Gerard Cox

IL-6 is an antiinflammatory cytokine required for controlling local or systemic acute inflammatory responses.

IL-6 is induced often together with the proinflammatory cytokines TNFalpha and IL-1 in many alarm conditions, and circulating IL-6 plays an important role in the induction of acute phase reactions. However, whether this endogenous IL-6 plays any additional pro- or antiinflammatory roles in local or systemic responses remains unclear. In this study, the role of IL-6 in acute inflammatory responses was investigated in animal models of endotoxic lung or endotoxemia by using IL-6+/+ and IL-6-/- mice. Aerosol exposure of endotoxin induced increased IL-6 and proinflammatory cytokines TNFalpha and MIP-2 and a neutrophilic response in the lung of IL-6+/+ mice. However, the levels of TNFalpha and MIP-2 and neutrophilia were significantly higher in the lung of IL-6-/- mice. The rate of neutrophil apoptosis in these mice was similar to that in IL-6+/+ mice. A low constitutive level of antiinflammatory cytokine IL-10 was not enhanced by endotoxin and remained similar in the lung in both IL-6+/+ and IL-6-/- mice. Systemically, intraperitoneal delivery of endotoxin resulted in much more pronounced circulating levels of TNFalpha, MIP-2, GM-CSF, and IFNgamma in IL-6-/- mice than in IL-6+/+ mice, and administration of recombinant IL-6 to IL-6-/- mice abolished these differences. In contrast, circulating IL-10 levels were induced to a similar degree in both IL-6+/+ and IL-6-/- mice. Thus, our studies reveal that endogenous IL-6 plays a crucial antiinflammatory role in both local and systemic acute inflammatory responses by controlling the level of proinflammatory, but not antiinflammatory, cytokines, and that these antiinflammatory activities by IL-6 cannot be compensated for by IL-10 or other IL-6 family members.

Tiotropium in Combination with Placebo, Salmeterol, or Fluticasone–Salmeterol for Treatment of Chronic Obstructive Pulmonary Disease: A Randomized Trial

