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Rahimi B, Khoshnam Rad N, Amini S, Gholamzadeh M, Roostaei G, Yousefi Mokri M, Abtahi H. Comparison of ICS dose reduction vs. montelukast discontinuation for step-down therapy in well-controlled asthma: a pilot randomized controlled trial. BMC Pulm Med 2025; 25:167. [PMID: 40205376 PMCID: PMC11980050 DOI: 10.1186/s12890-025-03629-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2024] [Accepted: 03/25/2025] [Indexed: 04/11/2025] Open
Abstract
BACKGROUND While asthma guidelines advocate for reducing inhaled corticosteroid (ICS) doses in well-controlled patients, limited evidence exists to directly support this approach. This study aimed to compare the effectiveness of ICS dose reduction versus montelukast discontinuation as step-down strategies in adults with well-controlled asthma. METHODS This single-center, pilot randomized controlled trial enrolled 73 adults with well-controlled asthma. Participants were randomized to either Group A: ICS Dose Reduction (n = 37) or Group B: Montelukast Discontinuation (n = 36). Both groups received standard care and their designated intervention for three months. The primary outcome was asthma control measured by the ACT score. Secondary outcomes included lung function, asthma exacerbation frequency, treatment failure rates, and cough symptoms. Medication adherence was assessed using dose counters and pill counts. RESULTS There was no significant difference in overall asthma control between the groups, as measured by the ACT score (p = 0.42). However, patients in Group A (reduced ICS) experienced significantly fewer treatment failures compared to Group B (discontinued montelukast) at three months (p = 0.01). No serious adverse events were reported. CONCLUSION Although the ACT scores did not significantly differ between the groups, we did observe a trend towards fewer treatment failures in the ICS reduction group. This suggests that reducing ICS doses may help to maintain asthma control and reduce the risk of exacerbations. However, further research is warranted to confirm these findings in larger, long-term studies. TRIAL REGISTRATION IRCT Registration Number IRCT2016052428037N1, Retrospectively registered, Registration Date 20,160,701.
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Affiliation(s)
- Besharat Rahimi
- Thoracic Research Center, Imam Khomeini Hospital Complex, Tehran University of Medical Sciences, Tehran, Iran
| | - Niloofar Khoshnam Rad
- Thoracic Research Center, Imam Khomeini Hospital Complex, Tehran University of Medical Sciences, Tehran, Iran.
| | - Shahideh Amini
- Rajaie Cardiovascular Medical and Research Institute, Tehran, Iran
| | - Marsa Gholamzadeh
- Health Information and Medical Informatics Department, Tehran University of Medical Sciences, Tehran, Iran
| | - Ghazal Roostaei
- Thoracic Research Center, Imam Khomeini Hospital Complex, Tehran University of Medical Sciences, Tehran, Iran
| | - Mahsa Yousefi Mokri
- Department of Pharmacy, Uppsala Biomedical Center, Uppsala University, P.O. Box 580, SE-751 23, Uppsala, Sweden
| | - Hamidreza Abtahi
- Thoracic Research Center, Imam Khomeini Hospital Complex, Tehran University of Medical Sciences, Tehran, Iran.
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Hjortdahl F, Soendergaard MB, Hansen S, Bjerrum AS, von Bülow A, Hilberg O, Bonnesen B, Johnsen CR, Johansson SL, Rasmussen LM, Schmid JM, Ulrik CS, Walls AB, Porsbjerg C, Håkansson KEJ. Supratherapeutic Inhaled Corticosteroid Use in Patients Initiating on Biologic Therapies for Severe Asthma: A Nationwide Cohort Study. Lung 2025; 203:42. [PMID: 40069448 PMCID: PMC11897081 DOI: 10.1007/s00408-025-00796-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2024] [Accepted: 02/25/2025] [Indexed: 03/15/2025]
Abstract
BACKGROUND In severe asthma, intensive ("supratherapeutic") doses of inhaled corticosteroids (ICS) are often used. The prevalence of supratherapeutic ICS use and its impact on corticosteroid-related comorbidities is poorly understood. We aimed to describe the prevalence of supratherapeutic ICS use in severe asthma, its relation to corticosteroid-related comorbidities, and changes in prescribed and redeemed ICS dose after 12 months of biologic therapy. METHODS Patients from the nationwide Danish Severe Asthma Register (DSAR) receiving biologic therapy > 12 months were included. Supratherapeutic doses were defined as > 1600 µg budesonide daily. Baseline characteristics, comorbidity burden, and change in ICS use after 12 months of biologic therapy was stratified according to ICS use at baseline. RESULTS We included 652 patients in our analyses and 156 (24%) were supratherapeutic ICS users prior to initiation of biologic therapy. Supratherapeutic ICS users had a higher baseline prevalence of cataracts at 14 vs 8.1%; p = 0.025. No differences in other corticosteroid-related comorbidities were observed. No change in prevalence of prescribed supratherapeutic ICS was seen after 12 months of biologic therapy. However, a reduction in ICS adherence among supratherapeutic users was observed with 72% of patients demonstrating > 80% adherence at 12 months, compared to 83% at baseline (p < 0.001). CONCLUSION Supratherapeutic doses of ICS were used by almost one-fourth of the patients prior to initiation of biologic therapy and were associated with a higher prevalence of cataracts. Physician-driven ICS reduction was rare, yet supratherapeutic ICS users were found to self-regulate ICS therapy when treated with biologic therapy.
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Affiliation(s)
- Frederikke Hjortdahl
- Department of Respiratory Medicine, Copenhagen University Hospital, Bispebjerg, Copenhagen, Denmark
| | | | - Susanne Hansen
- Department of Respiratory Medicine, Copenhagen University Hospital, Bispebjerg, Copenhagen, Denmark
- Centre for Clinical Research and Prevention, Frederiksberg Hospital, Copenhagen, Denmark
| | - Anne-Sofie Bjerrum
- Department of Respiratory Diseases and Allergy, Aarhus University Hospital, Aarhus, Denmark
| | - Anna von Bülow
- Department of Respiratory Medicine, Copenhagen University Hospital, Bispebjerg, Copenhagen, Denmark
| | - Ole Hilberg
- Sygehus Lillebælt, Vejle Sygehus, Vejle, Denmark
| | - Barbara Bonnesen
- Department of Respiratory Medicine, Gentofte University Hospital, Hellerup, Denmark
| | | | | | | | - Johannes Martin Schmid
- Department of Respiratory Diseases and Allergy, Aarhus University Hospital, Aarhus, Denmark
| | | | - Anne Byriel Walls
- Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Capital Region Hospital Pharmacy, Rigshospitalet, Copenhagen, Denmark
| | - Celeste Porsbjerg
- Department of Respiratory Medicine, Copenhagen University Hospital, Bispebjerg, Copenhagen, Denmark
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Zhou T, Li Q, Zhang K, Zhang M, Li H, Wu W. Network pharmacology prediction and molecular docking-based strategy to explore the potential mechanism of Ginseng-Schisandra Chinensis decoction against asthma. Fitoterapia 2025; 181:106388. [PMID: 39798886 DOI: 10.1016/j.fitote.2025.106388] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2024] [Revised: 12/22/2024] [Accepted: 01/08/2025] [Indexed: 01/15/2025]
Abstract
BACKGROUND Ginseng-Schisandra chinensis (GSC) decoction has shown good efficacy in the treatment of asthma (AS), but its t mechanism in the treatment of asthma is still not fully understood. PURPOSE This study aims to elucidate the therapeutic mechanism of GSC for AS by identifying the active components of GSC. METHODS The chemical composition of GSC was analyzed using UHPLC-MS/MS. The network pharmacology method combined with TCMSP and GeneCards database was used to identify potential targets and enriched pathways related to AS treatment. Use AutoDock for molecular docking to evaluate the binding affinity of active ingredients to core targets. Finally, the LPS-induced A549 cell inflammation model was used to evaluate the effect of GSC on the release of inflammatory cytokines. RESULTS The main components in GSC, including ginsenosides (Rf, Rd, Rg2, Ro, Rg5, Rh1) and lignans (schisandrin A, B, schisandrol A, B, schisandrin ester A) were identified. Network analysis revealed 139 intersection targets and highlighted STAT3, TNF, EGFR, IL1B, and AKT1 as key targets, with the PI3K/AKT signaling pathway as the main pathway. Experimental results showed that GSC significantly reduced the levels of IL-1β, IL-6 and TNF-α in LPS-induced A549 cells (p < 0.01), indicating its powerful anti-inflammatory effect. CONCLUSION GSC plays a role in treating asthma by targeting STAT3, TNF, IL-1β and AKT1, regulating the PI3K/AKT signaling pathway and inhibiting the release of inflammatory cytokines. These findings provide a basis for the clinical application of GSC.
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Affiliation(s)
- Ting Zhou
- Jilin Ginseng Academy, Changchun University of Chinese Medicine, Changchun 130117, China
| | - Qingqing Li
- Jilin Ginseng Academy, Changchun University of Chinese Medicine, Changchun 130117, China
| | - Kaiyue Zhang
- Jilin Ginseng Academy, Changchun University of Chinese Medicine, Changchun 130117, China
| | - Meng Zhang
- Jilin Ginseng Academy, Changchun University of Chinese Medicine, Changchun 130117, China
| | - Hui Li
- Jilin Ginseng Academy, Changchun University of Chinese Medicine, Changchun 130117, China.
| | - Wei Wu
- Jilin Ginseng Academy, Changchun University of Chinese Medicine, Changchun 130117, China.
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Hayes B, Mahady S, McGuire A, Sforza A, Sforza J, Piedimonte G, Skoner DP. Dangers of under-treatment and over-treatment with inhaled corticosteroids in children with asthma. Pediatr Pulmonol 2025; 60:e27327. [PMID: 39513639 PMCID: PMC11731317 DOI: 10.1002/ppul.27327] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/13/2024] [Revised: 09/25/2024] [Accepted: 10/08/2024] [Indexed: 11/15/2024]
Abstract
Two children, both under the care of specialists for mild persistent asthma, flirted with mortality. One lost and one won the battle. A 16-year-old boy never received ICS therapy despite extensive airway inflammation and remodeling and died due to mismanagement of an asthma exacerbation. A 6-year-old girl developed iatrogenic Cushing's syndrome during 18 months of continuous treatment with high, FDA-unapproved doses of both ICS and INCS and nearly died during an adrenal crisis. The role of ICS under-treatment and over-treatment and the possibility that recommendations in asthma guidelines and information in FDA package labels could have prevented both outcomes are explored.
