Safety and tolerability of stereotactic radiotherapy combined with durvalumab with or without tremelimumab in advanced non-small cell lung cancer, the phase I SICI trial.

INTRODUCTION: This phase I study primarily addresses the safety and tolerability of Stereotactic radiotherapy on the primary tumor combined with double Immune Checkpoint Inhibition (SICI) in patients with non-small cell lung cancer (NSCLC). Increasing the release of neoantigens by radiotherapy might enhance response to immunotherapy. Especially, by targeting trunk mutations in the primary tumor. MATERIALS AND METHODS: In three sequential cohorts, immunotherapy regimes combined with stereotactic body radiotherapy (SBRT) on the primary tumor (1x20 Gy on 9 cc) were studied in stage IIIB/IV NSCLC patients progressing on chemotherapy. The first cohort (n = 3) received durvalumab. The second (n = 6) received a combination of tremelimumab and durvalumab followed by durvalumab monotherapy. The third cohort (n = 6) was similar except that the combination was reversed. Descriptive statistics were used to assess safety parameters and the exploratory outcomes of efficacy. Adverse events were reported using NCI CTCAE version 4.03. Exhaled breath was analyzed at baseline. RESULTS: Fifteen patients were included. Median irradiated volume was 9.13 cc, on a median primary tumor volume of 79 cc. There were seven patients with grade 1-2, and two patients with grade 3 treatment related adverse events. There was 1 dose limiting toxicity (colitis) with double immunotherapy. CONCLUSION: The combination of SBRT to the primary tumor and double immunotherapy in advanced NSCLC patients is safe and feasible.

The Microbiome in Bronchial Biopsies from Smokers and Ex-Smokers with Stable COPD - A Metatranscriptomic Approach.

Current knowledge about the respiratory microbiome is mainly based on 16S ribosomal RNA gene sequencing. Newer sequencing approaches, such as metatranscriptomics, offer the technical ability to measure the viable microbiome response to environmental conditions such as smoking as well as to explore its functional role by investigating host-microbiome interactions. However, knowledge about its feasibility in respiratory microbiome research, especially in lung biopsies, is still very limited. RNA sequencing was performed in bronchial biopsies from clinically stable smokers (n = 5) and ex-smokers (n = 6) with COPD not using (inhaled) steroids. The Trinity assembler was used to assemble non-human reads in order to allow unbiased taxonomical and microbial transcriptional analyses. Subsequently, host-microbiome interactions were analyzed based on associations with host transcriptomic data. Ultra-low levels of microbial mass (0.009%) were identified in the RNA-seq data. Overall, no differences were identified in microbiome diversity or transcriptional profiles of microbial communities or individual microbes between COPD smokers and ex-smokers in the initial test dataset as well as a larger replication dataset. We identified an upregulated host gene set, related to the simultaneous presence of Bradyrhizobium, Roseomonas, Brevibacterium.spp., which were related to PERK-mediated unfolded protein response (UPR) and expression of the microRNA-155-5p. Our results show that metatranscriptomic profiling in bronchial biopsy samples from stable COPD patients yields ultra-low levels of microbial mass. Further, this study illustrates the potential of using transcriptional profiling of the host and microbiome to gain more insight into their interaction in the airways.

Colistin dry powder inhalation with the Twincer™: An effective and more patient friendly alternative to nebulization.