Context Physicians use multiple medications to treat chronic obstructive pulmonary disease (COPD). Contribution In this multicenter trial, 449 adults with moderate or severe COPD were randomly assigned to receive tiotropium and placebo, tiotropium and salmeterol, or tiotropium and fluticasonesalmeterol for 1 year. About 63%, 65%, and 60% of patients, respectively, had exacerbations. The third group, but not the second group, had better lung function and fewer hospitalizations than the first group. Caution Many patients discontinued assigned medications. Implications Adding fluticasonesalmeterol to tiotropium may improve lung function and decrease hospitalizations, but it does not affect reduce exacerbations in patients with moderate or severe COPD. The Editors Most patients with moderate or severe chronic obstructive pulmonary disease (COPD) experience chronic progressive dyspnea that is not alleviated by short-acting bronchodilators. It is therefore not surprising that many patients are treated with multiple inhaled medications to optimize their lung function and minimize symptoms (1). Published guidelines on COPD state that the goals of pharmacologic therapy should be to control symptoms, improve health status, and reduce the frequency of COPD exacerbations (2, 3), and many published guidelines advocate combining different classes of long-acting bronchodilators or inhaled steroids to achieve these goals (2, 3). In the past several years, several studies have shown that treatment of COPD with the long-acting anticholinergic tiotropium (47); the long-acting 2-agonist salmeterol (810); or products that combine inhaled steroids and long-acting 2-agonists, such as fluticasonesalmeterol or budesonideformoterol (1114), improve dyspnea and quality of life and decrease exacerbation rates compared with placebo. However, no studies have assessed whether therapy with a combination of these products provides greater clinical benefit than does therapy with these agents used alone. 2-Agonists and anticholinergics work by different mechanisms to cause bronchodilation (15), and inhaled corticosteroids may have an anti-inflammatory effect in COPD (16). Thus, it makes theoretical and intuitive sense that combining these therapies might be more beneficial than therapy with 1 agent alone. However, safety concerns, such as side effects associated with long-term use of long-acting 2-agonists and inhaled corticosteroids, and economic issues related to the additional costs of these medications may argue against routine use of inhaled medication polypharmacy without evidence of efficacy. We therefore conducted a randomized, double-blind, placebo-controlled clinical trial to determine whether combining tiotropium with salmeterol or fluticasonesalmeterol produces greater improvements in clinical outcomes for adults with moderate or severe COPD compared with tiotropium therapy alone. Methods Design We designed a parallel-group, 3-group, randomized, double-blind, placebo-controlled trial in patients with moderate or severe COPD that was conducted from October 2003 to January 2006. The study protocol has been published elsewhere (17). The research ethics boards of all participating centers approved the study, and all trial participants provided written informed consent. Setting and Participants We enrolled patients with diagnosed moderate or severe COPD from 27 Canadian medical centers. Twenty centers were academic hospitalbased pulmonary clinics, 5 were community-based pulmonary clinics, and 2 were community-based primary care clinics. Eligible patients had to have had at least 1 exacerbation of COPD that required treatment with systemic steroids or antibiotics within the 12 months before randomization. Additional inclusion criteria were age older than 35 years; a history of 10 pack-years or more of cigarette smoking; and documented chronic airflow obstruction, with an FEV1FVC ratio less than 0.70 and a postbronchodilator FEV1 less than 65% of the predicted value. We excluded patients with a history of physician-diagnosed asthma before 40 years of age; those with a history of physician-diagnosed chronic congestive heart failure with known persistent severe left ventricular dysfunction; those receiving oral prednisone; those with a known hypersensitivity or intolerance to tiotropium, salmeterol, or fluticasonesalmeterol; those with a history of severe glaucoma or severe urinary tract obstruction, previous lung transplantation or lung volume reduction surgery, or diffuse bilateral bronchiectasis; and those who were pregnant or were breastfeeding. Persons with a recent COPD exacerbation requiring oral or intravenous antibiotics or steroids were required to wait until treatment with these agents had been discontinued for 28 days before entering the study. Randomization and Interventions We randomly assigned patients to 1 of 3 treatment groups for 52 weeks: tiotropium (Spiriva [Boehringer Ingelheim Pharma, Ingelheim, Germany]), 18 g once daily, plus placebo inhaler, 2 puffs twice daily; tiotropium, 18 g once daily, plus salmeterol (Serevent [GlaxoSmithKline, Research Triangle Park, North Carolina]), 25 g/puff, 2 puffs twice daily; or tiotropium, 18 g once daily, plus fluticasonesalmeterol (Advair [GlaxoSmithKline]), 250/25 g/puff, 2 puffs twice daily. Randomization was done through central allocation of a randomization schedule that was prepared from a computer-generated random listing of the 3 treatment allocations, blocked in variable blocks of 9 or 12 and stratified by site. Neither research staff nor patients were aware of the treatment assignment before or after randomization. All study patients were provided with inhaled albuterol and were instructed to use it when necessary to relieve symptoms. Any treatment with inhaled corticosteroids, long-acting 2-agonists, and anticholinergics that the patient may have been using before entry was discontinued on entry into the study. Therapy with other respiratory medications, such as oxygen, antileukotrienes, and methylxanthines, was continued in all patient groups. Tiotropium was administered by using a Handihaler device (Boehringer Ingelheim). Study drugs were administered through a pressurized metered-dose inhaler using a spacer device (Aerochamber Plus, Trudell Medical, London, Ontario, Canada), and patients were taught the correct inhalation technique to ensure adequate drug delivery. The metered-dose inhalers containing placebo, salmeterol, and fluticasonesalmeterol were identical in taste and appearance, and they were enclosed in identical tamper-proof blinding devices. The medication canisters within the blinding devices were stripped of any identifying labeling. Adherence to therapy was assessed by weighing the returned inhaler canisters. Measurements and Outcomes The primary outcome was the proportion of patients in each treatment group who experienced a COPD exacerbation within 52 weeks of randomization. Respiratory exacerbations were defined, according to the 2000 Aspen Lung Conference Consensus definition, as a sustained worsening of the patients respiratory condition, from the stable state and beyond normal day-to-day variations, necessitating a change in regular medication in a patient with underlying COPD (18). An acute change in regular COPD medications was defined as physician-directed, short-term use of oral or intravenous steroids, oral or intravenous antibiotics, or both therapies. Secondary outcomes were the mean number of COPD exacerbations per patient-year; the total number of exacerbations that resulted in urgent visits to a health care provider or emergency department; the number of hospitalizations for COPD; the total number of hospitalizations for all causes; and changes in health-related quality of life, dyspnea, and lung function. Health-related quality of life was assessed by using the St. Georges Respiratory Questionnaire (19), dyspnea was assessed by using the Transitional Dyspnea Index (20) and the dyspnea domain of the Chronic Respiratory Disease Questionnaire (21), and lung function was assessed by measuring the FEV1 according to established criteria of the American Thoracic Society. Follow-up Procedures Patients were monitored for exacerbations by monthly telephone calls. Exacerbations and all secondary outcomes were also assessed through patient visits at baseline and at 4, 20, 36, and 52 weeks after randomization. For every suspected exacerbation, we contacted both the patient and the patients treating physician to ensure that the medical encounter had been prompted by acute respiratory symptoms and a full report, including physician, emergency department, and hospital records that described the circumstances of each suspected exacerbation, was prepared. The assembled data from the visit for the suspected exacerbation were presented to a blinded adjudication committee for review, and the committee confirmed whether the encounter met the study definition of COPD exacerbation. For the purposes of the trial, we considered that a patient had experienced a new COPD exacerbation if he or she had not been receiving oral steroids and antibiotics for at least 14 days after the previous exacerbation. Patients were followed for the full 52-week duration of the trial, and primary and secondary outcomes were recorded throughout the 1-year period regardless of whether patients had experienced an exacerbation or discontinued treatment with study medications. We did not break the study blinding for patients who prematurely discontinued treatment with study medications. Adverse events were captured by the research coordinators through monthly patient telephone interviews and at scheduled patient visits by using checklists of potential side effects. Physicians rated events as expected or unexpected, and they were asked to rate event severity and attribute causality of adverse events to the study drugs. Statistical Analysis We designed the study to detect an 18% absolute d