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Affiliation(s)
- Breanne Hayes
- West Virginia University School of MedicineMorgantownWest VirginiaUSA
| | - Stacey Mahady
- West Virginia University School of MedicineMorgantownWest VirginiaUSA
| | | | | | | | | | - David P. Skoner
- West Virginia University School of MedicineMorgantownWest VirginiaUSA
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Li H, Lin J, Zhang Q, Wang J, Li C. Domiciliary monitoring of exhaled nitric oxide in the management of asthma: a pilot study. BMC Pulm Med 2024; 24:244. [PMID: 38760654 PMCID: PMC11102187 DOI: 10.1186/s12890-024-03031-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2024] [Accepted: 04/22/2024] [Indexed: 05/19/2024] Open
Abstract
BACKGROUND Whether asthma patients could benefit from home monitoring for fractional exhaled nitric oxide (flow of 50 mL/s, FeNO50) is unknown. We explore the application value of home monitoring FeNO50 in daily asthma management. METHODS Twenty-two untreated, uncontrolled asthma patients were selected. Medical history, blood and sputum samples, pulmonary function, Asthma Control Test (ACT), and other clinical data of the subjects were collected. All subjects underwent daily monitoring for four weeks using a FeNO50 monitor and mobile spirometry (mSpirometry). The diurnal differences and dynamic changes were described. Compare the effect-acting time and the relative plateau of treatment between FeNO50 and mSpirometry monitoring. RESULTS In the first two weeks, the morning median (IQR) level of FeNO50 was 44 (35, 56) ppb, which was significantly higher than the evening median level [41 (32, 53) ppb, P = 0.028]. The median (IQR) effect-acting time assessed by FeNO50 was 4 (3, 5) days, which was significantly earlier than each measure of mSpirometry (P < 0.05). FeNO50 reached the relative plateau significantly earlier than FEV1 (15 ± 2 days vs. 21 ± 3 days, P < 0.001). After treatment, the daily and weekly variation rates of FeNO50 showed a gradually decreasing trend (P < 0.05). The ACT score, sputum eosinophils, and blood eosinophils also significantly improved (P ≤ 0.01). CONCLUSIONS The daily home monitoring of FeNO50 in asthmatic patients showed significant circadian rhythm, and the sensitivity of FeNO50 in evaluating the response to treatment was higher than mSpirometry. The daily and weekly variation rates of FeNO50 change dynamically with time, which may be used to assess the condition of asthma.
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Affiliation(s)
- Hongwen Li
- Department of Geriatric Respiratory Disease, Shandong Provincial Hospital, Affiliated to Shandong First Medical University, Jinan, China
| | - Jiangtao Lin
- Department of Pulmonary and Critical Care Medicine, China-Japan Friendship Hospital, No 2, East Yinghua Road, Chaoyang District, Beijing, 100029, China.
| | - Qing Zhang
- Department of Pulmonary and Critical Care Medicine, The first affiliated hospital of Nanchang University, Nanchang, China
| | - Jingru Wang
- State Key Laboratory of Respiratory Disease, National Clinical Research Center of Respiratory Disease, Guangzhou Institute of Respiratory Health, First Affiliated Hospital of Guangzhou Medical University, Guangdong, China
| | - Chunxiao Li
- Department of Pulmonary and Critical Care Medicine, China-Japan Friendship Hospital, No 2, East Yinghua Road, Chaoyang District, Beijing, 100029, China
- Peking University China-Japan Friendship School of Clinical Medicine, Beijing, China
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Boulet LP, Abbott C, Brusselle G, Edwards D, Oppenheimer J, Pavord ID, Pizzichini E, Sagara H, Slade D, Wechsler ME, Gibson PG. Baseline Characteristics and ICS/LAMA/LABA Response in Asthma: Analyses From the CAPTAIN Study. THE JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY. IN PRACTICE 2024; 12:1244-1253.e8. [PMID: 38309696 DOI: 10.1016/j.jaip.2024.01.039] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/31/2023] [Revised: 09/27/2023] [Accepted: 01/25/2024] [Indexed: 02/05/2024]
Abstract
BACKGROUND Findings from CAPTAIN (NCT02924688) suggest that treatment response to fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) differs according to baseline type 2 inflammation markers in patients with moderate to severe asthma. Understanding how other patient physiologic and clinical characteristics affect response to inhaled therapies may guide physicians toward a personalized approach for asthma management. OBJECTIVE To investigate, using CAPTAIN data, the predictive value of key demographic and baseline physiologic variables in patients with asthma (lung function, bronchodilator reversibility, age, age at asthma onset) on response to addition of the long-acting muscarinic antagonist UMEC to inhaled corticosteroid/long-acting β2-agonist combination FF/VI, or doubling the FF dose. METHODS Prespecified and post hoc analyses of CAPTAIN data were performed using categorical and continuous variables of key baseline characteristics to understand their influence on treatment outcomes (lung function [trough FEV1], annualized rate of moderate/severe exacerbations, and asthma control [Asthma Control Questionnaire]) following addition of UMEC to FF/VI or doubling the FF dose in FF/VI or FF/UMEC/VI. RESULTS Adding UMEC to FF/VI led to greater improvements in trough FEV1 versus doubling the FF dose across all baseline characteristics assessed. Doubling the FF dose was generally associated with numerically greater reductions in the annualized rate of moderate/severe exacerbations compared with adding UMEC, independent of baseline characteristics. Adding UMEC and/or doubling the FF dose generally led to improvements in Asthma Control Questionnaire scores irrespective of baseline characteristics. CONCLUSIONS Unlike previous findings with type 2 biomarkers, lung function, bronchodilator reversibility, age and age at asthma onset do not appear to predict response to inhaled therapy.
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Affiliation(s)
| | | | | | | | | | | | - Emilio Pizzichini
- GSK, Brentford, Middlesex, United Kingdom; Federal University of Santa Catarina, Santa Catarina, Brazil
| | | | | | | | - Peter G Gibson
- Department of Respiratory and Sleep Medicine, John Hunter Hospital, Hunter Medical Research Institute, Newcastle, New South Wales, Australia; Centre of Excellence in Severe Asthma, University of Newcastle, Newcastle, New South Wales, Australia
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Agarwal CD, Palka JM, Gajewski AJ, Khan DA, Brown ES. The efficacy of citalopram or escitalopram in patients with asthma and major depressive disorder. Ann Allergy Asthma Immunol 2024; 132:374-382. [PMID: 37952772 DOI: 10.1016/j.anai.2023.11.004] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2023] [Revised: 11/07/2023] [Accepted: 11/07/2023] [Indexed: 11/14/2023]
Abstract
BACKGROUND Major depressive disorder is common in people with asthma. Yet, few studies have evaluated depression treatment in those with asthma. OBJECTIVE To explore the relationship between antidepressant use, depressive symptoms, and asthma control, pooled data from 3 randomized trials of either citalopram or escitalopram were assessed. METHODS Linear fixed effects and binary logistic regression analyses were conducted with between-subject covariates including treatment group, (original) study, and demographics. The within-subject effect of visit, and a treatment group-visit (between-within) interaction effect, were also evaluated. Analyses were repeated in a high asthma exacerbation subgroup having at least 3 oral corticosteroid bursts in the previous 12 months. Outcomes included the Hamilton rating scale for depression (HAM-D17), the 7-item asthma control questionnaire (ACQ), and oral corticosteroid use (yes or no). RESULTS In the pooled sample (n = 255), the antidepressant treatment group exhibited lower HAM-D17 overall (P ≤ .001) and a lower likelihood for oral corticosteroid use (P ≤ .001) relative to the placebo group. In the high-exacerbation subgroup (n = 96), treatment group participants had lower overall asthma control questionnaire (P = .004) and HAM-D17 scores (P ≤ .001), and a lower likelihood of oral corticosteroid use (P = .003), relative to placebo participants. All treatment group interaction effects were not significant. CONCLUSION Citalopram or escitalopram exhibited efficacy in reducing depressive symptoms and the need for rescue oral corticosteroids in patients with asthma and major depressive disorder. Future work should determine whether selective serotonin reuptake inhibitors are effective at improving asthma outcomes in those with asthma who are not depressed. TRIAL REGISTRATION Clinicaltrials.gov Identifier: NCT00621946 and NCT01324700 (one study was conducted before ClinicalTrials.gov requirements).
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Affiliation(s)
- Catherine D Agarwal
- Department of Psychiatry, The University of Texas Southwestern Medical Center, Dallas, Texas
| | - Jayme M Palka
- Department of Psychiatry, The University of Texas Southwestern Medical Center, Dallas, Texas
| | - Alexander J Gajewski
- Department of Psychiatry, The University of Texas Southwestern Medical Center, Dallas, Texas
| | - David A Khan
- Division of Allergy and Immunology, Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, Texas
| | - E Sherwood Brown
- Department of Psychiatry, The University of Texas Southwestern Medical Center, Dallas, Texas; The Altshuler Center for Education and Research, Metrocare Services, Dallas, Texas.
