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2. Severe Asthma Standard-of-Care Background Medication Reduction With Benralizumab: ANDHI in Practice Substudy

Author

Pohl, Wolfgang, Doberer, Daniel, Martinot, Jean Benoit, Deschampheleire, Maud, Himpe, Ulrike, Chapman, Kenneth, Cheema, Amarjit, Dorscheid, Delbert, Ramsey, Clare, Rolf, Jeffrey, Walker, Brandie, Olivenstein, Ronald, Poirier, Claude, Larivee, Pierre, Bjerrum, Anne Sofie, Titlestad, Ingrid, Hilberg, Ole, Kilpeläinen, Maritta, Bonniaud, Philippe, Taillé, Camille, Tiotiu, Iuliana-Angelica, Girodet, Pierre-Olivier, Blanc, François-Xavier, Pradelli, Johana, Didier, Alain, Nocent Ejnaini, Cecilia, Deslee, Gaetan, Pison, Christophe, Douadi, Youcef, Mahay, Guillaume, Devouassoux, Gilles, Melloni, Boris, Roux, Pauline-Marie, Bourdin, Arnaud, Fry, Stephanie, Schaum, Thomas, Schulz, Christian, Skowasch, Dirk, Taube, Christian, Welte, Tobias, Gleiber, Wolfgang, Brehler, Randolf, Schreiber, Jens, Schuette, Wolfgang, Kronsbein, Juliane, Bonnet, Reiner, Beck, Ekkehard, Lacedonia, Donato, Senna, Gianenrico, Caruso, Cristiano, Crimi, Nunzio, Blasi, Francesco, Santus, Pierachille, Canonica, Giorgio Walter, Guarnieri, Gabriella, Pelaia, Girolamo, Milanese, Manlio, Micheletto, Claudio, Corsico, Angelo Guido, Scichilone, Nicola, Spadaro, Giuseppe, Langeveld, Bas, Holters, Jurgen, Willem van den Berg, Jan, Smit, Arthur, Conemans, Lennart, van Veen, Helena, Staaks, Gerald, Lehmann, Sverre, Echave-Sustaeta, Jose Maria, Ribas, Christian Domingo, de Luiz Martinez, Gustavo, Gonzalez Perez, Ruperto, Garcia Rivero, Juan Luis, Gall, Xavier Muñoz, Soto Campos, Jose Gregorio, Mozo, Paloma Campo, Pan, Carmen Vidal, Fernandez, Ana Gomez-Bastero, Tellez, Sergio Campos, Rivera, Carlos Martinez, Bobolea, Irina Diana, Guerrero, Raquel Morillo, Garcia, Ismael Ali, Rodriguez Hermosa, Juan Luis, Stenfors, Nikolai, Tunsäter, Alf, Curiac, Dan, von Garnier, Christophe, Leuppi, Joerg, Schmid-Grendelmeier, Peter, Nasser, Shuaib, Chaudhuri, Rekha, Nordstrom, Monica, Saralaya, Dinesh, Pfeffer, Paul, Mansur, Adel, Short, Philip, Wenzel, Sally, Cherry, William Brett, Zafra, Heidi, Gonzalez, Erika, Soong, Weily, Davis, Benjamin, Kao, Neil, Hussain, Iftikhar, Maselli Caceres, Diego Jose, Harris, James, Calhoun, William, Rodicio, Ileana, Kaufman, David, Moss, Mark, Sztejman, Eric, DeLeon, Samuel, Sumino, Kaharu, Kashyap, Ravindra, Leflein, Jeffrey, Hajal, Rizan, Fakih, Faisal, Hill, David, Lin, Robert, Jarratt, Mikell, Subramaniam, Vijay, Sussman, Robert, Mumneh, Nayla, Reibman, Joan, Darveaux, Jared, Tan, Ricardo, Tanus, Tonny, Sikand, Vinay, Marshall, Gailen, Mehta, Hemalini, Cole, Jeremy, Goodman, Brad, Goss, Deborah, Bardelas, Jose, Milstone, Aaron, Mehta, Vinay, Clore, Lee, Millard, Mark, Palumbo, Michael, Puppala, Dileep, Leong, Mila, Prenner, Bruce, Robinette, Emory, Heidarian Raissy, Hengameh, Fost, David, Pleskow, Warren, Marcus, Michael, Ilowite, Jonathan, Moore, Wendy, Steven, Gary, De la Cruz, Luis, Chupp, Geoffrey, Berger, William, Randolph, Christopher, Holguin, Fernando, Kureishy, Shahrukh, Campbell, Edward, Peche, Rudi, Pini, Laura, Papi, Alberto, Beghé, Bianca, Peveri, Silvia, Henriquez Santa, Aythamy, Ramos Gonzalez, Jacinto, Vinge, Ines, St. John, Roy, Louis, Renaud, Harrison, Tim W., Chanez, Pascal, Menzella, Francesco, Philteos, George, Cosio, Borja G., Lugogo, Njira L., de Luiz, Gustavo, Burden, Annie, Adlington, Timothy, Keeling, Nanna, Kwiatek, Justin, and Garcia Gil, Esther

Published
2023
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4. Onset of effect and impact on health-related quality of life, exacerbation rate, lung function, and nasal polyposis symptoms for patients with severe eosinophilic asthma treated with benralizumab (ANDHI): a randomised, controlled, phase 3b trial

