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Background: Induced sputum cytology and protein biomarkers can be used to assess airways infl ammation. Increases in sputum iron have been described in infl ammatory lung disease. We hypothesized that other sputum metals may be affected by airways infl ammation and investigated their potential value as biomarkers. Methods: Sputum was obtained from 20 healthy control subjects and from patients with infl ammatory pulmonary diseases (23 with cystic fi brosis [CF], 16 with bronchiectasis, 17 with asthma, and 23 with COPD), and iron, zinc, manganese, and copper were measured. Fourteen patients with CF were also studied through an exacerbation cycle. Results: Sputum zinc and iron were elevated in CF and non-CF bronchiectasis vs controls ( P , .001, zinc; P , .01 iron). Manganese was elevated in asthma ( P , .01) and bronchiectasis ( P , .05) vs controls. Copper was elevated in CF vs controls ( P , .05). Zinc decreased ( P , .01) following treatment of CF exacerbation. In subjects with CF zinc levels correlated with other biomarkers. Conclusions: These results suggest a relationship of high concentrations of total zinc and iron with airways infl ammation in CF and non-CF bronchiectasis, with longitudinal changes being observed in CF. Further work is required to elucidate potential infl ammatory mechanisms related to these observations. CHEST 2010; 137(3):635–641

BackgroundFor cystic fibrosis (CF) patients there is a lack of good assays of disease activity and response to new therapeutic interventions, including gene therapy. Current measures of airways inflammation severity are insensitive or non-specific.MethodsBronchoalveolar lavage fluid from 39 CF children and 38 respiratory disease controls was obtained at bronchoscopy and analysed by surface enhanced laser desorption ionisation time of flight (SELDI-TOF) mass spectrometry. Recognized proteins were assessed for CF disease specificity. Individual protein identification of specific peaks was performed.Results1277 proteins/peptides, > 4 kDa, were detected using 12 different surfaces and binding conditions. 202 proteins/peptides were differentially expressed in the CF samples (p < 0.001), 167 up-regulated and 35 down-regulated. The most discriminatory biomarker had a mass of 5.163 kDa. The most abundant, with a mass of 10.6 kDa, was identified as s100 A8 (calgranulin A).ConclusionsThe application of SELDI-TOF mass spectrometry allows evaluation of proteins in BAL fluid avoiding the limitations of only analysing predetermined proteins and potentially identifying proteins not previously appreciated as biomarkers. Its application to cystic fibrosis should enable appropriate evaluation of evolving illness, of gene therapy and other new therapies.

Summary Background Treatment of acute asthma is based on rapid reversal of bronchospasm and airway inflammation. Magnesium sulphate (MgSO 4 ) is known to have a bronchodilator effect on smooth muscle but studies have shown conflicting results on its efficacy in acute asthma, although its use is recommended in national and international guidelines. Aims To determine if intravenous MgSO 4 , when used as an adjunct to standard therapy, improves the outcome in acute asthma. Methods A double blind, randomised placebo controlled trial comparing 1.2g MgSO 4 with standard therapy in adult patients with acute asthma. Patients had a PEF ⩽75% predicted and all were treated with oxygen, nebulised salbutamol and ipratropium, and IV hydrocortisone. They then received 1.2g IV MgSO 4 or placebo. Outcome measures were % predicted PEF at 60min and hospital admission rates. Results One hundred and twenty nine patients were studied. Placebo and active treatment groups were well matched at baseline. MgSO 4 had no benefit with regards hospital admission rates or % predicted PEF at 60min ( p =0.48) for the whole group, or for subgroups of life-threatening ( p =0.85), severe ( p =0.63) and moderate ( p =0.67) acute asthma. Conclusion This study did not show additional benefit from 1.2g IV MgSO 4 when given as an adjunct to standard therapy for acute asthma.