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8
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Ong MS, Sordillo JE, Dahlin A, McGeachie M, Tantisira K, Wang AL, Lasky-Su J, Brilliant M, Kitchner T, Roden DM, Weiss ST, Wu AC. Machine Learning Prediction of Treatment Response to Inhaled Corticosteroids in Asthma. J Pers Med 2024; 14:246. [PMID: 38540988 PMCID: PMC10970828 DOI: 10.3390/jpm14030246] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2023] [Revised: 02/16/2024] [Accepted: 02/21/2024] [Indexed: 11/03/2024] Open
Abstract
BACKGROUND Although inhaled corticosteroids (ICS) are the first-line therapy for patients with persistent asthma, many patients continue to have exacerbations. We developed machine learning models to predict the ICS response in patients with asthma. METHODS The subjects included asthma patients of European ancestry (n = 1371; 448 children; 916 adults). A genome-wide association study was performed to identify the SNPs associated with ICS response. Using the SNPs identified, two machine learning models were developed to predict ICS response: (1) least absolute shrinkage and selection operator (LASSO) regression and (2) random forest. RESULTS The LASSO regression model achieved an AUC of 0.71 (95% CI 0.67-0.76; sensitivity: 0.57; specificity: 0.75) in an independent test cohort, and the random forest model achieved an AUC of 0.74 (95% CI 0.70-0.78; sensitivity: 0.70; specificity: 0.68). The genes contributing to the prediction of ICS response included those associated with ICS responses in asthma (TPSAB1, FBXL16), asthma symptoms and severity (ABCA7, CNN2, PTRN3, and BSG/CD147), airway remodeling (ELANE, FSTL3), mucin production (GAL3ST), leukotriene synthesis (GPX4), allergic asthma (ZFPM1, SBNO2), and others. CONCLUSIONS An accurate risk prediction of ICS response can be obtained using machine learning methods, with the potential to inform personalized treatment decisions. Further studies are needed to examine if the integration of richer phenotype data could improve risk prediction.
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Affiliation(s)
- Mei-Sing Ong
- PRecisiOn Medicine Translational Research (PROMoTeR) Center, Department of Population Medicine, Harvard Medical School and Harvard Pilgrim Health Care, Boston, MA 02215, USA; (J.E.S.); (A.C.W.)
| | - Joanne E. Sordillo
- PRecisiOn Medicine Translational Research (PROMoTeR) Center, Department of Population Medicine, Harvard Medical School and Harvard Pilgrim Health Care, Boston, MA 02215, USA; (J.E.S.); (A.C.W.)
| | - Amber Dahlin
- Channing Division of Network Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA 02115, USA; (A.D.); (M.M.); (A.L.W.); (J.L.-S.); (S.T.W.)
| | - Michael McGeachie
- Channing Division of Network Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA 02115, USA; (A.D.); (M.M.); (A.L.W.); (J.L.-S.); (S.T.W.)
| | - Kelan Tantisira
- Division of Pediatric Respiratory Medicine, Department of Pediatrics, University of California San Diego and Rady Children’s Hospital, San Diego, CA 92123, USA;
| | - Alberta L. Wang
- Channing Division of Network Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA 02115, USA; (A.D.); (M.M.); (A.L.W.); (J.L.-S.); (S.T.W.)
| | - Jessica Lasky-Su
- Channing Division of Network Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA 02115, USA; (A.D.); (M.M.); (A.L.W.); (J.L.-S.); (S.T.W.)
| | - Murray Brilliant
- Marshfield Clinic Research Institute, Marshfield, WI 54449, USA; (M.B.); (T.K.)
- Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232, USA;
| | - Terrie Kitchner
- Marshfield Clinic Research Institute, Marshfield, WI 54449, USA; (M.B.); (T.K.)
| | - Dan M. Roden
- Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232, USA;
| | - Scott T. Weiss
- Channing Division of Network Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA 02115, USA; (A.D.); (M.M.); (A.L.W.); (J.L.-S.); (S.T.W.)
| | - Ann Chen Wu
- PRecisiOn Medicine Translational Research (PROMoTeR) Center, Department of Population Medicine, Harvard Medical School and Harvard Pilgrim Health Care, Boston, MA 02215, USA; (J.E.S.); (A.C.W.)
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Halpin DMG. Bronchodilator Responsiveness in Asthma and Chronic Obstructive Pulmonary Disease: Time to Stop Chasing Shadows. Am J Respir Crit Care Med 2024; 209:349-351. [PMID: 38190497 PMCID: PMC10878380 DOI: 10.1164/rccm.202312-2248ed] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2023] [Accepted: 01/05/2024] [Indexed: 01/10/2024] Open
Affiliation(s)
- David M G Halpin
- University of Exeter Medical School University of Exeter Exeter, United Kingdom
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Al-Moamary MS, Alhaider SA, Allehebi R, Idrees MM, Zeitouni MO, Al Ghobain MO, Alanazi AF, Al-Harbi AS, Yousef AA, Alorainy HS, Al-Hajjaj MS. The Saudi initiative for asthma - 2024 update: Guidelines for the diagnosis and management of asthma in adults and children. Ann Thorac Med 2024; 19:1-55. [PMID: 38444991 PMCID: PMC10911239 DOI: 10.4103/atm.atm_248_23] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/01/2023] [Accepted: 10/31/2023] [Indexed: 03/07/2024] Open
Abstract
The Saudi Initiative for Asthma 2024 (SINA-2024) is the sixth version of asthma guidelines for the diagnosis and management of asthma for adults and children that was developed by the SINA group, a subsidiary of the Saudi Thoracic Society. The main objective of the SINA is to have guidelines that are up-to-date, simple to understand, and easy to use by healthcare workers dealing with asthma patients. To facilitate achieving the goals of asthma management, the SINA Panel approach is mainly based on the assessment of symptom control and risk for both adults and children. The approach to asthma management is aligned for age groups: adults, adolescents, children aged 5-12 years, and children aged <5 years. SINA guidelines have focused more on personalized approaches reflecting a better understanding of disease heterogeneity with the integration of recommendations related to biologic agents, evidence-based updates on treatment, and the role of immunotherapy in management. The medication appendix has also been updated with the addition of recent evidence, new indications for existing medication, and new medications. The guidelines are constructed based on the available evidence, local literature, and the current situation at national and regional levels. There is also an emphasis on patient-doctor partnership in the management that also includes a self-management plan.
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Affiliation(s)
- Mohamed Saad Al-Moamary
- Department of Medicine, College of Medicine, King Saud Bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia
| | - Sami A. Alhaider
- Department of Pediatrics, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia
| | - Riyad Allehebi
- Department of Medicine, King Fahad Medical City, Riyadh, Saudi Arabia
| | - Majdy M. Idrees
- Department of Medicine, Respiratory Division, Prince Sultan Military Medical City, Riyadh, Saudi Arabia
| | - Mohammed O. Zeitouni
- Department of Medicine, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia
| | - Mohammed O. Al Ghobain
- Department of Medicine, College of Medicine, King Saud Bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia
| | - Abdullah F. Alanazi
- Department of Medicine, College of Medicine, King Saud Bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia
| | - Adel S. Al-Harbi
- Department of Pediatrics, Prince Sultan Military Medical City, Riyadh, Saudi Arabia
| | - Abdullah A. Yousef
- Department of Pediatrics, College of Medicine, Imam Abdulrahman Bin Faisal University, Dammam, Saudi Arabia
| | - Hassan S. Alorainy
- Department of Respiratory Care, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia
| | - Mohamed S. Al-Hajjaj
- Department of Paediatrics, College of Medicine, University of Sharjah, Sharjah, United Arab Emirates
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Jiang L, Xu L, Liu H, Chen H, Wang W. Rhizoma Dioscoreae Nipponicae Relieves Asthma by Inducing the Ferroptosis of Eosinophils and Inhibiting the p38 MAPK Signaling Pathway. Crit Rev Immunol 2024; 44:77-87. [PMID: 38305338 DOI: 10.1615/critrevimmunol.2023050922] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/03/2024]
Abstract
Rhizoma Dioscoreae Nipponicae (RDN) is a traditional Chinese medicine that widely applied in the treatment of human diseases. This study aims to explore the therapeutic potential of RDN in asthma and the underlying mechanisms. A mouse model of asthma was established by the stimulation of ovalbumin (OVA). HE staining was performed to detect the pathological injuries of tracheal tissues. The protein expression of collagen I, FN1, α-SMA (airway remodeling markers), and p-p38 (a marker of the p38 MAPK pathway) were detected by Western blot. Eosinophils were then isolated from the model mice. Cell viability and ROS level were measured by CCK-8 and Flow cytometry, respectively. The mRNA expression of GPX4 and ACSL4 (ferroptosis markers) in eosinophils were measured by qRT-PCR. RDN significantly reduced the numbers of total cells and eosnophils in bronchoalveolar lavage fluid (BALF), inhibited inflammatory cell infiltration, and down-regulated remodeling markers (Collagen I, FN1, and α-SMA) in OVA-induced mice. The p38 MAPK pathway was blocked by the intervention of RDN in the model mice, and its blocking weakens the poor manifestations of OVA-induced asthma. In addition, RDN induced the ferroptosis of eosnophils both in vitro and in vivo. Blocking of the p38 MAPK pathway also enhanced the ferroptosis of eosnophils in vitro, evidenced by the decreased cell viability and GPX4 expression, and increased ROS level and ACSL4 expression. RDN induced the ferroptosis of eosinophils through inhibiting the p38 MAPK pathway, contributing to the remission of asthma.
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Affiliation(s)
- Libin Jiang
- Department of Geriatric Medicine, The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou, Zhejiang, China
| | - Liying Xu
- Department of Emergency, The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou, Zhejiang, China
| | - Huazuo Liu
- Department of Respiratory Medicine, Nanxun District Hospital of Traditional Chinese Medicine in Huzhou City, Huzhou, Zhejiang, China
| | - Hanwen Chen
- Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China
| | - Weiyi Wang
- The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine)
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12
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Wu C, Zhang R, Wang J, Chen Y, Zhu W, Yi X, Wang Y, Wang L, Liu P, Li P. Dioscorea nipponica Makino: A comprehensive review of its chemical composition and pharmacology on chronic kidney disease. Biomed Pharmacother 2023; 167:115508. [PMID: 37716118 DOI: 10.1016/j.biopha.2023.115508] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2023] [Revised: 09/06/2023] [Accepted: 09/12/2023] [Indexed: 09/18/2023] Open
Abstract
Chronic kidney disease (CKD) is a widespread ailment that significantly impacts global health. It is characterized by high prevalence, poor prognosis, and substantial healthcare costs, making it a major public health concern. The current clinical treatments for CKD are not entirely satisfactory, leading to a high demand for alternative therapeutic options. Chinese herbal medicine, with its long history, diverse varieties, and proven efficacy, offers a promising avenue for exploration. One such Chinese herbal medicine, Dioscorea nipponica Makino (DNM), is frequently used to treat kidney diseases. In this review, we have compiled studies examining the mechanisms of action of DNM in the context of CKD, focusing on five primary areas: improvement of oxidative stress, inhibition of renal fibrosis, regulation of metabolism, reduction of inflammatory response, and regulation of autophagy.
