic fibrosis (CF). To set up individual training protocols it is desirable to know the anaerobic threshold (AT). Established methods such as blood lactate measurements and ergometry can only be performed in specialized centers. Conconi showed that the heart rate threshold (HRT), i.e., the deflection point from the linear relationship between work load and heart rate, correlated significantly with the AT in healthy adults. To assess the reliability of the HRT in CF, we performed ergometry in 32 CF patients (mean age, 21.0 +/- 5.5 years; mean Shwachman score, 77.8 +/- 12.0) according to the Conconi protocol. The HRT was compared with the aerobic threshold (AeT) as determined by the V-slope method and with two turn points in the lactate performance curve (LTP1, LTP2). An HRT could be obtained in only 17 of the 32 patients (53%). In these 17 patients there was a significant correlation between HRT and the other thresholds, but the absolute values for the AT differed considerably: The mean HRT was 132% higher than the AeT according to Beaver, 107% higher than LTP1, and 19% higher than LTP2. Exercise protocols that rely solely on the HRT in CF will lead to excessive exertion during exercise training programs in these patients. According to these results the HRT of Conconi is not a suitable method to determine appropriate exercise levels in CF training programs and might even be harmful in CF patients. These results also indicate the need to test the reliability of a diagnostic procedure that has been developed only for healthy people.

Efficacy trial of bioresonance in children with atopic dermatitis.

Single case reports and uncontrolled studies claim significant improvements in patients with atopic diseases treated with bioresonance therapy, also called biophysical information therapy (BIT). To assess the efficacy of this alternative method of treatment, we performed a conventional double-blind parallel group study in children hospitalized for long-lasting atopic dermatitis. Over a period of 1.5 year, 32 children with atopic dermatitis, age range 1.5-16.8 years and hospitalized for 4-6 weeks at the Alpine Children's Hospital Davos, Switzerland, were randomized according to sex, age and severity of the skin disease to receive conventional inpatient therapy and either a putatively active or a sham (placebo) BIT treatment. Short- and long-term outcome within 1 year were assessed by skin symptom scores, sleep and itch scores, blood cell activation markers of allergy, and a questionnaire. Hospitalization and conventional therapy in a high altitude climate resulted in immediate and sustained amelioration of the disease state in both the BIT-treated and sham-treated groups. BIT had no significant additive measurable effect on the outcome variables determined in this study. The statement by protagonists of this alternative form of therapy that BIT can considerably influence or even cure atopic dermatitis was not confirmed using for the first time a conventional double-blind study design. Considering the high costs and false promises caused by the promotors of this kind of therapy, it is concluded that BIT has no place in the treatment of children with atopic dermatitis.

Aerosol therapy in patients with cystic fibrosis.

Aerosol therapy is one of the mainstays of treatment, together with regular physiotherapy, in patients with cystic fibrosis. Inhalation can contribute to hydration of the epithelial lining fluid as well as delivering different drugs directly to the lungs. Topically administered antibiotics can protect the lungs from Pseudomonas infection, recombinant DNase, amiloride and beta-agonists can have a positive effect on the mucociliary clearance, and steroid inhalations can reduce inflammation. Therefore, all these drugs are part of a comprehensive treatment strategy contributing to improvement in lung function and quality of life. Gene therapy and pharmacological correction of the chloride channel defect are perspectives for the future. Aerosol therapy, however, is somewhat cumbersome and requires strict patient education.

One year follow-up study of endocrine and lung function of asthmatic children on inhaled budesonide.

Inhaled corticosteroids have become a mainstay in the management of chronic asthma. Their use had been considered safe, although some degree of adrenal suppression has been demonstrated after 2 and 4 weeks of treatment with either 400 microg x day(-1) of beclomethasone dipropionate or budesonide. To weigh the benefits and risks of long-term treatment, 12 children with moderately severe asthma were assessed in a follow-up study on budesonide 200 microg b.i.d. After 1 yr, the nocturnal cortisol production was significantly reduced by 19%, but no greater compared to 2 and 4 weeks of treatment. Growth and growth hormone levels were normal. Lung function tests were significantly better, not only versus baseline values but also versus 2 and 4 weeks of treatment. We conclude that systemic effects of inhaled corticosteroids in conventionally low doses do not accumulate with length of treatment, whilst lung function parameters will continue to improve. Therefore, inhaled corticosteroids once started in asthmatic children not controlled on other medications should be continued, but their use should be carefully considered and the minimal dose required to control the asthma employed.