Study objectives: To investigate whether differing airway interleukin (IL)-18 levels may be implicated in the pathogenesis of asthma and sarcoidosis. Setting: University teaching hospital. Patients and methods: IL-18 levels were measured in BAL fluid and in the supernatant of lipopolysaccharide (LPS)-stimulated alveolar macrophages obtained by BAL from 15 patients with sarcoidosis, 11 patients with asthma, and 13 healthy subjects. We also examined the relationship between IL-18 levels and macrophage and lymphocyte concentrations in BAL fluid. IL-18 was measured using an in-house enzyme-linked immunosorbent assay. Results: IL-18 levels were significantly lower in BAL fluid from patients with asthma (median, 0.0 pg/mL; interquartile range, 0.0 to 0.0 pg/mL) compared to patients with sarcoidosis (median, 222.0 pg/10 6 ; interquartile range, 110 to 340 pg/mL; p 0.009, Mann Whitney rank-sum test) and healthy control subjects (median, 162 pg/mL; interquartile range, 38 to 203 pg/mL; p 0.025, Mann Whitney rank-sum test). Individual analyses comparing IL-18 levels with BAL macrophage counts, and IL-18 with lymphocyte counts in the three groups showed no correlation between these indexes. The mean levels of IL-18 in unstimulated macrophage supernatants were 410 pg/10 6 cells for patients with asthma, 723.4 pg/10 6 cells for patients with sarcoidosis, and 734.8 pg/10 6 cells for healthy control subjects (p > 0.05). Stimulated macrophages from patients with sarcoidosis responded with increasing amounts of IL-18 at lower doses of LPS than macrophages from healthy control subjects or patients with asthma. Conclusion: Our findings suggest that inherently low levels of IL-18 may be associated with the pathogenesis of asthmatic airway inflammation. (CHEST 2002; 121:1421–1426)

Asthma patients who continue to experience symptoms despite taking regular inhaled corticosteroids represent a management challenge. Leukotrienes play a key role in asthma pathophysiology, and since pro-inflammatory leukotrienes are poorly suppressed by corticosteroids it seems rational to add a leukotriene receptor antagonist (LTRA) when a low to moderate dose of inhaled corticosteroids does not provide sufficient disease control. Long acting beta2-agonist (LABA) treatment represents an alternative to LTRAs and both treatment modalities have been shown to provide additional disease control when added to corticosteroid treatment. To compare the relative clinical benefits of adding either a LTRA or a LABA to asthma patients inadequately controlled by inhaled corticosteroids, a randomized, double-blind, multi-centre, 48-week study will be initiated at approximately 120 centres throughout Europe, Latin America, Middle East, Africa and the Asia-Pacific region in early 2000. The study will compare the oral LTRA montelukast with the inhaled LABA salmeterol, each administered on a background of inhaled fluticasone, on asthma attacks, quality of life, lung function, eosinophil levels, healthcare utilization, and safety, in approximately 1200 adult asthmatic patients. The requirements for study enrollment include a history of asthma, FEV1 or PEFR values between 50% and 90% of the predicted value together with > or = 12% improvement in FEV1 after beta-agonist administration, a minimum pre-determined level of asthma symptoms and daily beta-agonist medication. The study will include a 4-week run-in period, during which patients previously taking inhaled corticosteroids are switched to open-label fluticasone (200 microg daily), followed by a 48-week double-blind, treatment period in which patients continuing to experience abnormal pulmonary function and daytime symptoms are randomized to receive montelukast (10 mg once daily) and salmeterol placebo, or inhaled salmeterol (100 microg daily) and montelukast placebo. All patients will continue with inhaled fluticasone (200 microg daily). During the study, asthma attacks, overnight asthma symptoms, and morning peak expiratory flow rate will be assessed using patient diary cards; quality of life will also be assessed using an asthma-specific quality-of life questionnaire. The results of this study are expected to provide physicians with important clinical evidence to help them make a rational and logical treatment choice for asthmatic patients experiencing breakthrough symptoms on inhaled corticosteroids.

