No approved-drug candidate for t2-high asthma is corroborated in the literature DeepSearch retrieved. Some conditions are managed with non-pharmacological care — a device, surgery or physical therapy — rather than a medicine; that may be the case here, or the literature we found may simply be too sparse yet to support a drug-repurposing angle.
RCSB Protein Data Bank · entry 9NDU · 1.98 Å · ligand 1-hydrazinophthalazine (HLZ). Experimental structure, not a prediction.
Bitter taste receptors (TAS2Rs) are expressed in human bronchi. Non-selective TAS2R agonists chloroquine, quinine, caffeine, strychnine and diphenidol produced bronchial relaxation as effective and potent as theophylline but much less potent than formoterol and isoproterenol in isolated human bronchi from resected lungs. Denatonium, saccharin and colchicine did not produce relaxation. The mechanism was independent of signalling pathways modulated by conventional bronchodilators and may be partly explained by inhibition of phosphatidylinositol-3-kinases. The study did not test any TAS2R agonist in patients.
In 32 adult patients with mild to moderate asthma (19 uncontrolled, 13 controlled) and 8 healthy volunteers, extracellular IL-26 protein in bronchoalveolar lavage fluid was lower in the pooled asthma group (median 165 pg/mL) than in healthy volunteers (686 pg/mL). In uncontrolled asthma, IL-26 was higher than in controlled asthma but still tended lower than in healthy volunteers. IL-26 mRNA in BAL cells was higher in uncontrolled than controlled asthma. There was no correlation between IL-26 protein and asthma control test score in the pooled group. In uncontrolled asthma, patients with relatively low IL-26 protein had a clearly lower ACT score. The authors could not determine the role of inhaled corticosteroids because all but three patients were on a narrow range of low to moderate doses.
Tezepelumab, a monoclonal antibody binding thymic stromal lymphopoietin, was assessed in a real-world retrospective single-centre study of 30 patients with severe asthma. After 4 weeks, tezepelumab decreased fractional exhaled nitric oxide and blood basophil count, and lowered serum IL-2 and VEGF. These effects were observed in both T2-high and T2-low patients and in those with or without prior biologic therapy. No numbers for exacerbation reduction or lung function improvement were reported in the abstract.
In a separate cohort of 32 patients with asthma and airway hyperresponsiveness to mannitol, 18 had T2-low asthma (FeNO <25 ppb, sputum eosinophils <3%, blood eosinophils <300/µL). After 12 months of specialist management, airway hyperresponsiveness to mannitol improved similarly in T2-high (geometric mean PD15 from 150 mg to 488 mg) and T2-low (from 214 mg to 507 mg). There were no concomitant improvements in airway hyperresponsiveness to methacholine. In a Finnish registry study of 169 patients with severe uncontrolled asthma, 40% had T2-low disease. Average cumulative all-cause costs over four years were similar: €37,524 for T2-low and €34,712 for non-T2-low. Respiratory-related costs were also similar: €5,178 vs €5,209. Regression modelling predicted more inpatient days per patient-year for T2-low patients.
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
New England Journal of Medicine · 2006 · 291 citations · open access
The Effect of Telithromycin in Acute Exacerbations of Asthma
AbstractBACKGROUND: We conducted a double-blind, randomized, placebo-controlled study to evaluate the efficacy of telithromycin in patients with acute exacerbations of asthma. METHODS: A total of 278 adults with diagnosed asthma were enrolled within 24 hours after an acute exacerbation of asthma requiring short-term medical care. The patients were randomly assigned to receive 10 days of oral treatment with telithromycin (at a dose of 800 mg daily) or placebo in addition to usual care. Primary efficacy end points were a change from baseline over the treatment period in symptoms (as recorded by patients in a diary card) and in the peak expiratory flow in the morning at home. The presence of Chlamydophila pneumoniae or Mycoplasma pneumoniae was ascertained by serologic analysis, polymerase chain reaction, and culture. RESULTS: Of the two prespecified primary outcomes, only asthma symptoms showed a significantly greater reduction among patients receiving telithromycin than among those receiving placebo. Mean (+/-SD) scores on a test of asthma symptoms (on a 7-point scale, with 0 denoting no symptoms and 6 denoting severe symptoms) were 3.0+/-1.4 at baseline and 1.7+/-1.1 at the end of treatment for the telithromycin group and 2.8+/-1.3 at baseline and 2.0+/-1.0 at the end of treatment for the placebo group. The mean decrease in symptom scores during the treatment period was 1.3 for telithromycin and 1.0 for placebo (mean difference, -0.3; 95 percent confidence interval, -0.5 to -0.1; P=0.004). There was no significant treatment effect on the other primary outcome measure, a change in morning peak expiratory flow. Nausea was more common among patients in the telithromycin group than in the placebo group (P=0.01). Although 61 percent of patients had evidence of infection with C. pneumoniae, M. pneumoniae, or both, there was no relationship between bacteriologic status and the response to asthma treatment. CONCLUSIONS: This study provides evidence of the benefit of telithromycin in patients with acute exacerbations of asthma; the mechanisms of benefit remain unclear. (ClinicalTrials.gov number, NCT00273520.).