Skin test reactivity to recombinant Aspergillus fumigatus allergen I/a in patients with cystic fibrosis.

We evaluated the diagnostic value of recombinant Aspergillus fumigatus allergen I/a (rAsp f I/a) for skin testing in cystic fibrosis (CF) patients with allergic bronchopulmonary aspergillosis (ABPA), allergy to A. fumigatus and in CF controls not allergic to A. fumigatus. Skin prick test reactions to rAsp f I/a were 8.5-fold stronger in A.-fumigatus-allergic and 3.3-fold stronger in ABPA patients compared to the CF controls. Three out of 6 well-characterized ABPA patients had positive skin prick test reactions to rAsp f I/a; the same number reacted to crude A. fumigatus extracts. The skin prick test results to rAsp f I/a were significantly correlated with those to crude and commercial preparations. According to these results, rAsp f I/a represents a defined allergen that provides the possibility to perform skin prick tests in CF patients in a highly standardized way. In future, a larger panel of recombinant allergens might also pick up those CF patients with ABPA and allergy to A. fumigatus who did not react to this single allergen.

Bronchial constriction after nebulized tobramycin preparations and saline in patients with cystic fibrosis.

UNLABELLED: To assess the airway response to inhaled tobramycin we measured flow volume curves in 12 patients with cystic fibrosis. Immediately and/or 2 min after tobramycin inhalations there was a significant fall in lung function regardless of the concentration used; isotonic saline caused similar obstruction but not a complete cessation of peripheral airflows. The baseline oxygen saturation was significantly correlated with the fall in lung function. Ten minutes after inhalation lung function tests returned to baseline values. CONCLUSION: As salbutamol could significantly reduce airway obstruction tobramycin should always be inhaled in combination with a bronchodilator.

Pilot study to assess the effect of inhaled corticosteroids on lung function in patients with cystic fibrosis.

OBJECTIVE: To determine the effect of inhaled corticosteroids on lung function in patients with cystic fibrosis. STUDY DESIGN: We report a pilot study of 49 patients with cystic fibrosis and moderate to severe bronchial obstruction (forced expiratory volume in 1 second < or = 55% of the predicted value); 25 patients were given inhaled corticosteroids for 30 days (1500 micrograms of beclomethasone via spacer), and 24 patients had the same standard treatment but no inhaled corticosteroids. RESULTS: Forced vital capacity, forced expiratory volume in 1 second, and airway resistance showed significant improvement in both study groups, but thoracic gas volume and the diffusion capacity of the lung for carbon monoxide improved significantly only in the group given inhaled corticosteroids. When concomitant medications were taken into account, analysis of variance confirmed a significant effect of inhaled corticosteroids on the improvement of thoracic gas volume. CONCLUSION: Inhaled corticosteroids in combination with standard treatment can contribute to the improvement of lung function in patients with cystic fibrosis and moderate to severe bronchial obstruction. Our preliminary data seem encouraging enough to warrant a multicenter, long-term, blind control study.

Nocturnal cortisol secretion in healthy adults before and after inhalation of budesonide.

We have previously demonstrated dose-dependent nocturnal cortisol suppression by inhaled beclomethasone and budesonide in asthmatic children. This has now been confirmed in a controlled study. Eighteen healthy adults inhaled either a single evening dose of 400 micrograms budesonide or placebo or 400 micrograms budesonide twice daily for 2 wk. Overnight blood samplings for cortisol and adrenocorticotropic hormone were taken at the beginning of the trial, at the end of the treatment period, and after stopping the medications. Compared with placebo, the nocturnal cortisol production was significantly reduced by 40% after a single dose of budesonide (p = 0.020) and by 37% after 2 wk of budesonide (p = 0.045). These data indicate that there is a single-dose rather than a cumulative suppressive effect of inhaled corticosteroids using the specific dose and regimen studied in this protocol. The effect is not related to the underlying problem, namely asthma. The clinical relevance of these findings can only be elucidated in long-term follow-up studies. We believe that our findings explain the recent identification of abnormalities in bone turnover on inhaled corticosteroids in the absence of other systemic effects. The findings emphasize the need for a cautious step-wise approach to asthma therapy.