Background. Dysphonia is a known local adverse eAect of inhaled corticosteroids. This symptom was investigated by laryngoscopy and assessment in a voice laboratory. The eAects of changing the treatment of patients with dysphonia, reported whilst using the pMDI, to pMDI plus Nebuhaler 1 or Tubuhaler 1 was also assessed. Methods. Seventy-two patients reporting dysphonia and taking inhaled steroids from a pMDI entered a 12-week, open, parallel group study. Fifty-one completed the study per protocol; 26 in the Nebuhaler group [21 female, mean age 57 years (22‐77)] and 25 in the Turbuhaler 1 group [18 female, mean age 58 years (21‐81)]. A dysphonia diary card was completed weekly. Voice laboratory assessments and laryngoscopy were performed on entry and at 12 weeks. Results. There were no diAerences in voice laboratory data, laryngoscopic evidence of disordered glottic closure and diary data between the two groups at 12 weeks. At study entry laryngoscopic appearances were normal in almost half the patients. Vocal cord bowing was rarely seen. Glottic closure changed in nine patients during the study period, but there was no correlation with voice symptoms. The trend of symptomatic improvement of voice status in the Turbuhaler 1 group did not correlate with voice laboratory assessments and laryngoscopic evidence of disordered glottic closure. After 4 weeks, 40% of patients using Turbuhaler 1 and 8% in the Nebuhaler 1 group scored their voice status as better (P

Guidelines on asthma management recommend that in patients who still have symptoms on treatment with low-dose inhaled corticosteroids the first step should be an increase in inhaled corticosteroid dose. The addition of long-acting inhaled beta 2-adrenoceptor agonists is another option. We have compared these two strategies in a randomised, double-blind, parallel-group trial. We studied 429 adult asthmatic patients who still had symptoms despite maintenance treatment with 200 micrograms twice daily inhaled beclomethasone dipropionate (BDP). 3 did not provide verifiable data. Of the others, 220 were assigned salmeterol xinafoate (50 micrograms twice daily) plus BDP and 206 were assigned higher-dose BDP (500 micrograms twice daily) for 6 months. The mean morning peak expiratory flow increased from baseline in both groups, but the increase was greater in the salmeterol/BDP group than in the higher-dose BDP group at all time points (differences 16-21 L/min, p < 0.05). Mean evening PEF also increased with salmeterol/BDP but not with higher-dose BDP. There were significant differences in favour of salmeterol/BDP in diurnal variation of PEF (all time points) and in use of rescue bronchodilator (salbutamol) and daytime and night-time symptoms (some time points). There was no significant difference between the groups in adverse effects or exacerbations of asthma, indicating that in this group of patients regular beta 2-agonist therapy was not associated with any risk of deteriorating asthma control over 6 months. This study suggests a need for a flexible approach to asthma management.

Summary Pulmonary colonisation with Pseudomonas cepacia in patients with cystic fibrosis can be associated with increased morbidity and mortality. The modes of transmission of P cepacia are, however, unclear. We used selective media and phenotypic and genomic typing systems to investigate the acquisition of P cepacia by adults with cystic fibrosis. An analysis of isolates from 210 patients attending regional clinics in Edinburgh and Manchester between 1986 and 1992 showed that the main cause of increased isolations of P cepacia from 1989 was the emergence of an epidemic strain that had spread between patients in both clinics. Epidemiological evidence indicated that social contact was important in spread of the epidemic strain within and between clinics. We suggest that guidelines to limit the acquisition of P cepacia should not be restricted to patients in hospital, and that intimate or frequent social contact is associated with a high risk of cross-infection.