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Affiliation(s)
- Chenguang Wu
- Renal Division, Department of Medicine, Heilongjiang Academy of Chinese Medicine Sciences, Harbin, China
| | - Rui Zhang
- Renal Division, Department of Medicine, Heilongjiang Academy of Chinese Medicine Sciences, Harbin, China
| | - Jingjing Wang
- Renal Division, Department of Medicine, Heilongjiang Academy of Chinese Medicine Sciences, Harbin, China
| | - Yao Chen
- Renal Division, Department of Medicine, Heilongjiang Academy of Chinese Medicine Sciences, Harbin, China
| | - Wenhui Zhu
- Renal Division, Department of Medicine, Heilongjiang Academy of Chinese Medicine Sciences, Harbin, China
| | - Xiang Yi
- Renal Division, Department of Medicine, Heilongjiang Academy of Chinese Medicine Sciences, Harbin, China
| | - Yan Wang
- Department of Nephrology, Peking University People's Hospital, Beijing, China
| | - Lifan Wang
- Renal Division, Department of Medicine, Heilongjiang Academy of Chinese Medicine Sciences, Harbin, China.
| | - Peng Liu
- Shunyi Hospital, Beijing Hospital of Traditional Chinese Medicine, Beijing, China.
| | - Ping Li
- Beijing Key Lab for Immune-Mediated Inflammatory Diseases, China-Japan Friendship Hospital, Beijing, China.
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van Dijk YE, Rutjes NW, Golebski K, Şahin H, Hashimoto S, Maitland-van der Zee AH, Vijverberg SJH. Developments in the Management of Severe Asthma in Children and Adolescents: Focus on Dupilumab and Tezepelumab. Paediatr Drugs 2023; 25:677-693. [PMID: 37658954 PMCID: PMC10600295 DOI: 10.1007/s40272-023-00589-4] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 08/02/2023] [Indexed: 09/05/2023]
Abstract
Severe asthma in children and adolescents exerts a substantial health, financial, and societal burden. Severe asthma is a heterogeneous condition with multiple clinical phenotypes and underlying inflammatory patterns that might be different in individual patients. Various add-on treatments have been developed to treat severe asthma, including monoclonal antibodies (biologics) targeting inflammatory mediators. Biologics that are currently approved to treat children (≥ 6 years of age) or adolescents (≥ 12 years of age) with severe asthma include: anti-immunoglobulin E (omalizumab), anti-interleukin (IL)-5 (mepolizumab), anti-IL5 receptor (benralizumab), anti-IL4/IL13 receptor (dupilumab), and antithymic stromal lymphopoietin (TSLP) (tezepelumab). However, access to these targeted treatments varies across countries and relies on few and crude indicators. There is a need for better treatment stratification to guide which children might benefit from these treatments. In this narrative review we will assess the most recent developments in the treatment of severe pediatric asthma, as well as potential biomarkers to assess treatment efficacy for this patient population.
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Affiliation(s)
- Yoni E van Dijk
- Pulmonary Medicine, Amsterdam UMC, Location AMC, University of Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands
- Pediatric Pulmonology, Emma's Childrens Hospital, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
| | - Niels W Rutjes
- Pulmonary Medicine, Amsterdam UMC, Location AMC, University of Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands
- Pediatric Pulmonology, Emma's Childrens Hospital, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
| | - Korneliusz Golebski
- Pulmonary Medicine, Amsterdam UMC, Location AMC, University of Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands
| | - Havva Şahin
- Pediatric Pulmonology, Emma's Childrens Hospital, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
| | - Simone Hashimoto
- Pulmonary Medicine, Amsterdam UMC, Location AMC, University of Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands
- Pediatric Pulmonology, Emma's Childrens Hospital, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
| | - Anke-Hilse Maitland-van der Zee
- Pulmonary Medicine, Amsterdam UMC, Location AMC, University of Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands
- Pediatric Pulmonology, Emma's Childrens Hospital, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
| | - Susanne J H Vijverberg
- Pulmonary Medicine, Amsterdam UMC, Location AMC, University of Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands.
- Pediatric Pulmonology, Emma's Childrens Hospital, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands.
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Niu J, Guo W, Lu A, Han G, Wang G, Peng B, Zhao J. Comparison with gastric cancer-associated genes reveals the role of ferroptosis-related genes in eosinophils of asthma patients: A bioinformatic study. Medicine (Baltimore) 2023; 102:e35002. [PMID: 37832131 PMCID: PMC10578675 DOI: 10.1097/md.0000000000035002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/06/2023] [Accepted: 08/08/2023] [Indexed: 10/15/2023] Open
Abstract
Ferroptosis-inducing agents (FIAs) induced lipid-peroxidation-independent ferroptosis in eosinophils, thus ameliorating airway inflammation in asthmatic mice. Differences in ferroptosis-related genes (FerrGs) between eosinophils and cells in which FIAs induce canonical ferroptosis are supposed to contribute to this noncanonical ferroptosis but remain unclear. This study aims to explore these differences. This study used gastric cancer cells (GCCs) in stomach adenocarcinoma as the representative of cells in which FIAs induce canonical ferroptosis. FerrGs in Ferroptosis Database V2 respectively intersected with differentially expressed genes (DEGs) of eosinophils (E-MTAB-4660 dataset) and GCCs (GEPIA2 Stomach adenocarcinoma dataset) to obtain original ferroptosis DEGs (FerrDEGs). Then, they were subjected to Venn analysis to identify FerrDEGs shared by them and FerrDEGs exclusively expressed in eosinophils or GCCs. Identified genes were subjected to functional enrichment analysis, protein-protein interactions analysis, Hub genes analysis, and construction of the LncRNA-mediated ceRNA network. Sixty-six original FerrDEGs in eosinophils and 110 original FerrDEGs in GCCs were obtained. Venn analysis identified that eosinophils and GCCs shared 19 FerrDEGs that presented opposite expression directions and were involved in the ferroptosis pathway. Four upregulated and 20 downregulated FerrDEGs were exclusively expressed in eosinophils and GCCs, respectively. The former were enriched only in glycerolipid metabolism, while the latter were not enriched in pathways. Forty downregulated and 68 upregulated FerrDEGs were solely expressed in eosinophils and GCCs, respectively. The former was associated with the FoxO signaling pathway; the latter was related to glutathione metabolism and they were all implicated in autophagy. PPI analysis shows that the top 10 Hub genes of 66 original FerrDEGs and 44 exclusive FerrDEGs in eosinophils shared 9 genes (STAT3, NFE2L2, MAPK8, PTEN, MAPK3, TLR4, SIRT1, BECN1, and PTGS2) and they were also involved in the FoxO signaling pathway and autophagy pathway. Among them, PTEN is involved in forming a ceRNA network containing 3 LncRNAs, 3 miRNAs and 3 mRNAs. In contrast to FerrGs in cells in which FIAs induce canonical ferroptosis, the FerrGs in eosinophils differ in expression and in the regulation of ferroptosis, FoxO signaling pathway, and autophagy. It lays the groundwork for targeted induction of eosinophils lipid-peroxidation-independent ferroptosis in asthma.
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Affiliation(s)
- Jianfei Niu
- Dongzhimen Hospital of Beijing University of Chinese Medicine, Beijing, China
| | - Wei Guo
- Dongzhimen Hospital of Beijing University of Chinese Medicine, Beijing, China
| | - Aiyangzi Lu
- Hebei University of Chinese Medicine, Shijiazhuang, China
| | - Guanxiong Han
- Dongzhimen Hospital of Beijing University of Chinese Medicine, Beijing, China
| | - Guanqun Wang
- Dongzhimen Hospital of Beijing University of Chinese Medicine, Beijing, China
| | - Bihui Peng
- Dongzhimen Hospital of Beijing University of Chinese Medicine, Beijing, China
| | - Jiping Zhao
- Dongzhimen Hospital of Beijing University of Chinese Medicine, Beijing, China
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Plaza Moral V, Alobid I, Álvarez Rodríguez C, Blanco Aparicio M, Ferreira J, García G, Gómez-Outes A, Garín Escrivá N, Gómez Ruiz F, Hidalgo Requena A, Korta Murua J, Molina París J, Pellegrini Belinchón FJ, Plaza Zamora J, Praena Crespo M, Quirce Gancedo S, Sanz Ortega J, Soto Campos JG. GEMA 5.3. Spanish Guideline on the Management of Asthma. OPEN RESPIRATORY ARCHIVES 2023; 5:100277. [PMID: 37886027 PMCID: PMC10598226 DOI: 10.1016/j.opresp.2023.100277] [Citation(s) in RCA: 24] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/28/2023] Open
Abstract
The Spanish Guideline on the Management of Asthma, better known by its acronym in Spanish GEMA, has been available for more than 20 years. Twenty-one scientific societies or related groups both from Spain and internationally have participated in the preparation and development of the updated edition of GEMA, which in fact has been currently positioned as the reference guide on asthma in the Spanish language worldwide. Its objective is to prevent and improve the clinical situation of people with asthma by increasing the knowledge of healthcare professionals involved in their care. Its purpose is to convert scientific evidence into simple and easy-to-follow practical recommendations. Therefore, it is not a monograph that brings together all the scientific knowledge about the disease, but rather a brief document with the essentials, designed to be applied quickly in routine clinical practice. The guidelines are necessarily multidisciplinary, developed to be useful and an indispensable tool for physicians of different specialties, as well as nurses and pharmacists. Probably the most outstanding aspects of the guide are the recommendations to: establish the diagnosis of asthma using a sequential algorithm based on objective diagnostic tests; the follow-up of patients, preferably based on the strategy of achieving and maintaining control of the disease; treatment according to the level of severity of asthma, using six steps from least to greatest need of pharmaceutical drugs, and the treatment algorithm for the indication of biologics in patients with severe uncontrolled asthma based on phenotypes. And now, in addition to that, there is a novelty for easy use and follow-up through a computer application based on the chatbot-type conversational artificial intelligence (ia-GEMA).