Author

Pohl, Wolfgang, Voves, Robert, Deschampheleire, Maud, Louis, Renaud, Martinot, Jean-Benoit, Peché, Rudi, Chapman, Kenneth, Cheema, Amarjit, Dorscheid, Delbert, FitzGerald, J. Mark, Gagnon, Remi, Killorn, William Patrick, Olivenstein, Ronald, Philteos, George, Ramsey, Clare, Rolf, J. Douglass, Walker, Brandie, Hilberg, Ole, Skjold, Tina, Titlestad, Ingrid, Hakulinen, Auli, Kilpeläinen, Maritta, Ben Hayoun, Michèle, Bonniaud, Philippe, Bourdin, Arnaud, Chanez, Pascal, De Blay, Frédéric, Deslee, Gaëtan, Devouassoux, Gilles, Didier, Alain, Douadi, Youcef, Fry, Stéphanie, Garcia, Gilles, Girodet, Pierre-Olivier, Leroyer, Christophe, Magnan, Antoine, Mahay, Guillaume, Nocent, Cécilia, Pison, Christophe, Roux, Pauline-Marie, Taillé, Camille, Tiotiu, Juliana-Angelica, Beck, Ekkehard, Jandl, Margret, Kaehler, Christian, Kässner, Frank, Koesters, Frank, Kronsbein, Juliane, Schaum, Thomas, Schulz, Christian, Skowasch, Dirk, Taube, Christian, Welte, Tobias, de Roux, Andrés, Beghé, Bianca, Blasi, Francesco, Canonica, Giorgio Walter, Carpagnano, Giovanna, Caruso, Cristiano, Corsico, Angelo Guido, Constantino, Elio, Crimi, Nunzio, Maestrelli, Piero, Menzella, Francesco, Milanese, Manlio, Papi, Alberto, Pelaia, Girolamo, Pini, Laura, Santus, Pierachille, Savi, Eleonora, Scichilone, Nicola, Senna, Gianenrico, Spadaro, Giuseppe, Vaghi, Adriano, Gans, Steven, Hölters, Jurgen, Langeveld, B., Pieters, Willem, Staaks, G.H.A., van Veen, Ilonka, van den Berg, J.W.K., Einvik, Gunnar, Lehmann, Sverre, Ali García, Ismael, Almonacid, Carlos, Bobolea, Irina, Campo Mozo, Paloma, de Luiz, Gustavo, Domingo Ribas, Christian, Echave-Sustaeta María-Tomé, José María, García Rivero, Juan Luis, García-Cosío Piqueras, Borja, Gómez-Bastero Fernández, Ana, González Pérez, Ruperto, Henríquez Santa, Aythamy, Martínez Rivera, Carlos, Muñoz Gall, Xavier, Ramos, Jacinto, Gregorio Soto Campos, Jose, Vidal Pan, Carmen, Stenfors, Nikolai, Tunsäter, Alf, Vinge, Ines, Chaudhuri, Rekha, Harrison, Timothy, Mansur, Adel, Nasser, Shuaib, Nordstrom, Monica, Pfeffer, Paul, Saralaya, Dinesh, Short, Philip, Adlakha, Arun, Alpan, Oral, Averill, Francis, Badhwar, Anil, Bardelas, Jose, Baxter, Barbara, Bensch, George, Berger, William, Bernstein, Jonathan, Bridges, Tracy, Brimeyer, Ryan, Calhoun, William, Campbell, Edward, Cherry, William Brett, Chupp, Geoffrey, Clore, Lee, Cohn, John, Cole, Jeremy, Condemi, John, Cury, James, Davis, Benjamin, DeLeon, Samuel, Delacruz, Luis, Diaz, Joseph, Erb, David, Eziri, Emeka, Fakih, Faisal, Fiedler, Douglas, Fost, David, Fritz, Stephen, Gonzalez, Erika, Goodman, Brad, Gottlieb, Peter, Gottschlich, Gregory, Gower, Richard, Hajal, Rizan, Harris, James, Heidarian-Raissy, Hengameh, Heyder, Albrecht, Hill, David, Holguin, Fernando, Hussain, Iftikhar, Illowite, Jonathan, Jacobs, Joshua, Jarratt, Mikell, Kaiser, Harold, Kao, Neil, Kashyap, Ravindra, Kaufman, David, Kent, Edward, Kim, Kenneth, Klein, Ryan, Kraft, Monica, Kono, Ritsu, Kureishy, Shahrukh, Leflein, Jeffrey, Leong, Mila, Li, Huamin, Lin, Robert, Lugogo, Njira, Marcus, Michael, Maselli Caceres, Diego Jose, Mehta, Vinay, Mello, Curtis, Millard, Mark, Milstone, Aaron, Mohan, Arjun, Moore, Wendy, Moss, Mark, Mumneh, Nayla, O'Brien, Thomas, Ostransky, David, Palumbo, Michael, Parikh, Purvi, Parikh, Sudhir, Patel, Amit, Perez, Guido, Pleskow, Warren, Prenner, Bruce, Puppala, Dileep, Ramey, John, Reibman, Joan, Reyes, Ramon, Robinette, Emory, Rodicio, Ileana, Ryan, Stephen, Sekhsaria, Sudhir, Sigal, Barry, Sikand, Vinay, Soong, Weily, Spangenthal, Selwyn, St. John, Roy, Steven, Gary, Subramaniam, Vijay, Sumino, Kaharu, Sztejman, Eric, Tan, Ricardo A., Tanus, Tonny, Thompson, Charles, Thornblade, Carl, Villareal, Manuel, Wenzel, Sally, Zafra, Heidi, Ziedalski, Tomasz, Harrison, Tim W, Cosio, Borja G, Lugogo, Njira L, Burden, Annie, McDermott, Lawrence, Garcia Gil, Esther, and Zangrilli, James G

Published
2021
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6. Reduced decline of lung diffusing capacity in COPD patients with diabetes and metformin treatment

Author

Kahnert, Kathrin, Andreas, Stefan, Kellerer, Christina, Lutter, Johanna I., Lucke, Tanja, Yildirim, Önder, Lehmann, Mareike, Seissler, Jochen, Behr, Jürgen, Frankenberger, Marion, Bals, Robert, Watz, Henrik, Welte, Tobias, Trudzinski, Franziska C., Vogelmeier, Claus F., Alter, Peter, Jörres, Rudolf A., Bahmer, Thomas, Bewig, Burkhard, Ewert, Ralf, Stubbe, Beate, Ficker, Joachim H., Grohé, Christian, Held, Matthias, Henke, Markus, Herth, Felix, Kirsten, Anne-Marie, Koczulla, Rembert, Kronsbein, Juliane, Kropf-Sanchen, Cornelia, Herzmann, Christian, Pfeifer, Michael, Randerath, Winfried J., Seeger, Werner, Studnicka, Michael, Taube, Christian, Timmermann, Hartmut, Schmeck, Bernd, Vogelmeier, Claus, and Wirtz, Hubert

Subjects
Male, Epidemiology, Science, Vital Capacity, Medizin, Article, Body Mass Index, Cohort Studies, Pulmonary Disease, Chronic Obstructive, Sex Factors, Forced Expiratory Volume, Diabetes Mellitus, Humans, Hypoglycemic Agents, Lung, Aged, Multidisciplinary, Smoking, Age Factors, Middle Aged, respiratory system, Metformin, respiratory tract diseases, Pulmonary Emphysema, Pulmonary Diffusing Capacity, Medicine, Female, Drug therapy
Abstract

We studied whether in patients with COPD the use of metformin for diabetes treatment was linked to a pattern of lung function decline consistent with the hypothesis of anti-aging effects of metformin. Patients of GOLD grades 1–4 of the COSYCONET cohort with follow-up data of up to 4.5 y were included. The annual decline in lung function (FEV1, FVC) and CO diffusing capacity (KCO, TLCO) in %predicted at baseline was evaluated for associations with age, sex, BMI, pack-years, smoking status, baseline lung function, exacerbation risk, respiratory symptoms, cardiac disease, as well as metformin-containing therapy compared to patients without diabetes and metformin. Among 2741 patients, 1541 (mean age 64.4 y, 601 female) fulfilled the inclusion criteria. In the group with metformin treatment vs. non-diabetes the mean annual decline in KCO and TLCO was significantly lower (0.2 vs 2.3, 0.8 vs. 2.8%predicted, respectively; p 1 and FVC. These results were confirmed using multiple regression and propensity score analyses. Our findings demonstrate an association between the annual decline of lung diffusing capacity and the intake of metformin in patients with COPD consistent with the hypothesis of anti-aging effects of metformin as reflected in a surrogate marker of emphysema.