Effectiveness and safety of bronchial thermoplasty in the treatment of severe asthma: a multicenter, randomized, double-blind, sham-controlled clinical trial.

RATIONALE Bronchial thermoplasty (BT) is a bronchoscopic procedure in which controlled thermal energy is applied to the airway wall to decrease smooth muscle. OBJECTIVES To evaluate the effectiveness and safety of BT versus a sham procedure in subjects with severe asthma who remain symptomatic despite treatment with high-dose inhaled corticosteroids and long-acting beta(2)-agonists. METHODS A total of 288 adult subjects (Intent-to-Treat [ITT]) randomized to BT or sham control underwent three bronchoscopy procedures. Primary outcome was the difference in Asthma Quality of Life Questionnaire (AQLQ) scores from baseline to average of 6, 9, and 12 months (integrated AQLQ). Adverse events and health care use were collected to assess safety. Statistical design and analysis of the primary endpoint was Bayesian. Target posterior probability of superiority (PPS) of BT over sham was 95%, except for the primary endpoint (96.4%). MEASUREMENTS AND MAIN RESULTS The improvement from baseline in the integrated AQLQ score was superior in the BT group compared with sham (BT, 1.35 +/- 1.10; sham, 1.16 +/- 1.23 [PPS, 96.0% ITT and 97.9% per protocol]). Seventy-nine percent of BT and 64% of sham subjects achieved changes in AQLQ of 0.5 or greater (PPS, 99.6%). Six percent more BT subjects were hospitalized in the treatment period (up to 6 wk after BT). In the posttreatment period (6-52 wk after BT), the BT group experienced fewer severe exacerbations, emergency department (ED) visits, and days missed from work/school compared with the sham group (PPS, 95.5, 99.9, and 99.3%, respectively). CONCLUSIONS BT in subjects with severe asthma improves asthma-specific quality of life with a reduction in severe exacerbations and healthcare use in the posttreatment period. Clinical trial registered with www.clinialtrials.gov (NCT00231114).