https://doi.org/10.1056/nejmoa044080Respiratory Research · 2013 · 102 citations · open access
The expression and relaxant effect of bitter taste receptors in human bronchi
AbstractBACKGROUND: Bitter-taste receptors (TAS2Rs) have recently been involved in the relaxation of mouse and guinea pig airways, and increased expression of TAS2Rs was shown in blood leucocytes from asthmatic children. We sought to identify and characterize the TAS2Rs expressed in isolated human bronchi and the subtypes involved in relaxation. METHODS: Human bronchi were isolated from resected lungs and TAS2R transcripts were assessed with RT-qPCR. Relaxation to TAS2R agonists was tested in organ bath in the presence or absence of pharmacological modulators of the signalling pathways involved in bronchial relaxation. RESULTS: We detected the expression of TAS2R transcripts in human bronchi. The non-selective agonists chloroquine, quinine, caffeine, strychnine and diphenidol produced a bronchial relaxation as effective and potent as theophylline but much less potent than formoterol and isoproterenol. Denatonium, saccharin and colchicine did not produce relaxation. Receptor expression analysis together with the use of selective agonists suggest a predominant role for TAS2R5, 10 and 14 in bitter taste agonist-induced relaxation. The mechanism of relaxation was independent of the signalling pathways modulated by conventional bronchodilators and may be partly explained by the inhibition of phosphatidylinositol-3-kinases. CONCLUSIONS: The TAS2Rs may constitute a new therapeutic target in chronic obstructive lung diseases such as asthma.
https://doi.org/10.1186/1465-9921-14-134American Journal of Health-System Pharmacy · 2004 · 20 citations · open access
Omalizumab: a recombinant humanized anti-IgE antibody for allergic asthma
AbstractPURPOSE: The pharmacology, efficacy, dosage, adverse events, and economics of omalizumab are discussed. SUMMARY: Omalizumab, a recombinant DNA-derived humanized monoclonal antibody, binds to the C epsilon3 domain of immunoglobulin E (IgE) and forms complexes that inhibit the immune system's response to allergens by averting IgE-mediated inflammatory changes. Omalizumab exhibits a similar pharmacokinetic profile in adults, adolescents, and children. Omalizumab is indicated for adults and adolescents with moderate to severe persistent asthma who have a positive skin test or in vitro reactivity to a perennial aeroallergen and whose symptoms are inadequately controlled with inhaled corticosteroids. Because of the limited data regarding the safety and effectiveness of omalizumab in children, the drug is indicated for patients 12 years of age or older. The recommended starting dosage is 150-375 mg s.c. every two or four weeks. Dosages and frequency of dose administration are determined by total serum IgE level, measured before the start of treatment, and body weight. Omalizumab is generally well tolerated in adults and children with allergic asthma. Adverse events most commonly observed are injection-site reaction, viral infection, upper-respiratory-tract infection, sinusitis, headache, and pharyngitis. Three large phase III clinical trials demonstrated that omalizumab is more effective than placebo in controlling moderate to severe allergic asthma in patients who have poor disease control or exacerbations despite recommended therapy. Currently, there are no clinical comparisons of omalizumab with other standard treatments for asthma; therefore, it is difficult to determine its overall place in therapy. CONCLUSION: Omalizumab should be considered as a second-line therapy for patients with moderate to severe persistent allergic asthma.
https://doi.org/10.1093/ajhp/61.14.1449Journal of Allergy and Clinical Immunology · 2019 · 11 citations · open access
Enhanced local production of IL-26 in uncontrolled compared with controlled adult asthma
AbstractCurrent pharmacotherapy is insufficient for patients with poorly controlled asthma.1Global Initiative for Asthma Global strategy for asthma management and prevention.https://ginasthma.org/wp-content/uploads/2019/06/GINA-2019-main-report-June-2019-wms.pdfGoogle Scholar, 2Olin J.T. Wechsler M.E. Asthma: pathogenesis and novel drugs for treatment.BMJ. 2014; 349: g5517Crossref PubMed Scopus (151) Google Scholar To facilitate the development of novel and effective therapy, we need to improve the mechanistic understanding of this phenotype.3Bousquet J. Clark T.J. Hurd S. Khaltaev N. Lenfant C. O'Byrne P. et al.GINA guidelines on asthma and beyond.Allergy. 2007; 62: 102-112Crossref PubMed Scopus (257) Google Scholar The cytokine IL-26 is produced by TH17 cells.4Che K.F. Tengvall S. Levänen B. Silverpil E. Smith M. Awad M. et al.Interleukin-26 in antibacterial host defense of human lungs: effects on neutrophil mobilization.Am J Respir Crit Care Med. 2014; 190: 1022-1032Crossref PubMed Scopus (29) Google Scholar It potentiates the chemotactic response of human neutrophils in vitro and enhances endotoxin-induced accumulation of neutrophils and macrophages in the airways in vivo.4Che K.F. Tengvall S. Levänen B. Silverpil E. Smith M. Awad M. et al.Interleukin-26 in antibacterial host defense of human lungs: effects on neutrophil mobilization.Am J Respir Crit Care Med. 2014; 190: 1022-1032Crossref PubMed Scopus (29) Google Scholar, 5Bao A. Che K.F. Bozinovski S. Jie J. Gregory J. Kumlien-Georén S. et al.Recombinant human IL-26 facilitates the innate immune response to endotoxin in the bronchoalveolar space of Mice in Vivo.PLoS One. 2017; 12: e0188909Crossref PubMed Scopus (6) Google Scholar It also displays direct antibacterial properties in experimental models in vitro and in vivo.6Meller S. Di Domizio J. Voo K.S. Friedrich H.C. Chamilos G. Ganguly D. et al.T(H)17 cells promote microbial killing and innate immune sensing of DNA via interleukin 26.Nat Immunol. 