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Affiliation(s)
| | - Isam Alobid
- Otorrinolaringología, Hospital Clinic de Barcelona, España
| | | | | | - Jorge Ferreira
- Hospital de São Sebastião – CHEDV, Santa Maria da Feira, Portugal
| | | | - Antonio Gómez-Outes
- Farmacología clínica, Agencia Española de Medicamentos y Productos Sanitarios (AEMPS), Madrid, España
| | - Noé Garín Escrivá
- Farmacia Hospitalaria, Hospital de la Santa Creu i Sant Pau, Barcelona, España
| | | | | | - Javier Korta Murua
- Neumología Pediátrica, Hospital Universitario Donostia, Donostia-San, Sebastián, España
| | - Jesús Molina París
- Medicina de familia, semFYC, Centro de Salud Francia, Fuenlabrada, Dirección Asistencial Oeste, Madrid, España
| | | | - Javier Plaza Zamora
- Farmacia comunitaria, Farmacia Dr, Javier Plaza Zamora, Mazarrón, Murcia, España
| | | | | | - José Sanz Ortega
- Alergología Pediátrica, Hospital Católico Universitario Casa de Salud, Valencia, España
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Tsai CH, Lai ACY, Lin YC, Chi PY, Chen YC, Yang YH, Chen CH, Shen SY, Hwang TL, Su MW, Hsu IL, Huang YC, Maitland-van der Zee AH, McGeachie MJ, Tantisira KG, Chang YJ, Lee YL. Neutrophil extracellular trap production and CCL4L2 expression influence corticosteroid response in asthma. Sci Transl Med 2023; 15:eadf3843. [PMID: 37285400 DOI: 10.1126/scitranslmed.adf3843] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2022] [Accepted: 05/04/2023] [Indexed: 06/09/2023]
Abstract
The association between neutrophil extracellular traps (NETs) and response to inhaled corticosteroids (ICS) in asthma is unclear. To better understand this relationship, we analyzed the blood transcriptomes from children with controlled and uncontrolled asthma in the Taiwanese Consortium of Childhood Asthma Study using weighted gene coexpression network analysis and pathway enrichment methods. We identified 298 uncontrolled asthma-specific differentially expressed genes and one gene module associated with neutrophil-mediated immunity, highlighting a potential role for neutrophils in uncontrolled asthma. We also found that NET abundance was associated with nonresponse to ICS in patients. In a neutrophilic airway inflammation murine model, steroid treatment could not suppress neutrophilic inflammation and airway hyperreactivity. However, NET disruption with deoxyribonuclease I (DNase I) efficiently inhibited airway hyperreactivity and inflammation. Using neutrophil-specific transcriptomic profiles, we found that CCL4L2 was associated with ICS nonresponse in asthma, which was validated in human and murine lung tissue. CCL4L2 expression was also negatively correlated with pulmonary function change after ICS treatment. In summary, steroids fail to suppress neutrophilic airway inflammation, highlighting the potential need to use alternative therapies such as leukotriene receptor antagonists or DNase I that target the neutrophil-associated phenotype. Furthermore, these results highlight CCL4L2 as a potential therapeutic target for individuals with asthma refractory to ICS.
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Affiliation(s)
- Ching-Hui Tsai
- Institute of Biomedical Sciences, Academia Sinica, Taipei 115, Taiwan
| | | | - Yu-Cheng Lin
- Institute of Biomedical Sciences, Academia Sinica, Taipei 115, Taiwan
| | - Po-Yu Chi
- Institute of Biomedical Sciences, Academia Sinica, Taipei 115, Taiwan
| | - Yun-Chi Chen
- Institute of Biomedical Sciences, Academia Sinica, Taipei 115, Taiwan
| | - Yao-Hsu Yang
- Department of Pediatrics, National Taiwan University Hospital, Taipei 100, Taiwan
| | - Chien-Han Chen
- Department of Pediatrics, Fu Jen Catholic University Hospital, Fu Jen Catholic University, New Taipei City 243, Taiwan
- School of Medicine, College of Medicine, Fu Jen Catholic University, New Taipei City 242, Taiwan
| | - Sheng-Yeh Shen
- Department of Chest Medicine, MacKay Memorial Hospital, Taipei 104, Taiwan
| | - Tsong-Long Hwang
- Graduate Institute of Natural Products, School of Traditional Chinese Medicine, Chang Gung University, Taoyuan 333, Taiwan
- Department of Anesthesiology, Chang Gung Memorial Hospital, Taoyuan 333, Taiwan
| | - Ming-Wei Su
- Institute of Biomedical Sciences, Academia Sinica, Taipei 115, Taiwan
| | - I-Ling Hsu
- Institute of Biomedical Sciences, Academia Sinica, Taipei 115, Taiwan
| | - Yu-Chi Huang
- Institute of Biomedical Sciences, Academia Sinica, Taipei 115, Taiwan
| | - Anke H Maitland-van der Zee
- Department of Pulmonary Medicine, Amsterdam UMC, University of Amsterdam, 1105 AZ Amsterdam, Netherlands
- Department of Pediatric Respiratory Medicine, Emma's Children Hospital, Amsterdam UMC, University of Amsterdam, 1105 AZ Amsterdam, Netherlands
- Amsterdam Institute for Infection and Immunity, 1105 AZ Amsterdam, Netherlands
- Amsterdam Public Health, 1105 AZ Amsterdam, Netherlands
| | - Michael J McGeachie
- Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
| | - Kelan G Tantisira
- Division of Respiratory Medicine, Department of Pediatrics, University of California San Diego, San Diego, CA 92123, USA
| | - Ya-Jen Chang
- Institute of Biomedical Sciences, Academia Sinica, Taipei 115, Taiwan
- Institute of Translational Medicine and New Drug Development, China Medical University, Taichung 404, Taiwan
| | - Yungling L Lee
- Institute of Biomedical Sciences, Academia Sinica, Taipei 115, Taiwan
- College of Public Health, China Medical University, Taichung 404, Taiwan
- Biomedical Translation Research Center (BioTReC), Academia Sinica, Taipei 115, Taiwan
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Feng WL, Pu W, Li J, Yuan Y, Yan MZ, Yuan SL, Li YK, Wu JR, Xu SQ, Zhao J. The GLCCI1 rs37973 variant and the efficacy of inhaled corticosteroids in the treatment of asthma: A meta-analysis. THE CLINICAL RESPIRATORY JOURNAL 2023. [PMID: 37157161 DOI: 10.1111/crj.13627] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/27/2022] [Revised: 04/02/2023] [Accepted: 04/24/2023] [Indexed: 05/10/2023]
Abstract
OBJECTIVE This study investigated the relationship between the glucocorticoid-induced transcript 1 (GLCCI1) gene variant and the degree of improvement in lung function with inhaled corticosteroids (ICS). METHODS We searched the PubMed, Embase, Cochrane Library, CBM, CNKI and Wanfang databases to obtain studies on the GLCCI1 rs37973 variant and the efficacy of ICS in asthma. RESULTS The overall meta-analysis showed that patients with the GG phenotype (mutant homozygotes) exhibited significantly smaller forced expiratory volume in 1 sec (FEV1) change than patients with the AG phenotype (mutant heterozygous) (MD = -0.08, 95% CI [-0.12, -0.03], P = 0.001). Compared with the AA phenotype (wild homozygotes), the GG phenotype (MD = -4.23, 95% CI [-6.09, -2.38], P < 0.00001) and AG phenotype (MD = -1.92, 95% CI [-2.35, -1.49], P < 0.00001) had significantly smaller FEV1%pred changes. The FEV1 change subgroup analysis showed that the GG phenotype group was smaller than the AA phenotype group at 8 (MD = -0.53, 95% CI [-0.91, -0.14], P = 0.007), 12 (MD = -0.16, 95% CI [-0.30, -0.02], P = 0.02) and 24 (MD = -0.09, 95% CI [-0.17, -0.01], P = 0.02) weeks of treatment; the GG phenotype group was smaller than the AG phenotype group at 12 weeks (MD = -0.08, 95% CI [-0.15, -0.01], P = 0.02). CONCLUSION This meta-analysis suggests that the GLCCI1 rs37973 variant affects the efficacy of ICS and that the presence of the G allele attenuates the improvement in lung function with ICS.