BACKGROUND: Nebulization of antimicrobial drugs such as tobramycin and colistin is a cornerstone in the treatment of patients with cystic fibrosis (CF) infected with Pseudomonas aeruginosa. However, nebulization has a high treatment burden. The Twincer™ is a dry powder inhaler specifically developed for the inhalation of antibiotics such as colistin. The aim of this study was to compare patient outcomes and experience with colistin dry powder by the Twincer with nebulization of colistin or tobramycin in adult CF patients in a real-life setting. METHODS: This was a retrospective study from 01-01-2015 until 01-07-2018. Effectiveness was evaluated by comparing FEV1 decline and exacerbation rate during a mean of 4.1 years of nebulization therapy prior to the initiation of the Twincer against the same values during a mean of 1.7 years of treatment with the Twincer. RESULTS: Twenty-one patients were evaluated, of whom twelve could be included in the effectiveness analysis, with a total of twenty patient years. Of all patients 71.4% preferred therapy with the Twincer over nebulization. Twincer use resulted in high treatment adherence with an average adherence rate of 92.5%. There was no significant difference in annual decline in FEV1%pred prior to and after start changing from nebulization to the use of the Twincer powder inhaler (median decline -1.56 [-5.57-5.31] and 1.35 [-8.45-6.36]) respectively, p = 0.45 (linear mixed effect model)). No significant difference was found in the number of intravenous or combined total intravenous and oral antibiotic courses during Twincer therapy compared to when using nebulization (1.68 and 2.49 courses during Twincer therapy versus 1.51 and 2.94 courses during nebulization, p = 0.88 and p = 0.63). CONCLUSION: Colistin dry powder inhalation with the Twincer is a more patient friendly alternative to nebulization, and we did not observe significant differences in the clinical outcome, regarding lung function and exacerbation rates.

The distress thermometer as a prognostic tool for one-year survival among patients with lung cancer.

INTRODUCTION: The use of patient-reported outcome measures is increasingly advocated to support high-quality cancer care. We therefore investigated the added value of the Distress Thermometer (DT) when combined with known predictors to assess one-year survival in patients with lung cancer. METHODS: All patients had newly diagnosed or recurrent lung cancer, started systemic treatment, and participated in the intervention arm of a previously published randomised controlled trial. A Cox proportional hazards model was fitted based on five selected known predictors for survival. The DT-score was added to this model and contrasted to models including the EORTC-QLQ-C30 global QoL score (quality of life) or the HADS total score (symptoms of anxiety and depression). Model performance was evaluated through improvement in the -2 log likelihood, Harrell's C-statistic, and a risk classification. RESULTS: In total, 110 patients were included in the analysis of whom 97 patients accurately completed the DT. Patients with a DT score ≥5 (N = 51) had a lower QoL, more symptoms of anxiety and depression, and a shorter median survival time (7.6 months vs 10.0 months; P = 0.02) than patients with a DT score <5 (N = 46). Addition of the DT resulted in a significant improvement in the accuracy of the model to predict one-year survival (P < 0.001) and the discriminatory value (C-statistic) marginally improved from 0.69 to 0.71. The proportion of patients correctly classified as high risk (≥85% risk of dying within one year) increased from 8% to 28%. Similar model performance was observed when combining the selected predictors with QoL and symptoms of anxiety or depression. CONCLUSIONS: Use of the DT allows clinicians to better identify patients with lung cancer at risk for poor outcomes, to further explore sources of distress, and subsequently personalize care accordingly.

Serum periostin does not reflect type 2-driven inflammation in COPD.

Although Th2 driven inflammation is present in COPD, it is not clearly elucidated which COPD patients are affected. Since periostin is associated with Th2 driven inflammation and inhaled corticosteroid (ICS)-response in asthma, it could function as a biomarker in COPD. The aim of this study was to analyze if serum periostin is elevated in COPD compared to healthy controls, if it is affected by smoking status, if it is linked to inflammatory cell counts in blood, sputum and endobronchial biopsies, and if periostin can predict ICS-response in COPD patients.Serum periostin levels were measured using Elecsys Periostin immunoassay. Correlations between periostin and inflammatory cell count in blood, sputum and endobronchial biopsies were analyzed. Additionally, the correlation between serum periostin levels and treatment responsiveness after 6 and 30 months was assessed using i.e. ΔFEV1% predicted, ΔCCQ score and ΔRV/TLC ratio. Forty-five COPD smokers, 25 COPD past-smokers, 22 healthy smokers and 23 healthy never-smokers were included. Linear regression analysis of serum periostin showed positive correlations age (B = 0.02, 95%CI 0.01-0.03) and FEV1% predicted (B = 0.01, 95%CI 0.01-0.02) in healthy smokers, but not in COPD patients In conclusion, COPD -smokers and -past-smokers have significantly higher periostin levels compared to healthy smokers, yet periostin is not suitable as a biomarker for Th2-driven inflammation or ICS-responsiveness in COPD.