2015; 16: 970-979Crossref PubMed Scopus (28) Google Scholar Moreover, there is evidence for enhanced IL-26 protein in the airways for poorly controlled compared with controlled asthma, among children with the noneosinophilic endotype.7Konradsen J. Nordlund B. Levänen B. Hedlin G. Lindén A. The cytokine interleukin-26 as a biomarker in pediatric asthma.Respir Res. 2016; 17: 32Crossref PubMed Scopus (18) Google Scholar However, it is not known what is the case in adult patients with asthma nor in healthy volunteers.7Konradsen J. Nordlund B. Levänen B. Hedlin G. Lindén A. The cytokine interleukin-26 as a biomarker in pediatric asthma.Respir Res. 2016; 17: 32Crossref PubMed Scopus (18) Google Scholar Here, we addressed these matters by quantifying airway IL-26 protein in the airway lumen and tissue, as well as its gene expression in local leukocytes. We also related these outcomes to clinical characteristics and measures of inflammation. We included 32 adult patients treated according to the Global Initiative for Asthma guidelines,1Global Initiative for Asthma Global strategy for asthma management and prevention.https://ginasthma.org/wp-content/uploads/2019/06/GINA-2019-main-report-June-2019-wms.pdfGoogle Scholar, 2Olin J.T. Wechsler M.E. Asthma: pathogenesis and novel drugs for treatment.BMJ. 2014; 349: g5517Crossref PubMed Scopus (151) Google Scholar of which 19 by definition had uncontrolled (asthma control test [ACT] score, ≥20) and 13 had controlled (ACT score, <20) asthma, plus 8 healthy volunteers (see Table E1 in this article's Online Repository at www.jacionline.org). All patients reported weekly respiratory symptoms and displayed a positive methacholine provocation test result. All subjects underwent clinical characterization and bronchoscopy. The latter included bronchial and transbronchial biopsies as well as bronchoalveolar lavage (BAL). This article's Online Repository at www.jacionline.org contains additional methodological information. Most patients displayed sensitization against common airborne allergens (Table E1). The subgroup with uncontrolled asthma had a lower median FEV1 (% predicted) and was more responsive to methacholine than the subgroup with controlled asthma (Table E1). The subgroup with uncontrolled asthma tended to have treatment with a somewhat higher but still moderate dose of inhaled corticosteroids (ICSs) and to more frequently use beta2-adrenoceptor agonists, compared with the subgroup with controlled asthma. However, there was no statistically significant difference in terms of treatment here (Table E1). The median [IQR] concentration of IL-26 protein in cell-free BAL fluid was markedly lower (P = .029, n = 7-32) in the pooled group of all patients with asthma (165 [77-470] pg/mL) than in healthy volunteers (686 [436-1004] pg/mL, as shown in Fig 1, A). In the subgroup with uncontrolled asthma, this IL-26 concentration was higher than in the subgroup with controlled asthma, whereas it still tended to be lower than that in healthy volunteers (Fig 1, A). Among all BAL-cell subsets, there was a clear trend toward a difference between controlled and uncontrolled asthma for the median neutrophil count only (see Table E2 in this article's Online Repository at www.jacionline.org). In terms of BAL-cell counts, the IL-26 protein in cell-free BAL fluid displayed a negative correlation with lymphocytes, in the pooled group of all patients and in the subgroup with uncontrolled asthma (see Fig E1, B, in this article's Online Repository at www.jacionline.org). There were strong similar trends for total leukocytes in these groups (Fig E1, A). Moreover, there was a corresponding correlation for macrophages in the pooled group of all patients with asthma (Fig E1, C). For eosinophils there was a corresponding correlation in uncontrolled asthma (Fig E1, D) but there was no such correlation for neutrophils (Fig E1, E). In the pooled group of all patients with asthma, there was a clear negative correlation between IL-26 protein in cell-free BAL fluid and FEV1 (see Fig E2 in this article's Online Repository at www.jacionline.org) but no corresponding correlation within the subgroups of controlled or uncontrolled asthma. Likewise, we detected no correlations between the referred IL-26 protein and bronchial reactivity (PD20), FENO50, bronchial NO flux, alveolar NO concentration, or the dose of ICS among either of the groups with asthma (see this article's Online Repository at www.jacionline.org). In the pooled group of all patients with asthma, we detected no correlation between IL-26 protein in cell-free BAL fluid and ACT score (P = .21; r = −0.23; n = 31). However, in uncontrolled asthma, the median ACT score was clearly lower in subjects with relatively low (≤median in all patients) compared with those with relatively high (>median in all patients) concentration of IL-26 protein in cell-free BAL fluid (see Fig E3, A, in this article's Online Repository at www.jacionline.org). In contrast, the ACT score was similar regardless of whether the referred IL-26 protein was high or low in the subgroup with controlled asthma (Fig E3, B). Moreover, there was a clear positive correlation between IL-26 and IL-8 protein in cell-free BAL fluid from the pooled group of all patients with asthma (see Fig E4 in this article's Online Repository at www.jacionline.org). The median level of IL-26 mRNA in BAL cells was higher in the subgroup with uncontrolled compared with the subgroup with controlled asthma (Fig 1, B). The referred mRNA did not display any correlation with IL-26 protein in cell-free BAL fluid (see Table E3 in this article's Online Repository at www.jacionline.org), but it did display a clear positive correlation with FENO50 in all asthma groups (see Fig E5 in this article's Online Repository at www.jacionline.org) and a negative correlation with all BAL-cell counts in the subgroup with uncontrolled asthma (Table E3). We detected IL-26–positive cells in bronchial mucosa and alveolar lung parenchyma (including cells in the alveolar lumen) from all subjects (Fig 2, A). In alveolar lung parenchyma, the pooled group of patients with asthma displayed clearly (P = .045, n = 8-32) lower median (IQR) immunoreactivity for IL-26 protein (0.060 [0.037-0.077] % area), compared with healthy volunteers (0.12 [0.068-0.160] % area, as shown in Fig 2, B). However, there was no corresponding difference in bronchial mucosa (data not shown). In the subgroup with uncontrolled asthma, the referred immunoreactivity in alveolar lung parenchyma tended to be higher than that in the subgroup with controlled asthma, although lower than that in healthy volunteers (Fig 2, B). There was no corresponding difference in bronchial mucosa (Fig 2, C) or in cells in the alveolar lumen (Fig 2, D). The present study indicates that extracellular IL-26 protein in the peripheral airways is enhanced in adult patients with uncontrolled compared with controlled asthma. The results are also suggestive of both subgroups with asthma having lower extracellular IL-26 protein than do healthy volunteers. Similarly, the data sets on IL-26 mRNA in BAL leukocytes, as well as protein in alveolar parenchymal tissue, support the idea that there is more gene expression leading to higher protein production of IL-26 in uncontrolled compared with controlled asthma, and that there is less IL-26 protein in the peripheral airways of adult patients with asthma than in healthy volunteers. Although the ACT score represents a continuous variable rather than a threshold one, this score can be a clinically useful indicator of disease control with a borderline value of 20 as the established “divider” between uncontrolled and controlled asthma.1Global Initiative for Asthma Global strategy for asthma management and prevention.https://ginasthma.org/wp-content/uploads/2019/06/GINA-2019-main-report-June-2019-wms.pdfGoogle Scholar, 2Olin J.T. Wechsler M.E. Asthma: pathogenesis and novel drugs for treatment.BMJ. 2014; 349: g5517Crossref PubMed Scopus (151) Google Scholar, 3Bousquet J. Clark T.J. Hurd S. Khaltaev N. Lenfant C. O'Byrne P. et al.GINA guidelines on asthma and beyond.Allergy. 2007; 62: 102-112Crossref PubMed Scopus (257) Google Scholar Given this fact, our findings in the group defined as having uncontrolled asthma, including poorly controlled and uncontrolled disease, are intriguing. Here, we obtained evidence that, in uncontrolled asthma, low extracellular IL-26 protein signifies patients with an even poorer disease control. Possibly, these patients are unable to respond with enhanced local IL-26 protein, a response that may thus be both reactive and protective. The finding of a negative correlation between IL-26 protein in cell-free BAL fluid and FEV1 (% predicted) in the pooled group of all patients with asthma is also compatible with a reactive and protective cytokine response in terms of extracellular IL-26. Along these lines, the negative correlation between IL-26 protein in cell-free BAL fluid and lymphocytes, and eosinophils, in BAL samples from patients with uncontrolled asthma is suggestive of a reactive mechanism that serves to protect from excessive mobilization of key luminal leukocytes as well. The clear and positive correlation between IL-26 mRNA in BAL cells and FENO50 in all groups of patients with asthma is also suggestive of a reactive and protective role for IL-26. Even though both IL-26 mRNA in BAL cells and IL-26 protein in cell-free BAL fluid did display a higher median level in uncontrolled than in controlled asthma, there was no positive correlation between these 2 outcomes in patients or in healthy volunteers. We think that this can be explained as follows: Extracellular IL-26 protein in BAL samples reflects the production and release from several cellular sources, including structural cells such as bronchial epithelial cells and lung