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Summary Background Low density eosinophils are more prominent in asthmatic patients compared with healthy subjects, LDH are metabolically more active and produce more tissue-injuring and spasmogenic proteins than normal cosinophils. Objective and methid With a method providing information about eosinophils of 12 different densities we were able to study eosinophil density characierislics in 24 young patients in detail with allergic asthma in a stable phase, and in 21 patients after a bronchial allergen challenge. Results Study of the eosinophil density profile of patients and healthy controls revealed two density populations. Patients had more low density eosinophils than controls. In the patients eosinophil density characteristics and in particular the number of low density eosinophils correlated strongly with both FEV1% predicted (ρ=−0.66, P < 0.001) and REV1/FVC (ρ=−0.47, P < 0.01) as well as with bronchial responsiveness to histamine (ρ=−0.68, P < 0.001) and house dust mite (ρ=−0.37, P < 0.05). Allergen induced bronchial reactions were associated with an increase in the number (P < 0.001) and percentage (P < 0.05) of low density eosinophils. A selective rise in the number of eosinophils collected from fractions with a low density accounted for the observed rise in the total number of eosinophils, Density changes did not differ between patients with an isolated early reaction and patients with both an early and a late reaction, nor was there a relation between the severity of the late reaction and the shift in eosinophil density. Conclusion In conclusion, peripheral blood eosinophil density characteristics and in particular numbers of low density eosinophils are closely related with indicators of the asthma severity under stable conditions. Allergen inhalation induces a further shift towards lower density suggesting additional activation of the eosinophils.

The present results support a role for epithelial cells in the activation of T cells in an apparent antigen-independent manner. The transient expression of CD25 indicates a short acting T cells activation. Possibly, this event primes T cells to respond swiftly upon antigen-specific stimulation or to synthesize mediators that affect the local milieu. The molecular mechanism of interaction, although not well defined possibly involves LFA3-CD2 interactions. In T cell activation, via LFA3-CD2 interaction, the density of presented LFA3 molecules is critical. With the increase in the level of expression of LFA3 by epithelial cells this critical density may have been reached. However, based on what is known about T cell activation and CD25 expression in particular it is likely that additional signals such as soluble mediators are required for T cell activation by epithelial cells. Whether this mode of activation occurs in vivo remains to be established by studying ex vivo and in situ material. Not much is known about the expression of LFA3 by epithelial cells in vivo, nor about the stimuli that induce the upregulation of LFA3. In preliminary experiments with fluorescence microscopy we found that neither TNF-alpha nor IL-1 beta induce LFA3 in the same fashion as IFN-gamma. In conclusion, T cell activation by epithelial cells could be an important feature in inflammatory and immunological processes in mucosal systems such as the bronchi and deserves further research.

The present results support a role for epithelial cells in the activation of T cells in an apparent antigen-independent manner. The transient expression of CD25 indicates a short acting T cells activation. Possibly, this event primes T cells to respond swiftly upon antigen-specific stimulation or to synthesize mediators that affect the local milieu. The molecular mechanism of interaction, although not well defined possibly involves LFA3-CD2 interactions. In T cell activation, via LFA3-CD2 interaction, the density of presented LFA3 molecules is critical. With the increase in the level of expression of LFA3 by epithelial cells this critical density may have been reached. However, based on what is known about T cell activation and CD25 expression in particular it is likely that additional signals such as soluble mediators are required for T cell activation by epithelial cells. Whether this mode of activation occurs in vivo remains to be established by studying ex vivo and in situ material. Not much is known about the expression of LFA3 by epithelial cells in vivo, nor about the stimuli that induce the upregulation of LFA3. In preliminary experiments with fluorescence microscopy we found that neither TNF-alpha nor IL-1 beta induce LFA3 in the same fashion as IFN-gamma. In conclusion, T cell activation by epithelial cells could be an important feature in inflammatory and immunological processes in mucosal systems such as the bronchi and deserves further research.