Of 65 patients presenting with pulmonary eosinophilia to one Respiratory Unit during a 20-year period, 12 (18%) had systemic features associated with their pulmonary disease. Eleven had fever, three night sweats, three arthralgia, three vasculitic rashes and two weight loss. Anaemia, myalgia, peripheral neuropathy, mononeuritis, pericardial effusion and photosensitivity rash were each recorded in single patients. None had evidence of hypersensitivity to drugs, helminthes or other allergens. Ten of the 12 patients could be classified as cryptogenic pulmonary eosinophilia and two as Churg Strauss syndrome. Ten were female. The maximum recorded eosinophil counts were higher in the 12 patients with systemic features compared with the remaining 53 patients [mean (SD) 5613 (3883) vs. 2359 (3046) x 10(6) 1(-1), P < 0.02], whereas both asthma and recurrent episodes of eosinophilia were significantly less common. Steroid therapy achieved a good clinical response and radiological clearing in the majority of patients. All 12 patients were treated with prolonged duration oral prednisolone [mean (SEM) dose 8.5 (3.8) mg day-1 duration 5.5 (1.3) years]. The two patients with Churg Strauss syndrome required azathioprine in addition to long-term prednisolone. There were no deaths and currently four patients are off all steroids and six receive less than 5 mg day-1. During a median follow-up period of 11 years, there was no significant decline in FEV1 or VC, measured as percent predicted values. Persistent radiographic abnormalities consistent with fibrosis or bronchiectasis were not seen.(ABSTRACT TRUNCATED AT 250 WORDS)

High dose inhaled corticosteroids may cause suppression of the hypothalamo-pituitary-adrenal (HPA) axis. Several tests are available to screen for this suppression but it is not clear which is the most useful. HPA function was assessed in 78 adult asthmatics inhaling long-term, high dose (median 1600 μg; range 1200–2650 μg) beclomethasone dipropionate ( n = 69) or budesonide ( n = 9). Screening tests performed in all patients were 9 am serum cortisol, short tetracosactrin test and 24-h urine free cortisol excretion. Eleven patients also underwent insulin stress tests. Subnormal results were: 9 am cortisol −1 ; urine free cortisol −1 ; rise in cortisol in response to tetracosactrin or hypoglycaemia −1 and/or achieved cortisol −1 . HPA suppression (defined as subnormal results of at least two of the three initial tests and/or subnormal response to hypoglycaemia), was found in 16 patients. In the 11 patients who underwent insulin stress tests, results of all initial tests were normal in three, one test was abnormal in three and two tests were abnormal in four patients. All three tests were abnormal in the remaining patient. The response to hypoglycaemia was normal in the three patients whose screening tests were all normal; HPA suppression was present in seven patients and one patient had a borderline result. Close correlation was observed between the maximum cortisol during hypoglycaemia and both urine free cortisol ( r s =0·84; P =0·001) and post-tetracosactrin cortisol ( r =0·75; P 95%); 9 am cortisol was much less sensitive. Measuring 24-h urine free cortisol excretion is a simple, sensitive way of screening for clinically important hypothalamo-pituitary-adrenal suppression from high dose inhaled corticosteroids and avoids the risk of hypersensitivity reactions to tetracosactrin.

33 106 (32%) patients with limited disease (LD) small cell lung cancer (SCLC) achieved a bronchoscopically confirmed complete response (CR) following 4 courses of induction chemotherapy. These patients were offered ‘late intensification’ with high dose melphalan (HDM) (140 mg/m 2 ) and autologous bone marrow support. LDCR patients were advised also to receive radiotherapy to the primary site and prophylactic cranial irradiation (PCI). After a minimum follow-up of 3 years, the LDCR patients who received HDM ( n =13) have had a median disease-free survival (DFS) of 15 months and a median overall survival (OS) of 16 months, compared with a DFS of 9 months ( P =0.06) and OS of 11 months ( P =0.23) for patients who did not receive late intensification ( n =20). Chest radiotherapy and PCI reduced the frequency of recurrence at these sites. Only patients who had received both chest radiotherapy and PCI were disease-free at 18 months. In this non-randomised study it is not possible to state with certainty the contribution of consolidation treatment in SCLC. Nevertheless, in patients with chemosensitive limited disease, late intensification chemotherapy, chest radiotherapy and PCI all appear to have a positive effect on DFS.