Circulating fibrocytes are an indicator of poor prognosis in idiopathic pulmonary fibrosis.

RATIONALE The clinical management of idiopathic pulmonary fibrosis (IPF) remains a major challenge due to lack of effective drug therapy or accurate indicators for disease progression. Fibrocytes are circulating mesenchymal cell progenitors that are involved in tissue repair and fibrosis. OBJECTIVES To test the hypothesis that assay of these cells may provide a biomarker for activity and progression of IPF. METHODS Fibrocytes were defined as cells positive for CD45 and collagen-1 by flow cytometry and quantified in patients with stable IPF and during acute exacerbation of the disease. We investigated the clinical and prognostic value of fibrocyte counts by comparison with standard clinical parameters and survival. We used healthy age-matched volunteers and patients with acute respiratory distress syndrome as control subjects. MEASUREMENTS AND MAIN RESULTS Fibrocytes were significantly elevated in patients with stable IPF (n = 51), with a further increase during acute disease exacerbation (n = 7; P < 0.001 vs. control subjects). Patients with acute respiratory distress syndrome (n = 10) were not different from healthy control subjects or stable patients with IPF. Fibrocyte numbers were not correlated with lung function or radiologic severity scores, but they were an independent predictor of early mortality. The mean survival of patients with fibrocytes higher than 5% of total blood leukocytes was 7.5 months compared with 27 months for patients with less than 5% (P < 0.0001). CONCLUSIONS Fibrocytes are an indicator for disease activity of IPF and might be useful as a clinical marker for disease progression. This study suggests that quantification of circulating fibrocytes may allow prediction of early mortality in patients with IPF.

Secretory leukocyte proteinase inhibitor is a major leukocyte elastase inhibitor in human neutrophils.

Secretory leukocyte proteinase inhibitor (SLPI) is the main neutrophil elastase (HLE) inhibitor found in the upper airways during pulmonary inflammation. It has been shown to be synthesized and secreted in vitro by epithelial cells and has been localized in tracheal glands and bronchiolar epithelial cells by immunocytochemistry. In this study, using immunodetection and immunopurification techniques with specific anti‐SLPI immunoglobulin G (IgG), we show that SLPI is present as a native 14‐kDa molecule in neutrophil cytosol. In addition, we demonstrate that SLPI is the major inhibitor of HLE present in neutrophil cytosol because pre‐incubation with specific anti‐SLPI IgG was able to inhibit completely the anti‐HLE activity of the cytosol. SLPI can be secreted (probably in an inactive form) by neutrophils and its secretion is enhanced when the cells are stimulated with phorbol myristate acetate (PMA). Elafin, an elastase‐specific inhibitor, is also present in minute amounts in neutrophil cytosol and its secretion can be upregulated. The presence of SLPI in the cytosol of neutrophils may serve as a protective screen against proteinases spilling from azurophilic granules. An alternative or supplementary role may be the maintenance of a differentiated phenotype. J. Leukoc. Biol. 61: 695–702; 1997.

Bronchial thermoplasty: Long-term safety and effectiveness in patients with severe persistent asthma