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Affiliation(s)
- Wen-Ling Feng
- Department of Pharmacy, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, China
- College of Pharmacy, Xinjiang Medical University, Urumqi, Xinjiang, China
| | - Wen Pu
- Department of Pharmacy, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, China
| | - Jing Li
- Department of Pharmacy, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, China
| | - Yuan Yuan
- Department of Pharmacy, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, China
| | - Ming-Zhi Yan
- Department of Pharmacy, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, China
- State Key Laboratory of Pathogenesis, Prevention, and Treatment of Central Asian High Incidence Diseases, Clinical Medical Research Institute, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, China
- College of Pharmacy, Xinjiang Medical University, Urumqi, Xinjiang, China
| | - Shuang-Li Yuan
- Department of Pharmacy, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, China
- College of Pharmacy, Xinjiang Medical University, Urumqi, Xinjiang, China
| | - Yu-Kun Li
- Department of Pharmacy, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, China
- College of Pharmacy, Xinjiang Medical University, Urumqi, Xinjiang, China
| | - Jie-Ru Wu
- Department of Pharmacy, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, China
- College of Pharmacy, Xinjiang Medical University, Urumqi, Xinjiang, China
| | - Shao-Quan Xu
- Department of Pharmacy, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, China
- College of Pharmacy, Xinjiang Medical University, Urumqi, Xinjiang, China
| | - Jun Zhao
- Department of Pharmacy, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, China
- College of Pharmacy, Xinjiang Medical University, Urumqi, Xinjiang, China
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18
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Wang AL, Lahousse L, Dahlin A, Edris A, McGeachie M, Lutz SM, Sordillo JE, Brusselle G, Lasky-Su J, Weiss ST, Iribarren C, Lu MX, Tantisira KG, Wu AC. Novel genetic variants associated with inhaled corticosteroid treatment response in older adults with asthma. Thorax 2023; 78:432-441. [PMID: 35501119 PMCID: PMC9810110 DOI: 10.1136/thoraxjnl-2021-217674] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2021] [Accepted: 04/01/2022] [Indexed: 01/07/2023]
Abstract
INTRODUCTION Older adults have the greatest burden of asthma and poorest outcomes. The pharmacogenetics of inhaled corticosteroid (ICS) treatment response is not well studied in older adults. METHODS A genome-wide association study of ICS response was performed in asthmatics of European ancestry in Genetic Epidemiology Research on Adult Health and Aging (GERA) by fitting Cox proportional hazards regression models, followed by validation in the Mass General Brigham (MGB) Biobank and Rotterdam Study. ICS response was measured using two definitions in asthmatics on ICS treatment: (1) absence of oral corticosteroid (OCS) bursts using prescription records and (2) absence of asthma-related exacerbations using diagnosis codes. A fixed-effect meta-analysis was performed for each outcome. The validated single-nucleotide polymorphisms (SNPs) were functionally annotated to standard databases. RESULTS In 5710 subjects in GERA, 676 subjects in MGB Biobank, and 465 subjects in the Rotterdam Study, four novel SNPs on chromosome six near PTCHD4 validated across all cohorts and met genome-wide significance on meta-analysis for the OCS burst outcome. In 4541 subjects in GERA and 505 subjects in MGB Biobank, 152 SNPs with p<5 × 10-5 were validated across these two cohorts for the asthma-related exacerbation outcome. The validated SNPs included methylation and expression quantitative trait loci for CPED1, CRADD and DST for the OCS burst outcome and GM2A, SNW1, CACNA1C, DPH1, and RPS10 for the asthma-related exacerbation outcome. CONCLUSIONS Multiple novel SNPs associated with ICS response were identified in older adult asthmatics. Several SNPs annotated to genes previously associated with asthma and other airway or allergic diseases, including PTCHD4.
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Affiliation(s)
- Alberta L Wang
- Division of Allergy and Clinical Immunology, Brigham and Women's Hospital, Boston, Massachusetts, USA
- Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA
| | - Lies Lahousse
- Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands
- Department of Bioanalysis, Faculty of Pharmaceutical Sciences, Ghent University, Ghent, Belgium
| | - Amber Dahlin
- Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA
| | - Ahmed Edris
- Department of Bioanalysis, Faculty of Pharmaceutical Sciences, Ghent University, Ghent, Belgium
| | - Michael McGeachie
- Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA
| | - Sharon M Lutz
- PRecisiOn Medicine Translational Research (PROMoTeR) Center, Department of Population Medicine, Harvard Pilgrim Health Care Institute and Harvard Medical School, Boston, Massachusetts, USA
| | - Joanne E Sordillo
- PRecisiOn Medicine Translational Research (PROMoTeR) Center, Department of Population Medicine, Harvard Pilgrim Health Care Institute and Harvard Medical School, Boston, Massachusetts, USA
| | - Guy Brusselle
- Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands
- Department of Respiratory Medicine, Ghent University Hospital, Ghent, Belgium
- Department of Respiratory Medicine, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - Jessica Lasky-Su
- Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA
| | - Scott T Weiss
- Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA
| | - Carlos Iribarren
- Kaiser Permanente Division of Research, Kaiser Permanente, Oakland, California, USA
| | - Meng X Lu
- Kaiser Permanente Division of Research, Kaiser Permanente, Oakland, California, USA
| | - Kelan G Tantisira
- Division of Pediatric Respiratory Medicine, Rady's Children's Hospital-San Diego, University of California San Diego School of Medicine, San Diego, California, USA
| | - Ann C Wu
- PRecisiOn Medicine Translational Research (PROMoTeR) Center, Department of Population Medicine, Harvard Pilgrim Health Care Institute and Harvard Medical School, Boston, Massachusetts, USA
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19
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Niimi A, Fukunaga K, Taniguchi M, Nakamura Y, Tagaya E, Horiguchi T, Yokoyama A, Yamaguchi M, Nagata M. Executive summary: Japanese guidelines for adult asthma (JGL) 2021. Allergol Int 2023; 72:207-226. [PMID: 36959028 DOI: 10.1016/j.alit.2023.02.006] [Citation(s) in RCA: 24] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2023] [Accepted: 02/17/2023] [Indexed: 03/25/2023] Open
Abstract
Asthma is characterized by chronic airway inflammation, variable airway narrowing, and sensory nerve irritation, which manifest as wheezing, dyspnea, chest tightness, and cough. Longstanding asthma may result in airway remodeling and become intractable. Despite the increased prevalence of asthma in adults, asthma-associated deaths have decreased in Japan (0.94 per 100,000 people in 2020). The goals of asthma treatment include the control of symptoms and reduction of future risks. A functional partnership between physicians and patients is indispensable for achieving these goals. Long-term management with medications and the elimination of triggers and risk factors are fundamental to asthma treatment. Asthma is managed via four steps of pharmacotherapy ("controllers"), ranging from mild to intensive treatments, depending on disease severity; each step involves daily administration of an inhaled corticosteroid, which varies from low to high dosage. Long-acting β2 agonists, leukotriene receptor antagonists, sustained-release theophylline, and long-acting muscarinic antagonists are recommended as add-on drugs. Allergen immunotherapy is a new option that is employed as a controller treatment. Further, as of 2021, anti-IgE antibody, anti-IL-5 and anti-IL-5 receptor α-chain antibodies, and anti-IL-4 receptor α-chain antibodies are available for the treatment of severe asthma. Bronchial thermoplasty can be performed for asthma treatment, and its long-term efficacy has been reported. Algorithms for their usage have been revised. Comorbidities, such as allergic rhinitis, chronic rhinosinusitis, chronic obstructive pulmonary disease, and aspirin-exacerbated respiratory disease, should also be considered during the treatment of chronic asthma. Depending on the severity of episodes, inhaled short-acting β2 agonists, systemic corticosteroids, short-acting muscarinic antagonists, oxygen therapy, and other approaches are used as needed ("relievers") during exacerbation.
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Affiliation(s)
- Akio Niimi
- Department of Respiratory Medicine, Allergy and Clinical Immunology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.
| | - Koichi Fukunaga
- Pulmonary Division, Department of Medicine, Keio University School of Medicine, Tokyo, Japan
| | - Masami Taniguchi
- Center for Immunology and Allergology, Shonan Kamakura General Hospital, Kanagawa, Japan
| | - Yoichi Nakamura
- Medical Center for Allergic and Immune Diseases, Yokohama City Minato Red Cross Hospital, Yokohama, Japan
| | - Etsuko Tagaya
- Department of Respiratory Medicine, Tokyo Women's Medical University, Tokyo, Japan
| | - Takahiko Horiguchi
- Department of Respiratory Medicine, Toyota Regional Medical Center, Toyota, Japan
| | - Akihito Yokoyama
- Department of Respiratory Medicine and Allergology, Kochi Medical School, Kochi University, Kochi, Japan
| | - Masao Yamaguchi
- Division of Respiratory Medicine, Third Department of Medicine, Teikyo University Chiba Medical Center, Chiba, Japan
| | - Makoto Nagata
- Department of Respiratory Medicine, Saitama Medical University, Saitama, Japan; Allergy Center, Saitama Medical University Hospital, Saitama Medical University, Saitama, Japan
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Corren J, Wechsler ME, Chupp G, Roseti SL, Hellqvist Å, Martin N, Llanos JP, Ambrose CS, Colice G. Efficacy and safety of tezepelumab in patients with uncontrolled disease while receiving maintenance therapy for moderate or severe asthma. THE JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY. IN PRACTICE 2023; 11:943-945.e2. [PMID: 36375743 DOI: 10.1016/j.jaip.2022.10.042] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/09/2022] [Revised: 10/12/2022] [Accepted: 10/21/2022] [Indexed: 11/13/2022]
Affiliation(s)
- Jonathan Corren
- Department of Medicine, David Geffen School of Medicine, UCLA, Los Angeles, Calif.
| | | | - Geoffrey Chupp
- Department of Medicine, Yale School of Medicine, New Haven, Conn
| | - Stephanie L Roseti
- Late-stage Development, Respiratory and Immunology, BioPharmaceuticals R&D, AstraZeneca, Gaithersburg, Md
| | - Åsa Hellqvist
- Biometrics, Late-stage Development, Respiratory and Immunology, BioPharmaceuticals R&D, Gothenburg, Sweden
| | - Neil Martin
- Respiratory and Immunology, BioPharmaceuticals Medical, AstraZeneca, Cambridge, UK; Leicester NIHR Biomedical Research Centre, University of Leicester, Leicester, UK
| | | | - Christopher S Ambrose
- Respiratory and Immunology, BioPharmaceuticals Medical, AstraZeneca, Gaithersburg, Md
| | - Gene Colice
- Late-stage Development, Respiratory and Immunology, BioPharmaceuticals R&D, AstraZeneca, Gaithersburg, Md
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21
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McDowell PJ, Busby J, Heaney LG. Asthma Exacerbations in Severe Asthma: Why Systemic Corticosteroids May not Always Be the Best Treatment Option. CURRENT TREATMENT OPTIONS IN ALLERGY 2023. [DOI: 10.1007/s40521-023-00330-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/27/2023]
Abstract
Abstract
Purpose
Advances in the management of severe, eosinophilic asthma have improved, but asthma exacerbations continue to occur. This review aims to look at the evidence we have about why exacerbations may occur; their phenotype and why oral corticosteroids may not always be the best treatment option for all exacerbation of symptoms in individuals with severe asthma.
Recent findings
Studies dating back to the 1990s showed that asthma exacerbations across the spectrum of asthma severity were of different inflammatory endotypes. In addition, there is a wealth of evidence suggesting that eosinophilic inflammation is very responsive to corticosteroid therapy, but that non-eosinophilic inflammation is less so. Two recent UK-based studies have undertaken systematic phenotyping of exacerbations in severe asthma and have shown that there are a significant minority of exacerbation events with an increase in asthma symptoms, fall in lung function, but without evidence of raised T2 biomarkers.