Structural distress screening and supportive care for patients with lung cancer on systemic therapy: A randomised controlled trial.

INTRODUCTION: Gaining regular insight into the nature and severity of distress by a psychosocial nurse coupled with referral to psychosocial and/or paramedical healthcare provider(s) is an experimental supportive care approach. We sought to examine the effects of this approach on quality of life (QoL), patient's mood and satisfaction, end-of-life care and survival in patients with lung cancer. METHODS: Patients with newly diagnosed or recurrent lung cancer starting systemic therapy were randomly assigned to receive usual care or the experimental approach. Patients were followed up at 1, 7, 13 and 25 weeks after randomisation with the EORTC-QLQ-C30, the European Quality of Life-5D, the Hospital Anxiety and Depression Scale and the Patient Satisfaction Questionnaire-III. Primary outcome was the mean change in the EORTC-QLQ-C30 global QoL-score between 1 and 25 weeks. RESULTS: A total of 223 patients were randomised of whom 111 (50%) completed all four assessments (44% in the usual care group versus 55% in the experimental group). No significant difference was found in the mean change global QoL-score (-2.4, 95% CI: 12.1-7.2; P = 0.61), nor in the other patient-reported outcomes. Fewer patients in the experimental group received chemotherapy shortly before the end-of-life, and median survival was comparable (10.3 versus 10.1 months, P = 0.62). Of the 112 dropouts, 33 died and 79 discontinued participation for other reasons. CONCLUSIONS: This supportive care approach neither improved QoL nor other patient-reported outcomes in patients with lung cancer. However, it reduced the use of chemotherapy shortly before the end of life. Possibly, (late) side effects of systemic therapy may have obscured effects of our intervention on QoL. CLINICAL TRIAL REGISTRATION: NTR3540.

Regulation of YKL-40 expression by corticosteroids: effect on pro-inflammatory macrophages in vitro and its modulation in COPD in vivo.

BACKGROUND: Macrophages constitute a heterogeneous cell population with pro- (MΦ1) and anti-inflammatory (MΦ2) cells. The soluble chitinase-like-protein YKL-40 is expressed in macrophages and various other cell types, and has been linked to a variety of inflammatory diseases, including COPD. Dexamethasone strongly reduces YKL-40 expression in peripheral blood mononuclear cells (PBMC) in vitro. We hypothesized that: a) YKL-40 is differentially expressed by MΦ1 and MΦ2, b) is decreased by corticosteroids and c) that long-term treatment with inhaled corticosteroids (ICS) affects YKL-40 levels in serum and sputum of COPD patients. METHODS: Monocytes of healthy subjects were cultured in vitro for 7 days with either GM-CSF or M-CSF (for MΦ1 and MΦ2, respectively) and stimulated for 24 h with LPS, TNFα, or oncostatin M (OSM). MΦ1 and MΦ2 differentiation was assessed by measuring secretion of IL-12p40 and IL-10, respectively. YKL-40 expression in macrophages was measured by quantitative RT-PCR (qPCR) and ELISA; serum and sputum YKL-40 levels were analyzed by ELISA. RESULTS: Pro-inflammatory MΦ1 cells secreted significantly more YKL-40 than MΦ2, which was independent of stimulation with LPS, TNFα or OSM (p < 0.001) and confirmed by qPCR. Dexamethasone dose-dependently and significantly inhibited YKL-40 protein and mRNA levels in MΦ1. Serum YKL-40 levels of COPD patients were significantly higher than sputum YKL-40 levels but were not significantly changed by ICS treatment. CONCLUSIONS: YKL-40 secretion from MΦ1 cells is higher than from MΦ2 cells and is unaffected by further stimulation with pro-inflammatory agents. Furthermore, YKL-40 release from cultured monocyte-derived macrophages is inhibited by dexamethasone especially in MΦ1, but ICS treatment did not change YKL-40 serum and sputum levels in COPD. These results indicate that YKL-40 expression could be used as a marker for MΦ1 macrophages in vitro, but not for monitoring the effect of ICS in COPD. TRIAL REGISTRATION: ClinicalTrials.gov, registration number: NCT00158847.