BACKGROUND Bronchial thermoplasty (BT) has previously been shown to improve asthma control out to 2 years in patients with severe persistent asthma. OBJECTIVE We sought to assess the effectiveness and safety of BT in asthmatic patients 5 years after therapy. METHODS BT-treated subjects from the Asthma Intervention Research 2 trial (ClinicalTrials.govNCT01350414) were evaluated annually for 5 years to assess the long-term safety of BT and the durability of its treatment effect. Outcomes assessed after BT included severe exacerbations, adverse events, health care use, spirometric data, and high-resolution computed tomographic scans. RESULTS One hundred sixty-two (85.3%) of 190 BT-treated subjects from the Asthma Intervention Research 2 trial completed 5 years of follow-up. The proportion of subjects experiencing severe exacerbations and emergency department (ED) visits and the rates of events in each of years 1 to 5 remained low and were less than those observed in the 12 months before BT treatment (average 5-year reduction in proportions: 44% for exacerbations and 78% for ED visits). Respiratory adverse events and respiratory-related hospitalizations remained unchanged in years 2 through 5 compared with the first year after BT. Prebronchodilator FEV₁ values remained stable between years 1 and 5 after BT, despite a 18% reduction in average daily inhaled corticosteroid dose. High-resolution computed tomographic scans from baseline to 5 years after BT showed no structural abnormalities that could be attributed to BT. CONCLUSIONS These data demonstrate the 5-year durability of the benefits of BT with regard to both asthma control (based on maintained reduction in severe exacerbations and ED visits for respiratory symptoms) and safety. BT has become an important addition to our treatment armamentarium and should be considered for patients with severe persistent asthma who remain symptomatic despite taking inhaled corticosteroids and long-acting β₂-agonists.

Induced sputum, bronchoalveolar lavage and blood from mild asthmatics: inflammatory cells, lymphocyte subsets and soluble markers compared

Airway inflammation in asthma can be measured directly by invasive bronchoalveolar lavage (BAL), directly and relatively noninvasively by induced sputum and indirectly from peripheral blood. We compared cellular and fluid phase indices of inflammation in induced sputum, BAL and blood from 11 adults with mild stable asthma. On one day, induced sputum selected from saliva was collected and on the next, blood and BAL. Median results of sputum compared with BAL showed a higher number of nonsquamous cells (53 versus 0.8 x 10(6) cells x mL(-1), p=0.003), more neutrophils (34.3 versus 1.0%, p<0.001), CD4+ and CD19+ T-cells (76.5 versus 54.7%, p=0.01 and 5.2 versus 1.1%, p=0.03, respectively), fewer macrophages (603 versus 95.0%, p=0.002) and markedly higher levels of eosinophil cationic protein (ECP) (264 versus 2.0 microg x L(-1), p<0.001), tryptase (17.6 versus 2.2 UI x L(-1), p<0.001) and fibrinogen (1,400 versus 150 microg x L(-1), p=0.001). Sputum and BAL neutrophils and CD4+ T-cells were strongly correlated. Sputum and BAL differed from blood by having higher proportions of T-cells (94.9 and 98.9% versus 87.7%, p=0.002) and lower proportions of CD19+ T-lymphocytes (p=0.04 and 0.006). Sputum also differed from blood by having higher proportions of CD4+ T-cells (76.5 versus 51.4%, p=0.001), lower proportions of CD8+ cells (24.0 versus 403%, p=0.04) and a higher CD4+/CD8+ ratio (3.3 versus 1.4, p=0.01). We conclude that in mild asthmatics, sputum, bronchoalveolar lavage and blood measure different compartments of inflammation. Induced selected sputum has the advantage over bronchoalveolar lavage of higher density of cell recovery and stronger signal for fluid-phase markers.

Long-term (5 year) safety of bronchial thermoplasty: Asthma Intervention Research (AIR) trial

BackgroundBronchial thermoplasty (BT) is a bronchoscopic procedure that improves asthma control by reducing excess airway smooth muscle. Treated patients have been followed out to 5 years to evaluate long-term safety of this procedure.MethodsPatients enrolled in the Asthma Intervention Research Trial were on inhaled corticosteroids ≥200 μg beclomethasone or equivalent + long-acting-beta2-agonists and demonstrated worsening of asthma on long-acting-β2-agonist withdrawal. Following initial evaluation at 1 year, subjects were invited to participate in a 4 year safety study. Adverse events (AEs) and spirometry data were used to assess long-term safety out to 5 years post-BT.Results45 of 52 treated and 24 of 49 control group subjects participated in long-term follow-up of 5 years and 3 years respectively. The rate of respiratory adverse events (AEs/subject) was stable in years 2 to 5 following BT (1.2, 1.3, 1.2, and 1.1, respectively,). There was no increase in hospitalizations or emergency room visits for respiratory symptoms in Years 2, 3, 4, and 5 compared to Year 1. The FVC and FEV1 values showed no deterioration over the 5 year period in the BT group. Similar results were obtained for the Control group.ConclusionsThe absence of clinical complications (based on AE reporting) and the maintenance of stable lung function (no deterioration of FVC and FEV1) over a 5-year period post-BT in this group of patients with moderate to severe asthma support the long-term safety of the procedure out to 5 years.