fibroblasts, as well as leukocytes.4Che K.F. Tengvall S. Levänen B. Silverpil E. Smith M. Awad M. et al.Interleukin-26 in antibacterial host defense of human lungs: effects on neutrophil mobilization.Am J Respir Crit Care Med. 2014; 190: 1022-1032Crossref PubMed Scopus (29) Google Scholar, 8Che K.F. Kaarteenaho R. Lappi-BIanco E. Levänen B. Sun J. Wheelock Å. et al.Interleukin-26 production in human bronchial epithelial cells in response to viral stimulation: modulation by Th17 cytokines.Mol Med. 2017; 23: 247-257Crossref PubMed Scopus (12) Google Scholar, 9Che K.F. Sun J. Lindén A. Pharmacological modulation of endotoxin-induced release of IL-26 in human primary lung fibroblasts.Front Pharmacol. August 2019; ([Epub ahead of print])PubMed Google Scholar In contrast, the IL-26 mRNA that we quantified to assess gene expression is likely to originate exclusively from luminal leukocytes in the airways. Similarly for the case for extracellular IL-26 protein, we obtained evidence for a negative correlation between gene expression for IL-26 in airway leukocytes and counts for total leukocytes and lymphocytes in uncontrolled asthma. In the same subgroup, there was also a negative correlation for this gene expression and counts for neutrophils and macrophages. For neutrophils, this may seem paradoxical, because extracellular IL-26 and IL-8 protein do correlate in a positive manner in the pooled group of all patients with asthma, with indicated trends in the subgroups. We suspect that this finding relates to the fact that IL-26 can exert both pro- and anti-inflammatory actions in terms of release of the very same neutrophil-mobilizing cytokines, depending on the cellular target.4Che K.F. Tengvall S. Levänen B. Silverpil E. Smith M. Awad M. et al.Interleukin-26 in antibacterial host defense of human lungs: effects on neutrophil mobilization.Am J Respir Crit Care Med. 2014; 190: 1022-1032Crossref PubMed Scopus (29) Google Scholar With the exception of 3 patients with controlled asthma, all patients had treatment with a narrow range of low to moderate doses of ICSs. This fact makes it impossible to determine the role of ICSs with respect to the difference in local IL-26 production between uncontrolled and controlled asthma. However, we recently demonstrated that treatment with a glucocorticoid effectively inhibits the release of IL-26 protein in human lung fibroblasts in vitro.9Che K.F. Sun J. Lindén A. Pharmacological modulation of endotoxin-induced release of IL-26 in human primary lung fibroblasts.Front Pharmacol. August 2019; ([Epub ahead of print])PubMed Google Scholar Thus, from a hypothetical point of view, ICSs may account for the average decrease in extracellular IL-26 protein that we observed in the pooled group of all patients with asthma. The study protocol was approved by the Regional Board for Ethical Review in Lund (no. LU-412/03), and all participating subjects gave oral and written informed consent, in accordance with the recommendations of the code of ethics of the World Medical Association (Declaration of Helsinki). The inclusion criteria for the patients with asthma were mild to moderate disease according to the Global Initiative for Asthma guidelines,E1Global Initiative for AsthmaGlobal strategy for asthma management and prevention.https://ginasthma.org/wp-content/uploads/2019/06/GINA-2019-main-report-June-2019-wms.pdfGoogle Scholar a report of weekly respiratory symptoms, and a positive methacholine test result to confirm bronchial hyperresponsiveness. All study subjects underwent skin prick test and completed the ACT. All subjects were required to be nonsmokers at the time of investigations, with a smoking cessation date greater than or equal to 1 year before the inclusion in the present study. A historic tobacco load up to 10 pack years was accepted for inclusion. For the control group, we included healthy volunteers, for which any respiratory symptom, sensitization to airborne allergens, or confirmed bronchial hyperresponsiveness constituted exclusion criteria. We required that all subjects had to be free of clinical signs of respiratory tract infection during at least 3 weeks before investigation, to avoid confounding influence by microbes on the cytokine signaling or other aspects of the pathophysiology of asthma. All investigations were performed out of season for inhaled pollens. Bronchial responsiveness was assessed through a methacholine provocation test (ie, PD20-FEV1 ≤ 2,000 μg) performed as previously described.E2Aronsson D. Tufvesson E. Ankerst J. Bjermer L. Allergic rhinitis with hyper-responsiveness differ from asthma in degree of peripheral obstruction during metacholine challenge test.Clin Physiol Funct Imaging. 2008; 28: 81-85Crossref PubMed Scopus (20) Google Scholar Certain data sets from the study population that we used have been published elsewhere, in studies addressing specific aims other than those addressed in the present study.E3Andersson C.K. Tufvesson E. Aronsson D. Bergqvist A. Mori M. Bjermer L. et al.Alveolar mast cells shift to an FcεRI-expressing phenotype in mild atopic asthma: a novel feature in allergic asthma pathology.Allergy. 