Obesity in asthma: more neutrophilic inflammation as a possible explanation for a reduced treatment response.

BACKGROUND: The incidence of asthma and obesity is increasing worldwide, and reports suggest that obese patients have more severe asthma. We investigated whether obese asthma patients have more severe airway obstruction and airway hyper-responsiveness and a different type of airway inflammation than lean asthmatics. Furthermore, we assessed the effect of obesity on corticosteroid treatment response. METHODS: Patient data from four well-documented asthma cohorts were pooled (n = 423). We evaluated FEV(1) , bronchial hyper-responsiveness (PC(20) ) to either methacholine/histamine or adenosine 5'-monophosphate (AMP) (differential) cell counts in induced sputum and blood and corticosteroid treatment response in 118 patients. RESULTS: At baseline, FEV(1) , PC(20) methacholine or histamine, and PC(20) AMP values were comparable in 63 obese (BMI ≥ 30 kg/m(2) ) and 213 lean patients (BMI <25 kg/m(2) ). Obese patients had significantly higher blood neutrophils. These higher blood neutrophils were only seen in obese women and not in obese men. After a two-week treatment with corticosteroids, we observed less corticosteroid-induced improvement in FEV(1) %predicted in obese patients than in lean patients (median 1.7% vs 6.3% respectively, P = 0.04). The percentage of sputum eosinophils improved significantly less with higher BMI (P = 0.03), and the number of blood neutrophils increased less in obese than in lean patients (0.32 x10(3) /µl vs 0.57 x10(3) /µl, P = 0.046). CONCLUSIONS: We found no differences in asthma severity between obese and nonobese asthmatics. Interestingly, obese patients demonstrated more neutrophils in sputum and blood than nonobese patients. The smaller improvement in FEV(1) and sputum eosinophils suggests a worse corticosteroid treatment response in obese asthmatics.

Antinuclear autoantibodies are more prevalent in COPD in association with low body mass index but not with smoking history.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is associated with a higher prevalence of antinuclear autoantibodies (ANAs). However, a significant subgroup of patients is ANA negative. It remains to be determined which patient groups carry autoantibodies. METHODS: The association of smoking behaviour, disease status, gender, age and body mass index (BMI) with the presence of autoantibodies in the serum was determined in 124 patients with COPD and 108 non-COPD control subjects. In addition, the role of B cells in autoantibody generation in COPD was investigated by sequencing the antibody repertoire of B cells in the lungs of patients with COPD and of ex-smoking and never-smoking control subjects. RESULTS: Patients with COPD had a significantly higher risk of being serum positive for ANAs (OR 3.12, 95% CI 1.68 to 5.76, p<0.001). ANAs were not significantly associated with age, smoking status, gender or pack-years of smoking. Within the COPD population, subjects with BMI <22 kg/m2 had a significantly higher risk of ANAs (OR 4.93, 95% CI 1.50 to 16.50, p=0.009) than those with normal or high BMI. The antibody repertoire of B cells in the lungs of patients with COPD had a high frequency of positively charged CDR3 residues, a feature which is associated with self-reactive antibodies. CONCLUSION: The results show that COPD is a heterogeneous disease with respect to the prevalence of ANAs. ANAs are primarily associated with the presence of COPD and with low BMI, but not with smoking and forced expiratory volume in 1 s.