A randomized, controlled trial comparing thoracoscopy and limited thoracotomy for lung biopsy in interstitial lung disease

BACKGROUND Lung biopsies are frequently needed to diagnose diffuse interstitial lung diseases. A prospective randomized, controlled trial comparing limited thoracotomy (open lung biopsy) and thoracoscopy for lung biopsy was done. METHODS Ambulatory patients with a clinical diagnosis of diffuse interstitial lung disease were randomized to thoracoscopy or limited thoracotomy. Data on postoperative pain, narcotic requirements, operating room time, adequacy of biopsy, duration of chest tube drainage, length of hospital stay, spirometry, and complications were collected. RESULTS A total of 42 randomized patients underwent lung biopsy (thoracoscopy 20, thoracotomy 22). The two study groups were comparable with respect to age, gender, corticosteroid use, and preoperative spirometry. Visual analog scale pain scores were nearly identical in the two groups (p = 0.397). Total morphine dose was 50.8 +/- 27.3 mg in the thoracoscopy group and 52.5 +/- 25.6 mg in the thoracotomy group (p = 0.86). Spirometry (FEV1) values in the two groups were not significantly different on postoperative days 1, 2, 14, and 28 (p = 0.665). Duration of operation was similar in both groups (thoracoscopy 40 +/- 30 minutes, thoracotomy 37 +/- 15 minutes; p = 0.67). The thoracoscopy and thoracotomy groups had equivalent duration of chest tube drainage (thoracoscopy 38 +/- 28 hours, thoracotomy 31 +/- 26 hours; p = 0.47) and length of hospital stay (thoracoscopy 77 +/- 82 hours, thoracotomy 69 +/- 55 hours; p = 0.72). Definitive pathologic diagnoses were made in all patients. CONCLUSIONS There is no clinical or statistical difference in outcomes for thoracoscopic and thoracotomy approaches. Both thoracoscopy and thoracotomy are acceptable procedures for diagnostic lung biopsy in diffuse interstitial lung disease.

Persistence of effectiveness of bronchial thermoplasty in patients with severe asthma

BACKGROUND Bronchial thermoplasty (BT) has been demonstrated to be safe and effective in the treatment of severe persistent asthma out to at least 1 year. Preclinical studies have demonstrated that the reduction in airway smooth muscle after bronchial thermoplasty persists out to at least 3 years. OBJECTIVES To examine the persistence of effectiveness of BT 2 years posttreatment in subjects with severe asthma. METHODS Subjects participating in the long-term safety follow-up phase of the Asthma Intervention Research 2 (AIR2) Trial were evaluated by comparing the proportion of subjects who experienced exacerbations, adverse events, or healthcare utilization during the first year (year 1) after BT treatment with the proportion of subjects who experienced the same during the subsequent 12 months (year 2). RESULTS Severe exacerbations, respiratory adverse events, emergency department visits for respiratory symptoms, and hospitalizations for respiratory symptoms (proportion of subjects experiencing and rates of events), and stability of pre- and post-bronchodilator forced expiratory volume in 1 second (FEV(1)), were comparable between years 1 and 2. The proportion of subjects experiencing severe exacerbations in year 2 after BT was 23.0%, compared with 30.9% in year 1. CONCLUSIONS The reduction in the proportion of subjects experiencing severe exacerbations after BT is maintained for at least 2 years. Bronchial thermoplasty provides beneficial long-term effects on asthma outcomes in patients with severe asthma. TRIAL REGISTRATION clinicaltrials.gov, Identifier: NCT00231114.