Published
2022

7. The association of cognitive functioning as measured by the DemTect with functional and clinical characteristics of COPD: results from the COSYCONET cohort

Author

von Siemens, Sarah Marietta, Perneczky, Robert, Waschki, Benjamin, Lutter, Johanna I, Welte, Tobias, Jörres, Rudolf A, Kahnert, Kathrin, group, COSYCONET study, Andreas, Stefan, Bals, Robert, Behr, Jürgen, Vogelmeier, Claus F, Bewig, Burkhard, Buhl, Roland, Ewert, Ralf, Stubbe, Beate, Gogol, Manfred, Grohé, Christian, Hauck, Rainer, Held, Matthias, Jany, Berthold, Henke, Markus, Herth, Felix, Höffken, Gerd, Katus, Hugo A, Kirsten, Anne-Marie, Watz, Henrik, Koczulla, Rembert, Kenn, Klaus, Kronsbein, Juliane, Kropf-Sanchen, Cornelia, Lange, Christoph, Kauffmann-Guerrero, Diego, Zabel, Peter, Pfeifer, Michael, Randerath, Winfried J, Seeger, Werner, Studnicka, Michael, Taube, Christian, Teschler, Helmut, Timmermann, Hartmut, Virchow, J Christian, Vogelmeier, Claus, Alter, Peter, Wagner, Ulrich, Wirtz, Hubert, Trudzinski, Franziska C, and Söhler, Sandra

Subjects
Male, medicine.medical_specialty, epidemiology [Cognitive Dysfunction], psychology [Pulmonary Disease, Chronic Obstructive], Medizin, Comorbidity, Cohort Studies, 03 medical and health sciences, FEV1/FVC ratio, Pulmonary Disease, Chronic Obstructive, 0302 clinical medicine, Cognition, epidemiology [Pulmonary Disease, Chronic Obstructive], Surveys and Questionnaires, medicine, Dementia, Humans, COPD, Cognitive Dysfunction, ddc:610, Cognitive skill, Path analysis (statistics), Aged, lcsh:RC705-779, business.industry, Research, physiology [Cognition], diagnosis [Pulmonary Disease, Chronic Obstructive], lcsh:Diseases of the respiratory system, Middle Aged, medicine.disease, Mental Status and Dementia Tests, humanities, Cross-Sectional Studies, Cognitive impairment, diagnosis [Cognitive Dysfunction], 030228 respiratory system, Cohort, Physical therapy, Female, psychology [Cognitive Dysfunction], business, 030217 neurology & neurosurgery, Cognitive load
Abstract

Alterations of cognitive functions have been described in COPD. Our study aimed to disentangle the relationship between the degree of cognitive function and COPD characteristics including quality of life (QoL).Data from 1969 COPD patients of the COSYCONET cohort (GOLD grades 1–4; 1216 male/ 753 female; mean (SD) age 64.9 ± 8.4 years) were analysed using regression and path analysis. The DemTect screening tool was used to measure cognitive function, and the St. George‘s respiratory questionnaire (SGRQ) to assess disease-specific QoL.DemTect scores were =60 years of age. For statistical reasons, we used the average of both algorithms independent of age in all subsequent analyses. The DemTect scores were associated with oxygen content, 6-min-walking distance (6-MWD), C-reactive protein (CRP), modified Medical Research Council dyspnoea scale (mMRC) and the SGRQ impact score. Conversely, the SGRQ impact score was independently associated with 6-MWD, FVC, mMRC and DemTect. These results were combined into a path analysis model to account for direct and indirect effects. The DemTect score had a small, but independent impact on QoL, irrespective of the inclusion of COPD-specific influencing factors or a diagnosis of cognitive impairment.We conclude that in patients with stable COPD lower oxygen content of blood as a measure of peripheral oxygen supply, lower exercise capacity in terms of 6-MWD, and higher CRP levels were associated with reduced cognitive capacity. Furthermore, a reduction in cognitive capacity was associated with reduced disease-specific quality of life. As a potential clinical implication of this work, we suggest to screen especially patients with low oxygen content and low 6-MWD for cognitive impairment.

Published
2022
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8. Associations of oxygenated hemoglobin with disease burden and prognosis in stable COPD: Results from COSYCONET

Author

Trudzinski, F.C., Jörres, R.A., Alter, P., Kahnert, K., Waschki, B., Herr, C., Kellerer, C., Omlor, A., Vogelmeier, C.F., Fähndrich, S., Watz, H., Welte, T., Jany, B., Söhler, S., Biertz, F., Herth, F., Kauczor, H.-U., Bals, R., Andreas, Stefan, Behr, Jürgen, Bewig, Burkhard, Buhl, Roland, Ewert, Ralf, Stubbe, Beate, Ficker, Joachim H., Gogol, Manfred, Grohé, Christian, Hauck, Rainer, Held, Matthias, Henke, Markus, Höffken, Gerd, Katus, Hugo A., Kirsten, Anne-Marie, Koczulla, Rembert, Kenn, Klaus, Kronsbein, Juliane, Kropf-Sanchen, Lange, Christoph, Zabel, Peter, Pfeifer, Michael, Randerath, Winfried J., Seeger, Werner, Studnicka, Michael, Taube, Christian, Teschler, Helmut, Timmermann, Hartmut, Virchow, J. Christian, Wagner, and Wirtz, Hubert

Subjects
Adult, Male, medicine.medical_specialty, Exacerbation, Medizin, lcsh:Medicine, Severity of Illness Index, Gastroenterology, Article, Pulmonary Disease, Chronic Obstructive, 03 medical and health sciences, Medical research, 0302 clinical medicine, Internal medicine, medicine, Humans, 030212 general & internal medicine, Signs and symptoms, lcsh:Science, Survival rate, Aged, Oxygen saturation (medicine), Aged, 80 and over, Inflammation, COPD, Oxygenated Hemoglobin, Multidisciplinary, Proportional hazards model, business.industry, Hazard ratio, lcsh:R, Middle Aged, Prognosis, medicine.disease, Comorbidity, Survival Rate, Risk factors, 030228 respiratory system, Oxyhemoglobins, Female, lcsh:Q, Blood Gas Analysis, business, Biomarkers
Abstract