Effect of an inhaled adenosine A2A agonist on the allergen-induced late asthmatic response.

BACKGROUND: Adenosine receptor activation is suggested to play a role in asthmatic airway inflammation. Inhibition of adenosine receptors may have an effect on the late asthmatic response (LAR) after allergen inhalation and this mechanism could offer a potential new treatment in asthma. METHODS: We evaluated the effect of an inhaled adenosine-(2A) (A(2A))-receptor agonist (GW328267X), 25 microg, in 15 nonsmoking atopic asthmatics who underwent an inhaled allergen challenge following twice daily treatment for 1 week in a double-blind, placebo- and fluticasone propionate (250 microg) controlled study. RESULTS: In contrast to fluticasone, treatment with the A(2A)-receptor agonist neither significantly protect against the allergen-induced early and late asthmatic reaction, nor the accompanying inflammatory response as measured by sputum total cell counts, number of EG2+ cells, and the concentration of interleukin-8 and eosinophil cationic protein. CONCLUSION: The inhaled A(2A)-receptor agonist, GW328267X, 25 microg does not affect the allergen-induced LAR or the associated inflammatory response in asthma.

Airway remodeling in the smoke exposed guinea pig model.

Although small airway remodeling (SAR) leading to airflow obstruction is a common consequence of human cigarette smoking, the airways have been largely ignored in animal models of chronic obstructive pulmonary disease (COPD). We examined lung structure in a guinea pig model of chronic cigarette smoke exposure to ascertain whether smoke induced SAR, and to evaluate how these anatomic lesions correlate with physiologic changes. We used tissue from guinea pigs exposed to cigarette smoke or air for 6 mo. Pulmonary function tests were performed, and histologic sections were prepared. Airspace size (Lm) and changes in the structure of the small airways were evaluated by morphometric analysis. Chronic smoke exposure was associated with increased airway wall thickness and increased amounts of thick collagen fibers in the walls of the small airways, as well as with increased Lm. The increase in thick collagen fibers related negatively to peak expiratory volume (PEF) and the ratio of forced expiratory volume in 1 s to forced ventilatory capacity (FEV(0.1)/FVC), and positively to airway resistance. Physiologic lung volumes were predicted by airspace size, but residual volume (RV) and total lung capacity (TLC) also were related to airway wall thickness. Amounts of smooth muscle were not changed and did not predict any physiologic abnormalities. We conclude that cigarette smoke exposure results in SAR in the guinea pig, alterations that are reflected in increased airways resistance with diminished airflow and air trapping, mimicking human disease. This model should prove useful in further investigations into the mechanisms of airway remodeling.

Anti-inflammatory effects of inhaled carbon monoxide in patients with COPD: a pilot study.

In vitro and in vivo studies have shown that carbon monoxide (CO) has both anti-inflammatory and anti-oxidant capacities. Since chronic obstructive pulmonary disease (COPD) is characterised by inflammation and oxidative stress, low-dose CO could be of therapeutic use. The aim of the present study was to investigate the feasibility and anti-inflammatory effects of 100-125 ppm CO inhalation in patients with stable COPD. In total, 20 ex-smoking COPD patients with post-bronchodilator forced expiratory volume in one second (FEV(1)) >1.20 L and FEV(1)/forced vital capacity <70% were enrolled in a randomised, placebo-controlled, crossover study. Effects on inflammation were measured in induced sputum and blood. CO inhalation was feasible and patients' vital signs were unaffected; 2 h.day(-1) inhalation of low-dose CO on 4 consecutive days led to a maximal individual carboxyhaemoglobin level of 4.5%. Two exacerbations occurred in the CO period. CO inhalation led to trends in reduced sputum eosinophils (median reduction 0.25% point) and improved responsiveness to methacholine (median provocative concentration causing a 20% fall in FEV(1) 0.85 versus 0.63 mg.mL(-1)). Inhalation of 100-125 ppm carbon monoxide by patients with chronic obstructive pulmonary disease in a stable phase was feasible and led to trends in reduction of sputum eosinophils and improvement of responsiveness to methacholine. Further studies need to confirm the safety and efficacy in inflammatory lung diseases.