2011; 66: 1590-1597Crossref PubMed Scopus (18) Google Scholar, E4Andersson C.K. Bergqvist A. Mori M. Mauad T. Bjermer L. Erjefält J.S. Mast cell-associated alveolar inflammation in patients with atopic uncontrolled asthma.J Allergy Clin Immunol. 2011; 127: 905-912Abstract Full Text Full Text PDF PubMed Scopus (71) Google Scholar, E5Weitoft M. Andersson C. Andersson-Sjöland A. Tufvesson E. Bjermer L. Erjefält J. et al.Controlled and uncontrolled asthma display distinct alveolar tissue matrix compositions.Respir Res. 2014; 15: 67Crossref PubMed Scopus (41) Google Scholar, E6Tufvesson E. Andersson C. Weidner J. Erjefält J.S. Bjermer L. Inducible nitric oxide synthase expression is increased in the alveolar compartment of asthmatic patients.Allergy. 2017; 72: 627-635Crossref PubMed Scopus (13) Google Scholar An NIOX Flex instrument (Aerocrine AB, Stockholm, Sweden) was used to measure exhaled nitric oxide (NO) at flow rates of 50 (providing FENO50), 100, 200, and 300 mL/s, 3 to 4 times at each flow. Estimations of alveolar NO concentration and bronchial NO flux were made in a 2-compartment linear modelE7Tsoukias N.M. George S.C. A two-compartment model of pulmonary nitric oxide exchange dynamics.J Appl Physiol (1985). 1998; 85: 653-666Crossref PubMed Scopus (390) Google Scholar, E8Tufvesson E. Aronsson D. Ankerst J. George S.C. Bjermer L. Peripheral nitric oxide is increased in rhinitic patients with asthma compared to bronchial hyperresponsiveness.Respir Med. 2007; 101: 2321-2326Abstract Full Text Full Text PDF PubMed Scopus (29) Google Scholar flow rates of to 300 were was performed with local in accordance with clinical as previously in E. Andersson C. Weidner J. Erjefält J.S. Bjermer L. Inducible nitric oxide synthase expression is increased in the alveolar compartment of asthmatic patients.Allergy. 2017; 72: 627-635Crossref PubMed Scopus (13) Google Scholar A with a of was used with a The clinical for tissue have been E. Andersson C. Weidner J. Erjefält J.S. Bjermer L. Inducible nitric oxide synthase expression is increased in the alveolar compartment of asthmatic patients.Allergy. 2017; 72: 627-635Crossref PubMed Scopus (13) Google Scholar biopsies of the bronchial mucosa were in and of the biopsies of the alveolar lung parenchyma were performed by of by in the lower for the transbronchial biopsies were from the at a of 2 from the to the for BAL was performed 50 and in the The median of the BAL fluid was The BAL was and during at to cells and from the fluid The was and the obtained cell-free BAL fluid was C) The of BAL cells was in and a was used for for with as previously E. Andersson C. Weidner J. Erjefält J.S. Bjermer L. Inducible nitric oxide synthase expression is increased in the alveolar compartment of asthmatic patients.Allergy. 2017; 72: 627-635Crossref PubMed Scopus (13) Google Scholar The of BAL leukocytes was assessed total and counts for the total BAL An additional of the BAL cells was for of total BAL-cell mRNA by BAL-cell to n = for uncontrolled We cell-free BAL fluid samples for the of extracellular of IL-26 protein, a as previously K.F. Tengvall S. Levänen B. Silverpil E. Smith M. Awad M. et al.Interleukin-26 in antibacterial host defense of human lungs: effects on neutrophil mobilization.Am J Respir Crit Care Med. 2014; 190: 1022-1032Crossref PubMed Scopus Google Scholar The of was performed by and was used as an and results were as on been published K.F. Tengvall S. Levänen B. Silverpil E. Smith M. Awad M. et al.Interleukin-26 in antibacterial host defense of human lungs: effects on neutrophil mobilization.Am J Respir Crit Care Med. 2014; 190: 1022-1032Crossref PubMed Scopus Google Scholar The tissue biopsies were as previously C.K. Bergqvist A. Mori M. Mauad T. Bjermer L. Erjefält J.S. Mast cell-associated alveolar inflammation in patients with atopic uncontrolled asthma.J Allergy Clin Immunol. 2011; 127: 905-912Abstract Full Text Full Text PDF PubMed Scopus (71) Google Scholar these biopsies were in a and in for were made a and with the were at low to biopsies that had a The were for on the of the criteria 2 bronchial and 2 transbronchial biopsies were from each for IL-26 protein in tissue was performed with the a IL-26 were established by the IL-26 as well as by an control The tissue were an with a and were The were via the and were made to for IL-26 protein as well as the total tissue in and were from the The expression of tissue was in 2 bronchial and 2 transbronchial biopsies and a average for each was This tissue is referred to as immunoreactivity for IL-26 The was used for data the results are with median range The test was used for between several with with for test in specific The test was used for between 2 and correlation test was used for the of A value of less than was as a statistically significant result. n the of in all data The median BAL neutrophil count displayed a trend toward somewhat higher in controlled than in uncontrolled asthma, whereas the other were similar between the groups (Table Thus, with to BAL counts, there was no difference that statistically The exclusion of the had been did not markedly the in median of extracellular IL-26 protein in BAL samples and the outcomes (data not shown). For the pooled group of all patients with asthma, the median concentration of extracellular IL-26 protein in