We studied whether in patients with stable COPD blood gases (BG), especially oxygenated hemoglobin (OxyHem) as a novel biomarker confer information on disease burden and prognosis and how this adds to the information provided by the comorbidity pattern and systemic inflammation. Data from 2137 patients (GOLD grades 1–4) of the baseline dataset of the COSYCONET COPD cohort were used. The associations with dyspnea, exacerbation history, BODE-Index (cut-off ≤2) and all-cause mortality over 3 years of follow-up were determined by logistic and Cox regression analyses, with sex, age, BMI and pack years as covariates. Predictive values were evaluated by ROC curves. Capillary blood gases included SaO2, PaO2, PaCO2, pH, BE and the concentration of OxyHem [haemoglobin (Hb) x fractional SaO2, g/dL] as a simple-to-measure correlate of oxygen content. Inflammatory markers were WBC, CRP, IL-6 and -8, TNF-alpha and fibrinogen, and comorbidities comprised a broad panel including cardiac and metabolic disorders. Among BG, OxyHem was associated with dyspnoea, exacerbation history, BODE-Index and mortality. Among inflammatory markers and comorbidities, only WBC and heart failure were consistently related to all outcomes. ROC analyses indicated that OxyHem provided information of a magnitude comparable to that of WBC, with optimal cut-off values of 12.5 g/dL and 8000/µL, respectively. Regarding mortality, OxyHem also carried independent, additional information, showing a hazard ratio of 2.77 (95% CI: 1.85–4.15, p 8000/µL was 2.33 (95% CI: 1.60–3.39, p 2. It thus appears well suited for clinical use with minimal equipment, especially for GPs.

Published
2020

9. Biomarkers for Comorbidities Modulate the Activity of T-Cells in COPD

Author

Jameel, Kaschin Jamal, Gallert, Willem-Jakob, Yanik, Sarah D., Panek, Susanne, Kronsbein, Juliane, Jungck, David, Koch, Andrea, and Knobloch, Jürgen

Subjects
Male, Smokers, QH301-705.5, T-Lymphocytes, T-cells, Smoking, Comorbidity, Middle Aged, comorbidities, Article, Pulmonary Disease, Chronic Obstructive, Chemistry, Case-Control Studies, Germany, Cytokines, Humans, COPD, Female, ddc:610, Biology (General), QD1-999, Biomarkers
Abstract

In smoking-induced chronic obstructive pulmonary disease (COPD), various comorbidities are linked to systemic inflammation and infection-induced exacerbations. The underlying mechanisms are unclear but might provide therapeutic targets. T-cell activity is central in systemic inflammation and for infection-defense mechanisms and might be influenced by comorbidities. Hypothesis: Circulating biomarkers of comorbidities modulate the activity of T-cells of the T-helper type 1 (Th1) and/or T-cytotoxic type 1 (Tc1). T-cells in peripheral blood mononuclear cells (PBMCs) from non-smokers (NS), current smokers without COPD (S), and COPD subjects (total n = 34) were ex vivo activated towards Th1/Tc1 and were then stimulated with biomarkers for metabolic and/or cardiovascular comorbidities (Brain Natriuretic Peptide, BNP, chemokine (C-C motif) ligand 18, CCL18, C-X3-C motif chemokine ligand 1, CX3CL1, interleukin-18, IL-18) or for asthma- and/or cancer-related comorbidities (CCL22, epidermal growth factor, EGF, IL-17, periostin) each at 10 or 50 ng/mL. The Th1/Tc1 activation markers interferon-γ (IFNγ), tumor necrosis factor-α (TNFα), and granulocyte-macrophage colony-stimulating factor (GM-CSF) were analyzed in culture supernatants by Enzyme-Linked Immunosorbent Assay (ELISA). Ex-vivo activation induced IFNγ and TNFα without differences between the groups but GM-CSF more in S vs. NS. At 10 ng/mL, the different biomarkers increased or reduced the T-cell activation markers without a clear trend for one direction in the different categories of comorbidities or for the different T-cell activation markers. At 50 ng/mL, there was a clear shift towards suppressive effects, particularly for the asthma— and cancer-related biomarkers and in cells of S and COPD. Comorbidities might suppress T-cell immunity in COPD. This could explain the association of comorbidities with frequent exacerbations.

Published
2021

11. LABAs and p38MAPK Inhibitors Reverse the Corticosteroid-Insensitivity of IL-8 in Airway Smooth Muscle Cells of COPD

Author

Knobloch, Jürgen (PD Dr. rer. nat.), Jungck, David (Dr. med.), Kronsbein, Juliane (Dr. med.), Stölben, Erich (Prof. Dr. med.), Ito, Kazuhiro (Dr.), and Koch, Andrea (Prof. Dr. med.)

Subjects
p38mapk isoforms, Communication, long-acting-β2-agonist (laba), reversion of corticosteroid resistance, non-type 2 inflammation, lcsh:R, copd phenotypes, lcsh:Medicine, ddc:610, hormones, hormone substitutes, and hormone antagonists, respiratory tract diseases
Abstract

Airway inflammation in chronic obstructive pulmonary disease (COPD) is partially insensitive/resistant to inhaled corticosteroids (ICS). ICS plus bronchodilator therapy has been discussed for COPD phenotypes with frequent exacerbations and participation of corticosteroid-sensitive type 2/eosinophilic inflammation. Neutralization of non-type 2/IL-8-associated airway inflammation by reversion of its corticosteroid-resistance might be a future strategy for other phenotypes. Human airway smooth muscle cells (HASMCs) produce corticosteroid-insensitive IL-8 in response to TNF\(\alpha\) or LPS in stable disease stages or bacteria-induced exacerbations, respectively. p38-mitogen-activated-protein-kinases (p38MAPKs) are alternative therapeutic targets. Hypothesis: long-acting-\(\beta\)2-agonists (LABAs) reverse the corticosteroid-insensitivity of IL-8 by p38MAPK inhibition in HASMCs. Cultivated HASMCs from COPD subjects were pre-incubated with formoterol, salmeterol, fluticasone-propionate, BIRB796 (p38MAPK\(\alpha\), -\(\gamma\), -\(\delta\) inhibitor), and/or SB203580 (p38MAPK\(\alpha\) and -\(\beta\) inhibitor) before stimulation with TNF\(\alpha\) or LPS. IL-8 and MAPK-activities were measured by ELISA. Formoterol, salmeterol, and fluticasone did not or hardly reduced TNF\(\alpha\)- or LPS-induced IL-8. BIRB796 and SB203580 reduced TNF\(\alpha\)-induced IL-8. SB203580 reduced LPS-induced IL-8. Fluticasone/formoterol, fluticasone/salmeterol, and fluticasone/BIRB796, but not fluticasone/SB203580 combinations, reduced TNF\(\alpha\)-induced IL-8 stronger than single treatments. All combinations including fluticasone/SB203580 reduced LPS-induced IL-8 stronger than single treatments. TNF\(\alpha\) induced p38MAPK\(\alpha\) and -\(\gamma\) activity. LPS induced p38MAPK\(\alpha\) activity. Formoterol reduced TNF\(\alpha\)-induced p38MAPK\(\gamma\) and LPS-induced p38MAPK\(\alpha\) activity. LABAs reverse the corticosteroid-insensitivity of IL-8 in airway smooth muscles via p38MAPK\(\gamma\) in stable disease and via p38MAPK\(\alpha\) in exacerbations. Our pre-clinical data indicate a utility for also adding ICS in non-type 2 inflammatory COPD phenotypes to bronchodilator therapy. Depending on phenotype and disease stage, isoform-specific p38MAPK blockers might also reverse corticosteroid-resistance in COPD.