[Comments on screening spirometry for detection of COPD]. / Kanttekeningen bij screenend longfunctieonderzoek voor detectie van COPD.

World COPD day is an annual event intended to increase awareness of chronic obstructive pulmonary disease. During this day, in November 2006, free spirometry testing was offered to the public in approximately 100 places including hospitals, pharmacies, offices of GPs and tents on main squares throughout the Netherlands. The objective of this action is laudable. However, screening for COPD is generally considered ineffective. Furthermore, the application of a fixed ratio of forced expiratory volume in one second (FEV1) to forced vital capacity (FVC) (FEV1/FVC < 0.70) as recommended by the Global Initiative for Chronic Obstructive Lung Disease (GOLD) to detect airflow limitation, required for a diagnosis of COPD, may lead to underdiagnosis of COPD in the young and to overdiagnosis in the elderly. In addition, spirometry was generally performed without bronchodilation, thus further increasing the likelihood of a false-positive diagnosis ofCOPD. Smoking cessation is important in halting the progression of COPD. Therefore, identifying smokers at risk for developing COPD seems a logical reason for screening or case finding for COPD. However, it has not been clearly demonstrated that early detection of COPD may contribute to improved smoking cessation rates. Also, smokers with normal spirometry may be led to believe that smoking has no adverse effects on their health. Therefore, a different strategy should be adopted to increase awareness of COPD on the next World COPD day.

Increased number of B-cells in bronchial biopsies in COPD.

Recently, it has been shown that the accumulated volume of B-cells in small airways is increased in chronic obstructive pulmonary disease (COPD) Global Initiative for Chronic Obstructive Lung Disease (GOLD) stages 3 and 4. Little is known about the number of B-cells in central airways in COPD. The present authors hypothesised that the number of B-cells in bronchial biopsies of large airways is higher in patients with COPD than in controls without airflow limitation and higher in more severe COPD. Therefore, bronchial biopsies were collected from 114 COPD patients (postbronchodilator forced expiratory volume in one second (FEV1) 63+/-9 % predicted value, FEV1/inspiratory vital capacity (IVC) 48+/-9%) and 28 controls (postbronchodilator FEV1 108+/-12 % predicted value, FEV1/IVC 78+/-4%). Paraffin sections were stained for B-cells (CD20+) and their number was determined in the subepithelial area (excluding muscle, glands and vessels). B-cell numbers were higher in patients with COPD versus controls (8.5 versus 3.9 cells x mm(-2), respectively) and higher in patients with GOLD severity stage 3 (n = 11) than stage 2 (n = 103; 22.3 versus 7.8 cells x mm(-2)). No relationship was found between the number of B-cells and clinical characteristics within the chronic obstructive pulmonary disease group. The authors suggest that these increased B-cell numbers may have an important contribution to the pathogenesis of chronic obstructive pulmonary disease.

Provocation with adenosine 5'-monophosphate, but not methacholine, induces sputum eosinophilia.