Summary
The evidence to date would suggest that T2 biomarker low asthma exacerbations do not benefit from the administration of oral corticosteroids; in fact, the effect of the oral corticosteroids is harmful. However, there is a paucity of data to answer this question directly. Further research is needed to assess the evolution of non-T2 exacerbations not treated with OCS in a randomised, placebo-controlled, manner.
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22
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Tiotiu A, Bikov A, Gonzalez-Barcala FJ, Novakova S, Novakova P, Chong-Neto H, Santus P, Ansotegui I, Ivancevich JC, Kowal K, Mihaicuta S, Nedeva D, Canonica GW, Bernstein JA, Boulet LP, Braido F. Criteria to evaluate efficacy of biologics in asthma: a Global Asthma Association survey. Expert Rev Respir Med 2023; 17:507-516. [PMID: 37313643 DOI: 10.1080/17476348.2023.2223986] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2023] [Accepted: 06/07/2023] [Indexed: 06/15/2023]
Abstract
BACKGROUND Currently, there are no universally accepted criteria to measure the response to biologics available as treatment for severe asthma. This survey aims to establish consensus criteria to use for the evaluation of response to biologics after 4 months of treatment. METHOD Using Delphi methodology, a questionnaire including 10 items was validated by 13 international experts in asthma. The electronic survey circulated within the Interasma Scientific Network platform. For each item, five answers were proposed graduated from 'no importance' to 'very high importance' and by a score (A = 2 points; B = 4 points; C = 6 points; D = 8 points; E = 10 points). The final criteria were selected if the median score for the item was ≥7 and > 60% of responses according 'high importance' and 'very high importance'. All selected criteria were validated by the experts. RESULTS Four criteria were identified: reduce daily systemic corticosteroids dose by ≥50%; decrease the number of asthma exacerbations requiring systemic corticosteroids by ≥50%; have no/minimal side effects; and obtain asthma control according validated questionnaires. The consensual decision was that ≥3 criteria define a good response to biologics. CONCLUSIONS Specific criteria were defined by an international panel of experts and could be used as tool in clinical practice.
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Affiliation(s)
- Angelica Tiotiu
- Department of Pulmonology, University Hospital of Nancy, Nancy, France
- Development, Adaptation and Disadvantage. Cardiorespiratory Regulations and Motor Control Unit (EA 3450 DevAh), University of Lorraine, Nancy, France
| | - Andras Bikov
- North West Lung Centre, Wythenshawe Hospital, Manchester University Foundation Trust, Manchester, UK
- Division of Infection, Immunity and Respiratory Medicine, School of Biological Sciences, The University of Manchester, Manchester, UK
| | - Francisco-Javier Gonzalez-Barcala
- Department of Respiratory Medicine, University Hospital of Santiago de Compostela, Santiago de Compostela, Spain
- Spanish Biomedical Research Networking Centre-CIBERES, Health Research Institute of Santiago de Compostela (FIDIS), Santiago de Compostela, Spain
| | - Silviya Novakova
- Allergy Unit, Internal Consulting Department, University Hospital "St. George", Plovdiv, Bulgaria
| | - Plamena Novakova
- Clinic of Clinical Allergy, Medical University Sofia, Sofia, Bulgaria
| | - Herberto Chong-Neto
- Division of Allergy and Immunology, Complexo Hospital de Clínicas, Universidade Federal Do Paraná, Curitiba, Brazil
| | - Pierachille Santus
- Department of Biomedical and Clinical Sciences (DIBIC), Università Degli Studi Di Milano, Milano, Italy
- Division of Respiratory Diseases, "L. Sacco" University Hospital, Milano, Italy
| | - Ignacio Ansotegui
- Department of Allergy and Immunology, Hospital Quirónsalud Bizkaia, Bilbao, Spain
| | | | - Krzysztof Kowal
- Department of Allergology and Internal Medicine, Medical University of Bialystok, Bialystok, Poland
| | - Stefan Mihaicuta
- Center for Research and Innovation in Precision Medicine and Pharmacy, Timisoara, Romania
- Department of Pulmonology, "Victor Babes" University of Medicine and Pharmacy, Timisoara, Romania
| | - Denislava Nedeva
- Clinic of Asthma and Allergology, UMBAL Alexandrovska, Medical University Sofia, Sofia, Bulgaria
| | - Gorgio Walter Canonica
- Department of Biomedical Sciences, Humanitas University, Milan, Italy
- Asthma & Allergy Unit-IRCCS Humanitas Research Hospital, Milan, Italy
| | - Jonathan A Bernstein
- Department of Internal Medicine, Division of Immunology, Allergy Section University of Cincinnati, Cincinnati, OH, USA
| | - Louis Philippe Boulet
- Department of Medicine, Québec Heart and Lung Institute-Laval University, Quebec, Canada
| | - Fulvio Braido
- Department of Internal Medicine, University of Genoa, Genova, Italy
- Respiratory Unit for Continuity of Care IRCCS, Ospedale Policlinico San Martino, Genova, Italy
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23
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Rothe T, von Garnier C, Bridevaux PO, Charbonnier F, Clarenbach C, Gianella P, Jochmann A, Kern L, Nikolay P, Steurer-Stey C, Leuppi JD. The clinical features of asthma exacerbations in early-onset and eosinophilic late-onset asthma may differ significantly. Respir Med 2023; 206:107067. [PMID: 36563609 DOI: 10.1016/j.rmed.2022.107067] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/09/2022] [Revised: 11/27/2022] [Accepted: 11/30/2022] [Indexed: 12/13/2022]
Abstract
Over 20 years ago, the concept of asthma control was created and appropriate measurement tools were developed and validated. Loss of asthma control can lead to an exacerbation. Years ago, the term "clinically significant asthma exacerbation" was introduced to define when a loss of control is severe enough to declare it an asthma exacerbation. This term is also used by health insurances to determine when an exacerbation is eligible for reimbursement of biologics in clinical practice, however, it sometimes becomes apparent that a clear separation between loss of "asthma control" and an exacerbation is not always possible. In this review, we attempt to justify why exacerbations in early allergic asthma and adult eosinophilic asthma can differ significantly and why this is important in clinical practice as well as when dealing with health insurers.
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Affiliation(s)
- Thomas Rothe
- Pneumology, Cantonal Hospital GR Chur, Switzerland.
| | - Christophe von Garnier
- Division of Pulmonology, Lausanne University Hospital (CHUV) and University of Lausanne, Switzerland
| | | | | | | | | | - Anja Jochmann
- Pneumology, University Children Hospital Basel, Switzerland
| | - Lukas Kern
- Pneumology, Cantonal Hospital St. Gallen, Switzerland
| | | | - Claudia Steurer-Stey
- Dept. of Epidemiology, Biostatistics and Prevention, University Zürich, Switzerland
| | - Joerg D Leuppi
- University Clinic of Medicine, Kantonsspital Baselland, Liestal, Switzerland; University of Basel, Switzerland
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24
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Song R, Broytman O, Liang N, Setzke J, Setzke C, Wojdyla G, Pegelow DF, Osman F, Sorkness RL, Watters JJ, Teodorescu M. Four weeks of repetitive acute hypoxic preconditioning did not alleviate allergen-induced airway dysfunction in rats. Respir Physiol Neurobiol 2023; 307:103982. [PMID: 36332748 DOI: 10.1016/j.resp.2022.103982] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2021] [Revised: 10/26/2022] [Accepted: 10/29/2022] [Indexed: 11/06/2022]
Abstract
Clinical case series suggest beneficial effects of low-dose intermittent hypoxia in asthma. We tested cardiopulmonary effects of repetitive acute hypoxic preconditioning (RAHP) during allergic inflammation. Brown Norway rats were sensitized to house dust mites (HDM) and exposed to 4-week RAHP or normoxia (SHAM), concurrent with weekly HDM or saline (SAL) challenges. We assessed methacholine responses and lung HIF-1α expression at endpoint, and weekly blood pressure (BP). RAHP relative to SHAM: 1) in HDM-challenged rats, showed no protection against HDM-induced airway dysfunction and did not significantly impact BP (week 4 mean BP difference = 10.51 mmHg, p = 0.09) or HIF-1α expression; 2) in SAL-challenged rats, attenuated airway responses to methacholine, reduced BP (week 4 mean BP average difference = -8.72 mmHg, p = 0.04) and amplified HIF-1α expression (p = 0.0086). Four weeks of RAHP did not mitigate the allergen-induced lower airway dysfunction and may detrimentally affect BP. However, it elicited beneficial cardiopulmonary responses in SAL-challenged rats, concurrent with increased HIF-1α expression.
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Affiliation(s)
- Ruolin Song
- Department of Medicine, University of Wisconsin, Madison, WI, USA
| | - Oleg Broytman
- Department of Medicine, University of Wisconsin, Madison, WI, USA
| | - Nicole Liang
- Department of Medicine, University of Wisconsin, Madison, WI, USA
| | - Jonathan Setzke
- Department of Medicine, University of Wisconsin, Madison, WI, USA
| | | | - Gabriela Wojdyla
- Department of Medicine, University of Wisconsin, Madison, WI, USA
| | - David F Pegelow
- Department of Pediatrics, School of Medicine and Public Health,University of Wisconsin, Madison, WI, USA
| | - Fauzia Osman
- Department of Medicine, University of Wisconsin, Madison, WI, USA
| | - Ronald L Sorkness
- Department of Medicine, University of Wisconsin, Madison, WI, USA; School of Pharmacy, University of Wisconsin, Madison, WI, USA
| | - Jyoti J Watters
- Department of Comparative Biosciences, School of Veterinary Medicine, University of Wisconsin, Madison, WI, USA
| | - Mihaela Teodorescu
- Department of Medicine, University of Wisconsin, Madison, WI, USA; William S. Middleton Memorial VA Medical Center, Madison, WI, USA.