Published
2019

13. No evidence for WU polyomavirus infection in chronic obstructive pulmonary disease

Author

Ringshausen Felix C, Heckmann Marei, Weissbrich Benedikt, Neske Florian, Borg Irmgard, Knoop Umut, Kronsbein Juliane, Hauptmeier Barbara M, Schultze-Werninghaus Gerhard, and Rohde Gernot

Subjects
Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282, Infectious and parasitic diseases, RC109-216
Abstract

Abstract Human polyomaviruses are known to cause persistent or latent infections, which are reactivated under immunosuppression. Polyomaviruses have been found to immortalize cell lines and to possess oncogenic properties. Moreover, the recently discovered Merkel cell polyomavirus shows a strong association with human Merkel cell carcinomas. Another novel human polyomavirus, WU polyomavirus (WUPyV), has been identified in respiratory specimens from patients with acute respiratory tract infections (ARTI). WUPyV has been proposed to be a pathogen in ARTI in early life and immunocompromised individuals, but so far its role as a causative agent of respiratory disease remains controversial. The objective of our study was to determine the prevalence of WUPyV infections in adult hospitalized patients with acute exacerbation of chronic obstructive pulmonary disease (COPD) and to establish its potential clinical relevance by comparison to patients with stable COPD hospitalized for other reasons than acute exacerbation of COPD (AE-COPD). A total of 378 respiratory specimens, each 189 induced sputum and nasal lavage samples from 189 patients, who had been recruited in a prospective 2:1 ratio case-control set-up between 1999 and 2003, were evaluated for the presence of WUPyV DNA by real-time PCR. In the present study we could not detect WUPyV DNA in 378 respiratory specimens from 189 adult hospitalized patients with AE-COPD and stable COPD in four consecutive years. Persistence of viral replication or reactivation of latent WUPyV infection did not occur. WUPyV may not play a major role in adult immunocompetent patients with AE-COPD and stable COPD.

Published
2009
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15. Biomarkers for Comorbidities Modulate the Activity of T-Cells in COPD.

Author

Jamal Jameel, Kaschin, Gallert, Willem-Jakob, Yanik, Sarah D., Panek, Susanne, Kronsbein, Juliane, Jungck, David, Koch, Andrea, and Knobloch, Jürgen

Subjects
MONONUCLEAR leukocytes, GRANULOCYTE-macrophage colony-stimulating factor, OBSTRUCTIVE lung diseases, EPIDERMAL growth factor, GRANULOCYTES, ENZYME-linked immunosorbent assay, CEREBROSPINAL fluid
Abstract

In smoking-induced chronic obstructive pulmonary disease (COPD), various comorbidities are linked to systemic inflammation and infection-induced exacerbations. The underlying mechanisms are unclear but might provide therapeutic targets. T-cell activity is central in systemic inflammation and for infection-defense mechanisms and might be influenced by comorbidities. Hypothesis: Circulating biomarkers of comorbidities modulate the activity of T-cells of the T-helper type 1 (Th1) and/or T-cytotoxic type 1 (Tc1). T-cells in peripheral blood mononuclear cells (PBMCs) from non-smokers (NS), current smokers without COPD (S), and COPD subjects (total n = 34) were ex vivo activated towards Th1/Tc1 and were then stimulated with biomarkers for metabolic and/or cardiovascular comorbidities (Brain Natriuretic Peptide, BNP; chemokine (C-C motif) ligand 18, CCL18; C-X3-C motif chemokine ligand 1, CX3CL1; interleukin-18, IL-18) or for asthma- and/or cancer-related comorbidities (CCL22; epidermal growth factor, EGF; IL-17; periostin) each at 10 or 50 ng/mL. The Th1/Tc1 activation markers interferon-γ (IFNγ), tumor necrosis factor-α (TNFα), and granulocyte-macrophage colony-stimulating factor (GM-CSF) were analyzed in culture supernatants by Enzyme-Linked Immunosorbent Assay (ELISA). Ex-vivo activation induced IFNγ and TNFα without differences between the groups but GM-CSF more in S vs. NS. At 10 ng/mL, the different biomarkers increased or reduced the T-cell activation markers without a clear trend for one direction in the different categories of comorbidities or for the different T-cell activation markers. At 50 ng/mL, there was a clear shift towards suppressive effects, particularly for the asthma— and cancer-related biomarkers and in cells of S and COPD. Comorbidities might suppress T-cell immunity in COPD. This could explain the association of comorbidities with frequent exacerbations. [ABSTRACT FROM AUTHOR]

Published
2021
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16. Onset of effect and impact on health-related quality of life, exacerbation rate, lung function, and nasal polyposis symptoms for patients with severe eosinophilic asthma treated with benralizumab (ANDHI): a randomised, controlled, phase 3b trial