INTRODUCTION: Bronchial hyper-responsiveness is usually measured with direct stimuli such as methacholine (MCh) or histamine. Adenosine 5'-monophosphate (AMP), which acts indirectly via the secondary release of mediators, is another stimulus to measure bronchial hyper-responsiveness. AIM: To investigate whether provocation with inhaled AMP itself initiates an inflammatory response resulting in an influx of eosinophils into the airway lumen. METHODS: We have included 21 non-smoking atopic asthmatic subjects (mean FEV1 101% predicted, mean age 34 years). Each subject performed three sputum inductions on different days, at least seven days apart: one without previous provocation, one hour after PC20 methacholine, and one hour after PC20 AMP. RESULTS: After provocation with AMP, but not methacholine, the percentage of sputum eosinophils increased significantly (from 1.9+/-0.5% to 4.5+/-1% (P<0.01) and 1.9+/-0.5% (P=0.89)). No changes in the percentages of neutrophils, lymphocytes, macrophages, or bronchial epithelial cells were found. CONCLUSION: A provocation test with AMP leads to an increased percentage of sputum eosinophils. This observation cannot be explained by a non-specific response of the airways to a vigorous bronchoconstriction, since methacholine had no effect on inflammatory cells.

[Medical maintenance treatment of chronic obstructive pulmonary disease (COPD)]. / Medicamenteuze onderhoudsbehandeling bij chronisch obstructief longlijden (COPD).

Chronic obstructive pulmonary disease (COPD) is a chronic disorder of the lungs and airways that imposes a huge socioeconomic burden on both the patients and society. COPD is the only major chronic disease for which both the incidence and mortality are still rising worldwide. From the literature evidence-based insights can be obtained about maintenance medication for reducing symptoms and disease progression. Both anticholinergics and beta 2-sympathicomimetics have been proven to be effective bronchodilators for COPD, even though many patients fail to respond. This is confounded by the fact that a symptomatic response is not always reflected by an objective improvement in lung function. These substances do not have a favourable effect on the progressive deterioration of lung function. Theophyllines have limited effectiveness and the benefit-to-risk ratio is unfavourable. It has now been demonstrated that inhaled corticosteroids have no effect on the loss of lung function, and their prescription rates in patients with COPD should therefore be reduced. A reduction in exacerbation frequency seems to exist in some studies, yet this has not yet been conclusively demonstrated. Acetylcysteine has been proven to reduce exacerbation frequency. There is no place for maintenance therapy with antibiotics.

Accuracy of eosinophils and eosinophil cationic protein to predict steroid improvement in asthma.

BACKGROUND: There is a large variability in clinical response to corticosteroid treatment in patients with asthma. Several markers of inflammation like eosinophils and eosinophil cationic protein (ECP), as well as exhaled nitric oxide (NO), are good candidates to predict clinical response. AIM: We wanted to determine whether we could actually predict a favourable response to inhaled corticosteroids in individual patients. METHODS: One hundred and twenty patients with unstable asthma were treated with either prednisolone 30 mg/day, fluticasone propionate 1000 microg/day b.i.d. or fluticasone propionate 250 microg/day b.i.d., both via Diskhaler. They were treated during 2 weeks, in a double-blind, parallel group, double dummy design. We measured eosinophils and ECP in blood and sputum, and exhaled nitric oxide as inflammatory parameters before and after 2 weeks in order to predict the changes in forced expiratory volume in 1 s (FEV1), provocative concentration of methacholine causing a 20% fall in FEV1 (PC20 Mch), and asthma quality of life (QOL). Secondly, to test whether these results were applicable in clinical practice we determined the individual prediction of corticosteroid response. RESULTS: We found that changes in FEV1, PC20 Mch and QOL with corticosteroids were predominantly predicted by their respective baseline value and to a smaller extent by eosinophils in blood or sputum. ECP, measured in blood or sputum, was certainly not better than eosinophils in predicting clinical response to corticosteroids. Smoking status was an additional predictor for change in FEV1, but not for change in PC20 Mch or QOL. Prediction of a good clinical response was poor. For instance, high sputum eosinophils (> or = 3%) correctly predicted an improvement in PC20 Mch in only 65% of the patients. CONCLUSION: Our findings show that baseline values of the clinical parameters used as outcome parameters are the major predictors of clinical response to corticosteroids. Eosinophil percentage in blood or sputum adds to this, whereas ECP provides no additional information. Correct prediction of clinical response in an individual patient, however, remains poor with our currently used clinical and inflammatory parameters.