BAL fluid did not differ markedly for patients with low (≤median in the pooled group of all patients) or high (>median in the pooled group of all patients) count for eosinophils or neutrophils, (data not shown). All but included patients with asthma were against inhaled allergens (Table it impossible to the between of extracellular IL-26 protein in BAL samples in a statistically manner (P = for patients with asthma with sensitization compared with patients with asthma n = We did not any correlation between the of extracellular IL-26 protein in BAL fluid and bronchial reactivity = r = n = in the pooled group of all patients with asthma. The same was for FENO50 (P = r = n = bronchial NO flux (P = r = alveolar NO concentration (P = r = and the dose of ICSs (P = r = the immunoreactivity for IL-26 was as counts area, the the finding of immunoreactivity (% for IL-26 protein in peripheral parenchymal tissue from the pooled group of all patients with asthma compared with the group of healthy volunteers. Thus, this of immunoreactivity for the pooled group of patients with asthma compared with the group of healthy volunteers statistically significant as well (P = n = for uncontrolled and for controlled ICS dose to are as median (IQR) or n is defined as a positive skin prick test result to 1 or more airborne allergens For BAL be obtained from of the healthy volunteers are indicated for between uncontrolled and controlled asthma according to the beta2-adrenoceptor not dose of methacholine to a of in beta2-adrenoceptor are as median either as the total of cells in the BAL or as in % of all BAL For BAL-cell be obtained from a of patients with uncontrolled = and controlled = asthma are indicated for between uncontrolled and controlled asthma according to the of with correlation statistically significant correlation (P
https://doi.org/10.1016/j.jaci.2019.06.035International Immunopharmacology · 2025 · 11 citations · open access
Short-term therapeutic effectiveness of tezepelumab in patients with severe asthma: A real-world study
AbstractBACKGROUND: Tezepelumab is a fully human monoclonal antibody which specifically binds to thymic stromal lymphopoietin (TSLP), thus effectively inhibiting its pleiotropic pathogenic actions. Tezepelumab has been licensed for add-on biologic therapy of severe asthma, regardless of biomarker levels or phenotype expression. OBJECTIVE: The aim of this real-life, retrospective, single-centre investigation has been to evaluate the therapeutic efficacy of tezepelumab in different phenotypes of severe asthma. METHODS: At baseline and after 4 weeks of add-on therapy with tezepelumab, several clinical, functional and biologic parameters were assessed in 30 patients with either T2-high or T2-low severe asthma, who had been or not previously treated with other biologics. RESULTS: ). Tezepelumab also significantly decreased the levels of fractional exhaled nitric oxide (FeNO) and blood basophil count. Moreover, tezepelumab significantly lowered the serum concentrations of interleukin-2 (IL-2) and vascular endothelial growth factor (VEGF). The above clinical, functional, and biologic effects of tezepelumab were observed in both T2-high and T2-low severe asthmatic patients, as well as in subjects with or without previous therapeutic experiences based on the use of other biologics. CONCLUSIONS: The results of this real-world study suggest that tezepelumab can be used, in both T2-high and T2-low severe asthmatic patients, as a valuable add-on biologic drug characterized by a very fast onset of action.
https://doi.org/10.1016/j.intimp.2025.115185Journal of Managed Care Pharmacy · 2003 · 10 citations · open access
The Role of the Immune System in the Pathogenesis of Asthma and an Overview of the Diagnosis
AbstractA sthma is a chronic inflammatory disorder of the airways. Inflammation may be present even in patients with minimal or no symptoms. irflow obstruction usually is at least partially reversible, spontaneously or with treatment. 2 Obstruction may be the result of bronchoconstriction, bronchial edema, mucus plug formation, airway wall remodeling, or a combination of these factors. 2 ss Role of the Immune System Airway inflammation is an immune-mediated process involving inflammatory cells and mediators released by these cells. Airway inflammation is characterized by increased numbers of eosinophils, mast cells, macrophages, and T lymphocytes (T cells) in the mucosa and lumen. In persons with atopy (i.e., an inherited predisposition to produce immunoglobulin E [IgE] in response to exposure to common environmental allergens), inhaled allergens deposit on bronchial mucosal tissues where antigen-presenting cells (e.g., dendritic cells) process the allergen and present it to T cells (Figure Interleukin-4 causes B cells to induce formation of IgE specific to the allergen. Some of the IgE binds to the membranes of mast cells and other cells that contain preformed inflammatory mediators (e.g., histamine, tryptase, and lipid mediators, including leukotrienes, prostaglandins, thromboxanes, and platelet-activating factor). 3 Subsequent exposure to the allergen causes cross linking of the membrane-bound IgE, degranulation of mast cells, and release of the inflammatory mediators. These mediators contribute to acute-phase symptoms (e.g., wheezing) by causing airway smooth-muscle contraction, vasodilation, and increased vascular permeability and mucus secretion. ost patients with asthma also experience a late-phase reaction characterized by airway obstruction and hyperresponsiveness. 2 These effects are mediated by interleukin-5 and other cytokines that cause inflammatory cells (e.g., eosinophils, basophils, and neutrophils) in the bloodstream to adhere to the vascular endothelium. Diapedesis and cellular infiltration into bronchial tissues follow. The cells contain substances (e.g., basic proteins) that cause epithelial cell damage and disrupt the mucosal lining and also affect blood vessels, resulting in increased vascular permeability