Author

Harrison, Tim W, Chanez, Pascal, Menzella, Francesco, Canonica, Giorgio Walter, Louis, Renaud, Cosio, Borja G, Lugogo, Njira L, Mohan, Arjun, Burden, Annie, McDermott, Lawrence, Garcia Gil, Esther, Zangrilli, James G, Wolfgang Pohl, Robert Voves, Maud Deschampheleire, Renaud Louis, Jean-Benoit Martinot, Rudi Peché, Kenneth Chapman, Amarjit Cheema, Delbert Dorscheid, J Mark FitzGerald, Remi Gagnon, William Patrick Killorn, Ronald Olivenstein, George Philteos, Clare Ramsey, J Douglass Rolf, Brandie Walker, Ole Hilberg, Tina Skjold, Ingrid Titlestad, Auli Hakulinen, Maritta Kilpeläinen, Michèle Ben Hayoun, Philippe Bonniaud, Arnaud Bourdin, Pascal Chanez, Frédéric De Blay, Gaëtan Deslee, Gilles Devouassoux, Alain Didier, Youcef Douadi, Stéphanie Fry, Gilles Garcia, Pierre-Olivier Girodet, Christophe Leroyer, Antoine Magnan, Guillaume Mahay, Cécilia Nocent, Christophe Pison, Pauline-Marie Roux, Camille Taillé, Juliana-Angelica Tiotiu, Ekkehard Beck, Margret Jandl, Christian Kaehler, Frank Kässner, Frank Koesters, Juliane Kronsbein, Thomas Schaum, Christian Schulz, Dirk Skowasch, Christian Taube, Tobias Welte, Andrés de Roux, Bianca Beghé, Francesco Blasi, Giorgio Walter Canonica, Giovanna Carpagnano, Cristiano Caruso, Angelo Guido Corsico, Elio Constantino, Nunzio Crimi, Piero Maestrelli, Francesco Menzella, Manlio Milanese, Alberto Papi, Girolamo Pelaia, Laura Pini, Pierachille Santus, Eleonora Savi, Nicola Scichilone, Gianenrico Senna, Giuseppe Spadaro, Adriano Vaghi, Steven Gans, Jurgen Hölters, B Langeveld, Willem Pieters, G H A Staaks, Ilonka van Veen, J W K van den Berg, Gunnar Einvik, Sverre Lehmann, Ismael Ali García, Carlos Almonacid, Irina Bobolea, Paloma Campo Mozo, Gustavo de Luiz, Christian Domingo Ribas, José María Echave-Sustaeta María-Tomé, Juan Luis García Rivero, Borja García-Cosío Piqueras, Ana Gómez-Bastero Fernández, Ruperto González Pérez, Aythamy Henríquez Santa, Carlos Martínez Rivera, Xavier Muñoz Gall, Jacinto Ramos, Jose Gregorio Soto Campos, Carmen Vidal Pan, Nikolai Stenfors, Alf Tunsäter, Ines Vinge, Rekha Chaudhuri, Timothy Harrison, Adel Mansur, Shuaib Nasser, Monica Nordstrom, Paul Pfeffer, Dinesh Saralaya, Philip Short, Arun Adlakha, Oral Alpan, Francis Averill, Anil Badhwar, Jose Bardelas, Barbara Baxter, George Bensch, William Berger, Jonathan Bernstein, Tracy Bridges, Ryan Brimeyer, William Calhoun, Edward Campbell, William Brett Cherry, Geoffrey Chupp, Lee Clore, John Cohn, Jeremy Cole, John Condemi, James Cury, Benjamin Davis, Samuel DeLeon, Luis Delacruz, Joseph Diaz, David Erb, Emeka Eziri, Faisal Fakih, Douglas Fiedler, David Fost, Stephen Fritz, Erika Gonzalez, Brad Goodman, Peter Gottlieb, Gregory Gottschlich, Richard Gower, Rizan Hajal, James Harris, Hengameh Heidarian-Raissy, Albrecht Heyder, David Hill, Fernando Holguin, Iftikhar Hussain, Jonathan Illowite, Joshua Jacobs, Mikell Jarratt, Harold Kaiser, Neil Kao, Ravindra Kashyap, David Kaufman, Edward Kent, Kenneth Kim, Ryan Klein, Monica Kraft, Ritsu Kono, Shahrukh Kureishy, Jeffrey Leflein, Mila Leong, Huamin Li, Robert Lin, Njira Lugogo, Michael Marcus, Diego Jose Maselli Caceres, Vinay Mehta, Curtis Mello, Mark Millard, Aaron Milstone, Arjun Mohan, Wendy Moore, Mark Moss, Nayla Mumneh, Thomas O'Brien, David Ostransky, Michael Palumbo, Purvi Parikh, Sudhir Parikh, Amit Patel, Guido Perez, Warren Pleskow, Bruce Prenner, Dileep Puppala, John Ramey, Joan Reibman, Ramon Reyes, Emory Robinette, Ileana Rodicio, Stephen Ryan, Sudhir Sekhsaria, Barry Sigal, Vinay Sikand, Weily Soong, Selwyn Spangenthal, Roy St John, Gary Steven, Vijay Subramaniam, Kaharu Sumino, Eric Sztejman, Ricardo A Tan, Tonny Tanus, Charles Thompson, Carl Thornblade, Manuel Villareal, Sally Wenzel, Heidi Zafra, Tomasz Ziedalski, Centre recherche en CardioVasculaire et Nutrition = Center for CardioVascular and Nutrition research (C2VN), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Physiologie & médecine expérimentale du Cœur et des Muscles [U 1046] (PhyMedExp), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Pathologies Pulmonaires et Plasticité Cellulaire - UMR-S 1250 (P3CELL), Université de Reims Champagne-Ardenne (URCA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Tim W, Harrison, Pascal, Chanez, Francesco, Menzella, Giorgio Walter, Canonica, Renaud, Loui, Borja G, Cosio, Njira L, Lugogo, Arjun, Mohan, Annie, Burden, Lawrence, Mcdermott, Esther, Garcia Gil, Zangrilli, G, Jame, Pohl, Wolfgang, Voves, Robert, Deschampheleire, Maud, Louis, Renaud, Martinot, Jean-Benoit, Peché, Rudi, Chapman, Kenneth, Cheema, Amarjit, Dorscheid, Delbert, Mark FitzGerald, J, Gagnon, Remi, Patrick Killorn, William, Olivenstein, Ronald, Philteos, George, Ramsey, Clare, Douglass Rolf, J, Walker, Brandie, Hilberg, Ole, Skjold, Tina, Titlestad, Ingrid, Hakulinen, Auli, Kilpeläinen, Maritta, Ben Hayoun, Michèle, Bonniaud, Philippe, Bourdin, Arnaud, Chanez, Pascal, De Blay, Frédéric, Deslee, Gaëtan, Devouassoux, Gille, Didier, Alain, Douadi, Youcef, Fry, Stéphanie, Garcia, Gille, Girodet, Pierre-Olivier, Leroyer, Christophe, Magnan, Antoine, Mahay, Guillaume, Nocent, Cécilia, Pison, Christophe, Roux, Pauline-Marie, Taillé, Camille, Tiotiu, Juliana-Angelica, Beck, Ekkehard, Jandl, Margret, Kaehler, Christian, Kässner, Frank, Koesters, Frank, Kronsbein, Juliane, Schaum, Thoma, Schulz, Christian, Skowasch, Dirk, Taube, Christian, Welte, Tobia, de Roux, André, Beghé, Bianca, Blasi, Francesco, Walter Canonica, Giorgio, Carpagnano, Giovanna, Caruso, Cristiano, Guido Corsico, Angelo, Constantino, Elio, Crimi, Nunzio, Maestrelli, Piero, Menzella, Francesco, Milanese, Manlio, Papi, Alberto, Pelaia, Girolamo, Pini, Laura, Santus, Pierachille, Savi, Eleonora, Scichilone, Nicola, Senna, Gianenrico, Spadaro, Giuseppe, Vaghi, Adriano, Gans, Steven, Hölters, Jurgen, Langeveld, B, Pieters, Willem, A Staaks, G H, van Veen, Ilonka, K van den Berg, J W, Einvik, Gunnar, Lehmann, Sverre, Ali García, Ismael, Almonacid, Carlo, Bobolea, Irina, Campo Mozo, Paloma, de Luiz, Gustavo, Domingo Ribas, Christian, María Echave-Sustaeta María-Tomé, José, Luis García Rivero, Juan, García-Cosío Piqueras, Borja, Gómez-Bastero Fernández, Ana, González Pérez, Ruperto, Henríquez Santa, Aythamy, Martínez Rivera, Carlo, Muñoz Gall, Xavier, Ramos, Jacinto, Gregorio Soto Campos, Jose, Vidal Pan, Carmen, Stenfors, Nikolai, Tunsäter, Alf, Vinge, Ine, Chaudhuri, Rekha, Harrison, Timothy, Mansur, Adel, Nasser, Shuaib, Nordstrom, Monica, Pfeffer, Paul, Saralaya, Dinesh, Short, Philip, Adlakha, Arun, Alpan, Oral, Averill, Franci, Badhwar, Anil, Bardelas, Jose, Baxter, Barbara, Bensch, George, Berger, William, Bernstein, Jonathan, Bridges, Tracy, Brimeyer, Ryan, Calhoun, William, Campbell, Edward, Brett Cherry, William, Chupp, Geoffrey, Clore, Lee, Cohn, John, Cole, Jeremy, Condemi, John, Cury, Jame, Davis, Benjamin, Deleon, Samuel, Delacruz, Lui, Diaz, Joseph, Erb, David, Eziri, Emeka, Fakih, Faisal, Fiedler, Dougla, Fost, David, Fritz, Stephen, Gonzalez, Erika, Goodman, Brad, Gottlieb, Peter, Gottschlich, Gregory, Gower, Richard, Hajal, Rizan, Harris, Jame, Heidarian-Raissy, Hengameh, Heyder, Albrecht, Hill, DAVID STANLEY, Holguin, Fernando, Hussain, Iftikhar, Illowite, Jonathan, Jacobs, Joshua, Jarratt, Mikell, Kaiser, Harold, Kao, Neil, Kashyap, Ravindra, Kaufman, David, Kent, Edward, Kim, Kenneth, Klein, Ryan, Kraft, Monica, Kono, Ritsu, Kureishy, Shahrukh, Leflein, Jeffrey, Leong, Mila, Li, Huamin, Lin, Robert, Lugogo, Njira, Marcus, Michael, Jose Maselli Caceres, Diego, Mehta, Vinay, Mello, Curti, Millard, Mark, Milstone, Aaron, Mohan, Arjun, Moore, Wendy, Moss, Mark, Mumneh, Nayla, O'Brien, Thoma, Ostransky, David, Palumbo, Michael, Parikh, Purvi, Parikh, Sudhir, Patel, Amit, Perez, Guido, Pleskow, Warren, Prenner, Bruce, Puppala, Dileep, Ramey, John, Reibman, Joan, Reyes, Ramon, Robinette, Emory, Rodicio, Ileana, Ryan, Stephen, Sekhsaria, Sudhir, Sigal, Barry, Sikand, Vinay, Soong, Weily, Spangenthal, Selwyn, St John, Roy, Gary, Steven, Subramaniam, Vijay, Sumino, Kaharu, Sztejman, Eric, A Tan, Ricardo, Tanus, Tonny, Thompson, Charle, Thornblade, Carl, Villareal, Manuel, Wenzel, Sally, Zafra, Heidi, Ziedalski, Tomasz, UCL - SSS/IREC/MONT - Pôle Mont Godinne, UCL - (MGD) Service de pneumologie, Harrison T.W., Chanez P., Menzella F., Canonica G.W., Louis R., Cosio B.G., Lugogo N.L., Mohan A., Burden A., McDermott L., Garcia Gil E., Zangrilli J.G., Pohl W., Voves R., Deschampheleire M., Martinot J.-B., Peche R., Chapman K., Cheema A., Dorscheid D., FitzGerald J.M., Gagnon R., Killorn W.P., Olivenstein R., Philteos G., Ramsey C., Rolf J.D., Walker B., Hilberg O., Skjold T., Titlestad I., Hakulinen A., Kilpelainen M., Ben Hayoun M., Bonniaud P., Bourdin A., De Blay F., Deslee G., Devouassoux G., Didier A., Douadi Y., Fry S., Garcia G., Girodet P.-O., Leroyer C., Magnan A., Mahay G., Nocent C., Pison C., Roux P.-M., Taille C., Tiotiu J.-A., Beck E., Jandl M., Kaehler C., Kassner F., Koesters F., Kronsbein J., Schaum T., Schulz C., Skowasch D., Taube C., Welte T., de Roux A., Beghe B., Blasi F., Carpagnano G., Caruso C., Corsico A.G., Constantino E., Crimi N., Maestrelli P., Milanese M., Papi A., Pelaia G., Pini L., Santus P., Savi E., Scichilone N., Senna G., Spadaro G., Vaghi A., Gans S., Holters J., Langeveld B., Pieters W., Staaks G.H.A., van Veen I., van den Berg J.W.K., Einvik G., Lehmann S., Ali Garcia I., Almonacid C., Bobolea I., Campo Mozo P., de Luiz G., Domingo Ribas C., Echave-Sustaeta Maria-Tome J.M., Garcia Rivero J.L., Garcia-Cosio Piqueras B., Gomez-Bastero Fernandez A., Gonzalez Perez R., Henriquez Santa A., Martinez Rivera C., Munoz Gall X., Ramos J., Gregorio Soto Campos J., Vidal Pan C., Stenfors N., Tunsater A., Vinge I., Chaudhuri R., Harrison T., Mansur A., Nasser S., Nordstrom M., Pfeffer P., Saralaya D., Short P., Adlakha A., Alpan O., Averill F., Badhwar A., Bardelas J., Baxter B., Bensch G., Berger W., Bernstein J., Bridges T., Brimeyer R., Calhoun W., Campbell E., Cherry W.B., Chupp G., Clore L., Cohn J., Cole J., Condemi J., Cury J., Davis B., DeLeon S., Delacruz L., Diaz J., Erb D., Eziri E., Fakih F., Fiedler D., Fost D., Fritz S., Gonzalez E., Goodman B., Gottlieb P., Gottschlich G., Gower R., Hajal R., Harris J., Heidarian-Raissy H., Heyder A., Hill D., Holguin F., Hussain I., Illowite J., Jacobs J., Jarratt M., Kaiser H., Kao N., Kashyap R., Kaufman D., Kent E., Kim K., Klein R., Kraft M., Kono R., Kureishy S., Leflein J., Leong M., Li H., Lin R., Lugogo N., Marcus M., Maselli Caceres D.J., Mehta V., Mello C., Millard M., Milstone A., Moore W., Moss M., Mumneh N., O'Brien T., Ostransky D., Palumbo M., Parikh P., Parikh S., Patel A., Perez G., Pleskow W., Prenner B., Puppala D., Ramey J., Reibman J., Reyes R., Robinette E., Rodicio I., Ryan S., Sekhsaria S., Sigal B., Sikand V., Soong W., Spangenthal S., St. John R., Steven G., Subramaniam V., Sumino K., Sztejman E., Tan R.A., Tanus T., Thompson C., Thornblade C., Villareal M., Wenzel S., Zafra H., Ziedalski T., and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Pulmonary and Respiratory Medicine, Spirometry, Adult, Male, medicine.medical_specialty, Exacerbation, [SDV]Life Sciences [q-bio], Population, Settore MED/10 - Malattie Dell'Apparato Respiratorio, Placebo, Antibodies, Monoclonal, Humanized, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Double-Blind Method, Internal medicine, medicine, Humans, 030212 general & internal medicine, Anti-Asthmatic Agents, Patient Reported Outcome Measures, education, Sinusitis, Asthma, education.field_of_study, medicine.diagnostic_test, business.industry, Middle Aged, medicine.disease, Benralizumab, 3. Good health, Eosinophils, 030228 respiratory system, chemistry, Asthma Control Questionnaire, Disease Progression, Quality of Life, Female, business
Abstract