We have studied the effects of histamine on the proliferation and the intracellular cyclic adenosine monophosphate (cAMP) levels of T-lymphocyte clones (TLC) generated from bronchoalveolar lavage fluid (BALF) or peripheral blood (PB) from healthy and asthmatic persons. TLC from either compartment and from both groups of donors were heterogeneous in their response to histamine. In BALF-derived TLC, three types of responses were observed: histamine inhibited, stimulated, or did not modulate the anti-CD3-induced proliferation. Histamine directly and dose dependently inhibited the anti-CD3-induced proliferation of six (two asthmatic) of 12 CD4+ BALF TLC, stimulated two BALF TLC (both nonasthmatic), and did not modulate the proliferation of four BALF TLC. The maximal inhibition was 70%, the maximal stimulation 200%, both at 10(-3) M histamine. The stimulation of proliferation was associated with increased interleukin-2 (IL-2) production, whereas the inhibition of proliferation was associated with decreased IL-2 production and downregulation of IL-2 receptor expression. The inhibitory effects could be partly reversed by H2-receptor antagonists and could be mimicked by an H2-receptor agonist. In contrast, the stimulatory effect was not reversed or mimicked by H1 or H2 antagonists or agonists. The majority of CD4+ TLC responded to histamine with a rise in the intracellular cAMP levels. A rise in cAMP, however, was often but not always associated with an inhibition of proliferation. In addition, stimulation of proliferation occurred in the absence of a rise in cAMP. We compared cAMP rises in panels of TLC obtained with high cloning efficiencies from the PB from a healthy person and from an asthmatic person.(ABSTRACT TRUNCATED AT 250 WORDS)

We have prepared T-cell clones from bronchoalveolar lavage fluid (BALF) from four healthy, nonsmoking persons and from four patients with allergic asthma. T cells were cloned by direct limiting dilution and with the use of a fluorescent activated cell sorter with an automated cell deposition unit. T-cell clones from the blood (PB) were prepared as well. The cloning efficiencies of T cells from BALF ranged from 3 to 40% and were lower than those obtained from PB T cells (18 to 72%). The cloning conditions generated CD4+ as well as CD8+ clones. The very late antigen-4, VLA-4, was more frequently expressed on CD4+ T-cell clones from BALF than from the blood (P < 0.05). CD8+ clones from BALF were more frequently VLA-1+ than those from blood (P < < 0.01). Mitogen- and monoclonal antibody-driven proliferation of CD4+ clones showed that BALF clones were well responsive to proliferation stimuli similar to those from the blood. Analysis of interleukin-4 production by 10 BALF and 10 PB clones showed large variations between individual CD4+ clones (BALF: range, < 100 to 700 pg/ml; PB: range, < 100 to 1,100 pg/ml), indicating the generation of different types of clones, which was also clear from analysis of interferon-gamma production. The analysis of properties of BALF T-cell clones and their regulation will improve insight into immunologic reactions in the lungs

The effects of treatment with budesonide (200-mu-g twice daily) and terbutaline (500-mu-g four times daily) has been compared with the effects of placebo and terbutaline in 27 children with mild asthma, aged 7-14 years, in a double blind, randomised placebo controlled study over eight weeks. Bronchial responsiveness (PC20 histamine), lung function, the amplitude of diurnal variation in peak expiratory flow (PEF), and symptom scores were measured. Baseline FEV1 was over 70% predicted and PC20 histamine less than 8 mg/ml. Twelve children were treated with budesonide and terbutaline and 15 with placebo and terbutaline. After four and eight weeks of treatment the change in PC20 was significantly greater after terbutaline alone by 2.1 (95% CI 0.5-3.8) and 1.3 (95% CI 0.1-2.5) doubling doses respectively. Mean FEV1 did not change in either group. The change in afternoon and nocturnal PEF was significantly greater after budesonide and terbutaline than after terbutaline alone. The amplitude of diurnal variation in PEF did not change significantly in either group. Peak flow reversibility decreased in the budesonide group. There were no differences between treatments for cough and dyspnoea, but wheeze improved in the budesonide group. The children with mild asthma treated with budesonide and terbutaline showed improvement in bronchial responsiveness, afternoon and nocturnal PEF, and symptoms of wheeze and a fall in peak flow reversibility by comparison with those who received terbutaline alone.

The effects of treatment with budesonide (200 micrograms twice daily) and terbutaline (500 micrograms four times daily) has been compared with the effects of placebo and terbutaline in 27 children with mild asthma, aged 7-14 years, in a double blind, randomised placebo controlled study over eight weeks. Bronchial responsiveness (PC20 histamine), lung function, the amplitude of diurnal variation in peak expiratory flow (PEF), and symptom scores were measured. Baseline FEV1 was over 70% predicted and PC20 histamine less than 8 mg/ml. Twelve children were treated with budesonide and terbutaline and 15 with placebo and terbutaline. After four and eight weeks of treatment the change in PC20 was significantly greater after budesonide and terbutaline than after terbutaline alone by 2.1 (95% CI 0.5-3.8) and 1.3 (95% CI 0.1-2.5) doubling doses respectively. Mean FEV1 did not change in either group. The change in afternoon and nocturnal PEF was significantly greater after budesonide and terbutaline than after terbutaline alone. The amplitude of diurnal variation in PEF did not change significantly in either group. Peak flow reversibility decreased in the budesonide group. There were no differences between treatments for cough and dyspnoea, but wheeze improved in the budesonide group. The children with mild asthma treated with budesonide and terbutaline showed improvement in bronchial responsiveness, afternoon and nocturnal PEF, and symptoms of wheeze and a fall in peak flow reversibility by comparison with those who received terbutaline alone.