Identification of allergic bronchopulmonary aspergillosis in cystic fibrosis patients by recombinant Aspergillus fumigatus I/a-specific serology.

Before specific therapy, such as oral corticosteroids, can be commenced it is essential to distinguish full-blown allergic bronchopulmonary aspergillosis (ABPA) from allergy to A. fumigatus in patients with cystic fibrosis (CF). For this purpose we have evaluated the diagnostic value of recombinant A. fumigatus allergen I/a (rAsp f I/a)-specific serology in 55 patients with CF. Based on clinical presentation and laboratory data, 10 CF patients had ABPA, 27 had Aspergillus allergy, and 18 were not allergic to A. fumigatus (CF control group). The serologic assays revealed a 10-fold increase in rAsp fI/a-specific IgE, a 5-fold increase in rAsp fI/a-specific IgG1, and a 4-fold increase in rAsp fI/a-specific IgG4 antibodies in ABPA patients compared with the Aspergillus allergy and CF control groups. Sera from 11 CF patients were analyzed without knowledge of their clinical state or diagnosis of ABPA. All ABPA patients (4 of 11) were accurately identified. We conclude that rAsp fI/a-specific serology is a highly sensitive and specific test that can be used to identify ABPA reliably in CF patients.

Compliance with therapy in children with respiratory diseases.

Compliance with medical treatment was evaluated in 89 children and adolescents with respiratory diseases using two methods of assessment: a double blinded covert recording of the use of an air compressor for nebulization of drugs and the determination of theophylline levels in serum. In the covert monitoring of inhalation the overall compliance with the prescribed medication was 47.6%. In the open randomized theophylline trial, 56%-71% of the patients (according to uncontrolled or controlled intake of the drug) received a dosage of theophylline which was too low to achieve a sufficient serum level in the range of 10-20 mg/l. This, however, was also due to the fact that in 72% of the cases physicians prescribed doses which were substantially below the recommended amount of drug according to age and weight. It is, therefore, concluded that compliance of medication is based on the patients adherence to the medication, to the efficacy of the drug itself and the attitude of the physician.

High altitude climate therapy reduces peripheral blood T lymphocyte activation, eosinophilia, and bronchial obstruction in children with house-dust mite allergic asthma.

Asthma is a multifactorial disease of unknown etiology but often associated with atopy and inflammation. Previous studies in adult asthma have demonstrated the presence of activated T cells in blood, bronchoalveolar lavage (BAL) fluid, and bronchial tissue, and the relevance of their soluble products for eosinophil function. In view of these observations, it was hypothesized that similar pathogenetic mechanisms also occur in childhood asthma. In fact, peripheral blood T lymphocytes in 14 children with house-dust mite allergic asthma showed clear evidence of T cell activation as measured by the expression of CD25 and HLA-DR antigen. Without changing medication, significant reduction of the IL-2 receptor alpha-chain expression within the CD4+ lymphocyte population was observed after only 3 weeks of allergen avoidance. Within this time period, absolute and relative eosinophil numbers decreased to normal levels. After 5 weeks in an area of low house-dust mite exposure, lung function also presented evidence for clinical improvement of the asthmatic disease. These results indicate similar pathogenetic mechanisms in childhood and adult asthma. Furthermore, they suggest that allergen avoidance may contribute to the efficient therapy of asthma in patients with house-dust mite IgE-meditated allergy.

Aetiology of chronic suppurative lung disease.

Forty one (1%) of 4000 children referred for respiratory disease had chronic suppurative lung disease not due to cystic fibrosis. Further investigations showed congenital malformations in six (15%), primary ciliary dyskinesia syndrome in seven (17%), 11 had immunological abnormalities (27%), and two bronchiectasis due to aspiration (5%). Therefore the underlying cause for the disease was found in 63%. Identification of predisposing causes may facilitate prevention of further bronchial damage.