Cytokine-mediated interactions between monocytes/macrophages, lymphocytes, and eosinophils may be important in regulation of airway inflammation in asthma. Peripheral blood cytokine concentrations were measured in twenty adults with severe, acute asthma, ten with mild asthma (intermittent inhaled beta-agonists), twelve with chronic asthma (high-dose inhaled steroids), and in sixteen healthy subjects. Interleukin-1 beta, tumour necrosis factor, and interferon gamma were not detected in most subjects. Granulocyte macrophage colony-stimulating factor concentrations were higher in patients with severe asthma than in healthy subjects (median 179 vs 80 pg/ml; 95% confidence interval for difference 16-168; p = 0.009). Plasma concentrations of soluble interleukin-2 receptor (sIL-2R) were similar in all asthma groups (geometric mean in severe acute group 570 U/ml, mild group 559 U/ml, and chronic group 560 U/ml) and higher than those in healthy controls (361 U/ml, p less than 0.01). Sequential sIL-2R measurements were done in fifteen of the patients with severe acute asthma. There was no difference between baseline concentrations and those after 2 days of steroid treatment but by day 7 they had fallen significantly (ratio day 7/day 3 = 0.74, [95% CI 0.67-0.82]; p less than 0.001); however, there was no correlation with improvement in peak expiratory flow. This study provides further evidence for T-lymphocyte activation in asthma but shows that plasma sIL-2R is not a useful marker of disease activity.

The aim of the study was to find out whether asthma patients whose airways obstruction is sensitive (CS) or resistant (CR) to corticosteroid treatment also differ in their cutaneous vasoconstrictor response to a potent topical glucocorticoid. Corticosteroid resistance was defined by failure of forced expiratory volume in 1 s (FEV1) and peak expiratory flow rate to improve by at least 15% after a 2-week trial of corticosteroids (prednisolone 20 mg daily for 1 week, then 40 mg daily for 1 week) despite more than 15% improvement with inhaled beta agonists. Beclomethasone dipropionate in concentrations of 3 micrograms/ml, 10 micrograms/ml, 30 micrograms/ml, and 100 micrograms/ml was applied to forearm skin; the site was occluded under plastic and the degree of blanching assessed after 18 h. CS asthmatic subjects (n = 31), asthma patients with mild airways obstruction (n = 26), asthma patients taking long-term prednisolone (n = 13), and healthy volunteers showed similar vasoconstrictor responses. In CR asthmatic subjects (n = 15), the response (expressed in terms of either blanching intensity or the proportion of patients showing a positive response) was significantly lower than that in the CS group at concentrations of 3 micrograms/ml (p less than 0.01), 10 micrograms/ml (p less than 0.01), and 30 micrograms/ml (p less than 0.05), but not at 100 micrograms/ml. This resistance to glucocorticoids in the skin, together with reported evidence of glucocorticoid resistance in peripheral blood leucocytes, suggests a general defect in the ability of tissues to respond to glucocorticoids in CR asthma.

Summary Studies in experimental human lung cancer models have suggested that interferon may enhance significantly the response to some cytotoxic drugs. We have performed a phase II study of cisplatin (100 mg/m2 q.21 or 28 days) and alpha-2 interferon (3 or 5 MU three times weekly) in 68 patients with advanced non-small cell lung cancer and good performance status. As toxicity was acceptable, the dose of interferon and schedule of cisplatin were increased at the midpoint of the study. 46% (11/24) of patients with squamous carcinoma responded and an overall partial response rate of 30% was attained in 60 evaluable patients. There was no potentiation of haematological, renal or neurological toxicity but nausea and vomiting were severe. These results suggest that the combination has activity in this usually refractory disease.

Tremor and headaches are reported as common adverse events to &agonists. However, rapid, tachyphylaxis usually occurs. There is some concern with the short-acting /3,-agonist, fenoterol, which has the least selectivity for &compared with /3,-adrenoceptors (1). Bremner et al. (2) compared formoterol(24 pug), fenoterol(400 pug) and salbutamol (4OOpg) in an acute event study. Fenoterol had the greatest, and salbutamol the least, cardiac and metabolic effects. One question still to be answered is whether there is tachyphylaxis to the beneficial effects of &agonists. There are a number of studies that indicate that regular use of long-acting &agonists results in tolerance to bronchoprotective effects. However, in the clinic, sahneterol and formoterol work very well as bronchodilators following longterm administration, and therefore tachyphylaxis may be largely irrelevant both in terms of efficacy and safety.