Background: ANDHI was done to assess the efficacy of benralizumab, including onset of effect and impact on health-related quality of life (HRQOL), exacerbation rate, lung function, and nasal polyposis symptoms. Methods: This phase 3b, randomised, double-blind, parallel-group, placebo-controlled ANDHI study was completed in adults (aged 18–75 years) with severe eosinophilic asthma with at least 2 exacerbations in the previous year, despite high-dose inhaled corticosteroid plus additional controllers, screening blood eosinophil counts of at least 150 cells per μL, and an Asthma Control Questionnaire 6 (ACQ-6) score of 1·5 or more. Patients who met eligibility criteria were randomly assigned (2:1; stratified by previous exacerbation count [two, or three or more], maintenance oral corticosteroid use, and region), using an integrated web-based response system, to receive benralizumab at 30 mg every 8 weeks (first three doses given 4 weeks apart) or matched placebo for 24 weeks. Primary efficacy measure was annualised asthma exacerbation rate, with rate ratio (RR) calculated over the approximate 24-week follow-up. Secondary efficacy measures included change from baseline to end of treatment (week 24) in St George's Respiratory Questionnaire (SGRQ) total score (key secondary endpoint), FEV1, peak expiratory flow (PEF), ACQ-6, Predominant Symptom and Impairment Assessment (PSIA), Clinician Global Impression of Change (CGI-C), Patient Global Impression of Change (PGI-C), and Sino-Nasal Outcome Test-22 (SNOT-22). All efficacy analyses, except for SNOT-22, were summarised and analysed using the full analysis set on an intention-to-treat population (all randomly assigned patients receiving investigational product, regardless of protocol adherence or continued participation in the study). SNOT-22 was summarised for the subgroup of patients with physician-diagnosed nasal polyposis with informed consent. This study is registered with ClinicalTrials.gov, NCT03170271. Findings: Between July 7, 2017, and Sept 25, 2019, 656 patients received benralizumab (n=427) or placebo (n=229). Baseline characteristics were consistent with severe eosinophilic asthma. Benralizumab significantly reduced exacerbation risk by 49% compared with placebo (RR estimate 0·51, 95% CI 0·39–0·65; p5%) were nasopharyngitis (30 [7%]), headache (37 [9%]), sinusitis (28 [7%]), bronchitis (22 [5%]), and pyrexia (26 [6%]). Fewer serious adverse events were reported for benralizumab (23 [5%]) versus placebo (25 [11%]), and the only common serious adverse event (experienced by >1% of patients) was worsening of asthma, which was reported for nine (2%) patients in the benralizumab group and nine (4%) patients in the placebo group. Interpretation: Our results extend the efficacy profile of benralizumab for patients with severe eosinophilic asthma, showing early clinical benefits in patient-reported outcomes, HRQOL, lung function, and nasal polyposis symptoms. Funding: AstraZeneca.