https://doi.org/10.18553/jmcp.2003.9.s5.8Journal of Asthma · 2020 · 8 citations
Airway hyperresponsiveness to mannitol improves in both type 2 high and type 2 low asthma after specialist management
AbstractObjectives Type 2 low (T2-low) asthma is reported to respond less to anti-inflammatory treatment compared with Type 2 high (T2-high) asthma. Airway hyperresponsiveness (AHR) to mannitol, a marker of airway mast cell activation, may be indicative of response to treatment in patients with T2-low disease. We investigated whether AHR to mannitol improves in patients with T2-low asthma after specialist management.Methods Patients with asthma or suspected asthma, referred to our specialist outpatient clinic, were enrolled consecutively and assessed with FeNO, asthma control, blood eosinophils, mannitol and methacholine tests and induced sputum. T2-low asthma was defined in patients with FeNO < 25ppb and sputum eosinophils < 3% and blood eosinophils < 300µl−1 at inclusion. Patients with asthma and AHR to mannitol (PD15 ≤ 635 mg) were followed and reassessed after 12 months of specialist management.Results Thirty-two patients (Females: 56%, age: 22 years (15–59)) were followed. Fourteen (44%) with T2-high and 18 (56%) with T2-low asthma. Baseline AHR to mannitol was comparable: Gmean PD15: 150 mg (95% CI 61–368) and 214 mg (95% CI 106–432) for T2-high and T2-low asthma respectively (P = 0.51). Both groups improved equally: Gmean PD15: 488 mg (95% CI 311–767) and 507 mg (95% CI 345–746); corresponding to a doubling-dose of: 3.00 (95% CI 1.58–5.74, P = 0.003) and 2.28 (95% CI 1.47–3.53, P = 0.001) respectively. There were no concomitant improvements in AHR to methacholine.Conclusion Patients with asthma and AHR to mannitol improve similarly in responsiveness to mannitol after 12 months of specialist management regardless of Type 2 inflammatory biomarker levels. Mechanisms driving AHR in T2-low asthma need to be further elucidated.
https://doi.org/10.1080/02770903.2020.1780255Journal of Asthma and Allergy · 2024 · 2 citations · open access
Healthcare Resource Utilisation of Severe Uncontrolled T2low and Non-T2low Asthma in Finland During 2018-2021
AbstractPurpose: Patients with asthma and low levels of type 2 inflammatory biomarkers (T2 low) have limited effective treatment options. Such biomarkers include eg blood eosinophils (b-eos) and fractional exhaled nitric oxide (FeNO). The healthcare resource utilisation (HCRU) of severe uncontrolled T2 low asthma remains unexplored. Thus, this study aimed to estimate the HCRU of T2 low and non-T2 low severe uncontrolled asthma patients using real-world data in Finland. Patients and Methods: Adult patients with an asthma diagnosis during baseline (2012-2017) at the pulmonary department of Turku University Hospital were included and followed during 2018-2021, or until death. Total HCRU costs and respiratory-related HCRU costs were evaluated. The main drivers for the HCRU and costs were assessed with gamma and negative binomial regression models. Results: Of the severe uncontrolled asthma patients with T2 status available, 40% (N=66) were identified with T2 low and 60% (N=103) with non-T2 low asthma. The average cumulative cost per patient was similar in patients with T2 low compared with non-T2 low, with all-cause costs cumulating in four years of follow-up to 37,524€ (95% CI: 27,160, 47,888) in T2 low compared to 34,712€ (25,484, 43,940) in non-T2 low. The corresponding average cumulative respiratory-related costs were 5178€ (3150, 7205) in T2 low compared to 5209€ (4104, 6313) in non-T2 low. Regression modelling identified no differences between the T2-status groups when assessing all-cause healthcare costs per patient-year (PPY). On the other hand, the regression modelling predicted more inpatient days PPY for severe uncontrolled patients with T2 low status compared to the patients with non-T2 low status. Conclusion: Patients with uncontrolled severe T2 low asthma use equal healthcare resources as corresponding non-T2 low patients. This study brought new insights into the HCRU of severe uncontrolled asthma patients per T2 status, which has not previously been investigated.
https://doi.org/10.2147/jaa.s455911Disease module: DeepOracle (Open Targets). Structures: RDKit from PubChem SMILES. Literature: retrieved by DeepSearch across 234,678,978 indexed works (targeted per-candidate search), resolved on OpenAlex.
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