In their recent article on the effects of anti–tumor necrosis factor (TNF)in asthma, Erin and colleagues report that infliximab reduces the number of asthma exacerbations in symptomatic patients with moderate asthma who are taking inhaled corticosteroids (1). Although I recognize the need for new asthma treatment modalities, I have serious problems with the use of anti–TNFin this patient group as the drug can induce severe side effects. The dose of inhaled corticosteroids used was not high (in placebo and infliximab groups, respectively, 605 and 753 g/d of beclomethasone dipropionate equivalent). This can be considered a moderate dose, and increasing this dose or adding a longacting -agonist has been shown to result in a markedly better control of asthma (2) without a significant change in side effects. In addition, the study reports a decrease in exacerbations during a 12-wk period. Exacerbations were considered either moderate (two or more consecutive days with more symptoms or a decrease in morning PEF of more than 20%) or severe (requiring oral corticosteroids). In the placebo group, as many as 72% of the patients experienced an exacerbation, but it is not stated whether these were moderate or severe exacerbations. This is a rather high percentage, which suggests that all may have been moderate exacerbations. As severe exacerbations have a clearly higher impact on the patient, this information should be provided to judge the additional effect of infliximab. Anti–TNFis now used for patients with severe and invalidating complaints of Crohn’s disease or rheumatoid arthritis. Pulmonologists became familiar with this treatment when severe cases of tuberculosis were found in these patients. The incidence of anti–TNFinduced tuberculosis can be as high as 224/100,000 treated patients. Manifestations are often extrapulmonary, and in 24% of the cases there is disseminated disease (3, 4) with a significant risk of death. Physicians are now more aware of this problem, and when mycobacterial infections are suspected antituberculosis treatment is now advised. But there is still an increased risk as the protective effect of such treatment is estimated not to be higher than 60%. Therefore, in my opinion, anti–TNFshould be used with much care, and studies on the therapeutic value in asthma should be focused on patients with severe debilitating disease. In such cases, the effects of anti–TNFshould be studied in addition to the best current modalities, which are high doses of inhaled corticosteroids in combination with a long-acting -agonist.

Objective To compare the effectiveness of discontinuing treatment with amoxicillin after three days or eight days in adults admitted to hospital with mild to moderate-severe community acquired pneumonia who substantially improved after an initial three days9 treatment. Design Randomised, double blind, placebo controlled non-inferiority trial. Setting Nine secondary and tertiary care hospitals in the Netherlands. Participants Adults with mild to moderate-severe community acquired pneumonia (pneumonia severity index score ≤ 110). Interventions Patients who had substantially improved after three days9 treatment with intravenous amoxicillin were randomly assigned to oral amoxicillin (n = 63) or placebo (n = 56) three times daily for five days. Main outcome measures The primary outcome measure was the clinical success rate at day 10. Secondary outcome measures were the clinical success rate at day 28, symptom resolution, radiological success rates at days 10 and 28, and adverse events. Results Baseline characteristics were comparable, with the exception of symptom severity, which was worse in the three day treatment group. In the three day and eight day treatment groups the clinical success rate at day 10 was 93% for both (difference 0.1%, 95% confidence interval − 9% to 10%) and at day 28 was 90% compared with 88% (difference 2.0%, − 9% to 15%). Both groups had similar resolution of symptoms. Radiological success rates were 86% compared with 83% at day 10 (difference 3%, − 10% to 16%) and 86% compared with 79% at day 28 (difference 6%, − 7% to 20%). Six patients (11%) in the placebo group and 13 patients (21%) in the active treatment group reported adverse events (P = 0.1). Conclusions Discontinuing amoxicillin treatment after three days is not inferior to discontinuing it after eight days in adults admitted to hospital with mild to moderate-severe community acquired pneumonia who substantially improved after an initial three days9 treatment.