Published
2021

17. Exposure to welding fumes suppresses the activity of T-helper cells.

Author

Knobloch, Jürgen, Casjens, Swaantje, Lehnert, Martin, Yanik, Sarah D., Körber, Sandra, Lotz, Anne, Rupp, Jan, Raulf, Monika, Zschiesche, Wolfgang, Weiss, Tobias, Kronsbein, Juliane, Koch, Andrea, Brüning, Thomas, and Pesch, Beate

Subjects
*WELDING fumes, *OBSTRUCTIVE lung diseases, *CIGARETTE smoke, *SMOKING, *HAEMOPHILUS influenzae
Abstract

Welders have an increased susceptibility to airway infections with non-typeable Haemophilus influenzae (NTHi), which implicates immune defects and might promote pneumonia and chronic obstructive pulmonary disease (COPD). We hypothesized that welding-fume exposure suppresses Th1-lymphocyte activity. Non-effector CD4+ T-cells from blood of 45 welders (n = 23 gas metal arc welders, GMAW; n = 16 tungsten inert gas welders, TIG; n = 6 others) and 25 non-welders were ex vivo activated towards Th1 via polyclonal T-cell receptor stimulation and IL-12 (first activation step) and then stimulated with NTHi extract or lipopolysaccharide (LPS) (second activation step). IFNγ and IL-2 were measured by ELISA. In the first activation step, IFNγ was reduced in welders compared to non-welders and in the GMAW welders with higher concentrations of respirable particles compared to the lower exposed TIG welders. IFNγ was not influenced by tobacco smoking and correlated negatively with welding-fume exposure, respirable manganese, and iron. In the second activation step, NTHi and LPS induced additional IFNγ, which was reduced in current smokers compared to never smokers in welders as well as in non-welders. Analyzing both activation steps together, IFNγ production was lowest in smoking welders and highest in never smoking non-welders. IL-2 was not associated with any of these parameters. Welding-fume exposure might suppress Th1-based immune responses due to effects of particulate matter, which mainly consists of iron and manganese. For responses to NTHi this is strongest in smoking welders because welding fume suppresses T-cell activation towards Th1 and cigarette smoke suppresses the subsequent Th1-response to NTHi via LPS. Both effects are independent from IL-2-regulated T-cell proliferation. This might explain the increased susceptibility to infections and might promote COPD development. • Systemic T-cell defects in welders were investigated in a cell culture study. • Welding fume exposure suppresses the activation of CD4+ T-cells towards Th1. • The Th1 suppression might be concentration-dependently caused by particulate matter. • The Th1 response to H. influenzae is suppressed by welding fume and cigarette smoke. • Smoking welders are more affected than non-smoking welders or smoking non-welders. [ABSTRACT FROM AUTHOR]

Published
2020
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