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25
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Ham J, Lim M, Kim D, Kim HY. Memory-like innate lymphoid cells in the pathogenesis of asthma. Front Immunol 2022; 13:1005517. [PMID: 36466877 PMCID: PMC9712946 DOI: 10.3389/fimmu.2022.1005517] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2022] [Accepted: 10/17/2022] [Indexed: 09/13/2023] Open
Abstract
Innate lymphoid cells (ILCs) are recently discovered innate immune cells that reside and self-renew in mucosal tissues and serve as the first line of defense against various external insults. They include natural killer (NK) cells, ILC1s, ILC2s, ILC3s, and lymphoid tissue inducer cells. The development and functions of ILC1-3 reflect those of their adaptive immunity TH1, TH2, and TH17 T-cell counterparts. Asthma is a heterogeneous disease caused by repeated exposure to specific allergens or host/environmental factors (e.g., obesity) that stimulate pathogenic pulmonary immune cells, including ILCs. Memory used to be a hallmark of adaptive immune cells until recent studies of monocytes, macrophages, and NK cells showed that innate immune cells can also exhibit greater responses to re-stimulation and that these more responsive cells can be long-lived. Besides, a series of studies suggest that the tissue-resident innate lymphoid cells have memory-like phenotypes, such as increased cytokine productions or epigenetic modifications following repetitive exposure to allergens. Notably, both clinical and mouse studies of asthma show that various allergens can generate memory-like features in ILC2s. Here, we discuss the biology of ILCs, their roles in asthma pathogenesis, and the evidence supporting ILC memory. We also show evidence suggesting memory ILCs could help drive the phenotypic heterogeneity in asthma. Thus, further research on memory ILCs may be fruitful in terms of developing new therapies for asthma.
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Affiliation(s)
- Jongho Ham
- Department of Biomedical Sciences, Laboratory of Mucosal Immunology, Seoul National University College of Medicine, Seoul, South Korea
- Department of Biomedical Sciences, BK21 Plus Biomedical Science Project, Seoul National University College of Medicine, Seoul, South Korea
- CIRNO, Sungkyunkwan University, Suwon, South Korea
| | - MinYeong Lim
- Department of Biomedical Sciences, Laboratory of Mucosal Immunology, Seoul National University College of Medicine, Seoul, South Korea
- Department of Biomedical Sciences, BK21 Plus Biomedical Science Project, Seoul National University College of Medicine, Seoul, South Korea
- CIRNO, Sungkyunkwan University, Suwon, South Korea
| | - Dongmo Kim
- Department of Biomedical Sciences, Laboratory of Mucosal Immunology, Seoul National University College of Medicine, Seoul, South Korea
- Department of Biomedical Sciences, BK21 Plus Biomedical Science Project, Seoul National University College of Medicine, Seoul, South Korea
- CIRNO, Sungkyunkwan University, Suwon, South Korea
| | - Hye Young Kim
- Department of Biomedical Sciences, Laboratory of Mucosal Immunology, Seoul National University College of Medicine, Seoul, South Korea
- Department of Biomedical Sciences, BK21 Plus Biomedical Science Project, Seoul National University College of Medicine, Seoul, South Korea
- CIRNO, Sungkyunkwan University, Suwon, South Korea
- Institute of Allergy and Clinical Immunology, Seoul National University Medical Research Center, Seoul, South Korea
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26
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Marcos MC, Cisneros Serrano C. What is the added value of FeNO as T2 biomarker? FRONTIERS IN ALLERGY 2022; 3:957106. [PMID: 36032508 PMCID: PMC9403133 DOI: 10.3389/falgy.2022.957106] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2022] [Accepted: 07/20/2022] [Indexed: 11/17/2022] Open
Abstract
There is increasing evidence about the role of nitric oxide in type 2 (T2) immune response. Fraction of exhaled nitric oxide (FeNO) is a product of airways inflammation and it is increased in patients with asthma. Since Gustaffson published the first article about this biomarker in the 1990s, interest has continued to grow. Compared with other T2 biomarkers such as blood eosinophil count, induced sputum, or serum periostin, FeNO has some remarkable advantages, including its not invasive nature, easy repeatability, and possibility to be performed even in patients with severe airway obstruction. It is considered as an indicator of T2 inflammation and, by the same token, a useful predictor for inhaled steroid response. It is difficult to determine the utility of nitric oxide (NO) for initial asthma diagnosis. In such a heterogenous disease, a single parameter would probably not be enough to provide a complete picture. There is also an important variability among authors concerning FeNO cutoff values and the percentage of sensibility and specificity for diagnosis. Its high specificity indicates a potential role to “rule in” asthma; however, its lower sensibility could suggest a lower capacity to “rule out” this pathology. For this reason, if a diagnosis of asthma is being considered, FeNO should be considered along with other tests. FeNO has also shown its utility to detect response to steroids, adherence to treatment, and risk of exacerbation. Even though there is not enough quality of evidence to establish overall conclusions, FeNO could be an alternative procedure to diagnose or exclude asthma and also a predictive tool in asthma treated with corticosteroids.
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27
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Liu L, Zhang X, Zhang L, Liu Y, Zhang HP, Zhao SZ, Zhang J, Zhang WJ, Wang F, Wang L, Zhou AX, Li WM, Wang G, Gibson PG. Reduced bronchodilator reversibility correlates with non-type 2 high asthma and future exacerbations: A prospective cohort study. Respir Med 2022; 200:106924. [PMID: 35772189 DOI: 10.1016/j.rmed.2022.106924] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/18/2021] [Revised: 06/08/2022] [Accepted: 06/20/2022] [Indexed: 02/08/2023]
Abstract
BACKGROUND Given that airway obstruction in asthma is not always fully reversible, reduced bronchodilator reversibility (BDR) may be a special asthma phenotype. OBJECTIVE To explore the characteristics of BDRhigh/low phenotypes (defined using two BDR criteria) and their associations with asthma exacerbations (AEs). METHODS After baseline assessments, all patients were classified into BDRhigh or BDRlow phenotypes. This study consisted of 2 parts. Part I was a 12-month prospective observational cohort study designed to identify the clinical characteristics and associations with future AEs in BDRhigh/low phenotypes (n = 456). Part II, designed as a post hoc analysis of the data obtained in Part I, was conducted to assess the association between BDRhigh/low phenotypes and treatment responsiveness (n = 360). RESULTS Subjects with BDRlow phenotypes had better baseline asthma symptom control and was negatively associated with eosinophilic asthma and type 2 (T2) high asthma. During the 12-month follow-up, those with BDRlow phenotypes had a higher risk of severe AEs (SAEs) (guideline-based criterion: RRadj = 2.24, 95% CI = [1.25, 3.68]; Ward's criterion: RRadj = 2.46, 95% CI = [1.40, 4.00]) and moderate-to-severe AEs (MSAEs) (guideline-based criterion: RRadj = 1.83, 95% CI = [1.22, 2.56]; Ward's criterion: RRadj = 1.94, 95% CI = [1.32, 2.68]) in the following year according to logistic regression models. Similar findings were obtained with negative binominal regression models. BDRlow phenotype was a risk factor for an insensitive response to anti-asthma treatment (guideline-based criterion: ORadj = 1.96, 95% CI = [1.05, 3.65]; Ward's criterion: ORadj = 2.01, 95% CI = [1.12, 3.58]). CONCLUSION We identified that BDRlow phenotype was associated with non-T2 high asthma and future AEs. These findings have clinically relevant implications for asthma management.
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Affiliation(s)
- Lei Liu
- Pneumology Group, Department of Integrated Traditional Chinese and Western Medicine, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China; Department of Respiratory and Critical Care Medicine, Clinical Research Center for Respiratory Disease, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China; Laboratory of Pulmonary Immunology and Inflammation, Frontiers Science Center for Disease-related Molecular Network, Sichuan University, Chengdu, 610041, Sichuan, China
| | - Xin Zhang
- Pneumology Group, Department of Integrated Traditional Chinese and Western Medicine, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China; Department of Respiratory and Critical Care Medicine, Clinical Research Center for Respiratory Disease, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China; Laboratory of Pulmonary Immunology and Inflammation, Frontiers Science Center for Disease-related Molecular Network, Sichuan University, Chengdu, 610041, Sichuan, China
| | - Li Zhang
- Pneumology Group, Department of Integrated Traditional Chinese and Western Medicine, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China; Department of Respiratory and Critical Care Medicine, Clinical Research Center for Respiratory Disease, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China; Laboratory of Pulmonary Immunology and Inflammation, Frontiers Science Center for Disease-related Molecular Network, Sichuan University, Chengdu, 610041, Sichuan, China
| | - Ying Liu
- Pneumology Group, Department of Integrated Traditional Chinese and Western Medicine, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China; Department of Respiratory and Critical Care Medicine, Clinical Research Center for Respiratory Disease, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China; Laboratory of Pulmonary Immunology and Inflammation, Frontiers Science Center for Disease-related Molecular Network, Sichuan University, Chengdu, 610041, Sichuan, China
| | - Hong Ping Zhang
- Pneumology Group, Department of Integrated Traditional Chinese and Western Medicine, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China
| | - Shu Zhen Zhao
- Outpatient Department, West China Hospital, Sichuan University, Chengdu 610041, Sichuan, China
| | - Jie Zhang
- Department of Respiratory and Critical Care Medicine, The Second Affiliated Hospital of Jilin University, Changchun 130041, Jilin, China
| | - Wei Jie Zhang
- Department of Respiratory Disease, Jilin Province People's Hospital, Changchun, 130021, Jilin, China
| | - Fang Wang
- Department of Pathogen Biology, Basic Medical College, Jilin University, Changchun, 130021, Jilin, China
| | - Lei Wang
- Pneumology Group, Department of Integrated Traditional Chinese and Western Medicine, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China
| | - Anny Xiaobo Zhou
- Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, MA, USA
| | - Wei Min Li
- Department of Respiratory and Critical Care Medicine, Clinical Research Center for Respiratory Disease, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China.
| | - Gang Wang
- Department of Respiratory and Critical Care Medicine, Clinical Research Center for Respiratory Disease, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China; Laboratory of Pulmonary Immunology and Inflammation, Frontiers Science Center for Disease-related Molecular Network, Sichuan University, Chengdu, 610041, Sichuan, China.
| | - Peter Gerard Gibson
- Priority Research Centre for Healthy Lungs and Centre of Excellence in Severe Asthma, Faculty of Health and Medicine, University of Newcastle, Newcastle, NSW, Australia
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28
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Chan R, Lipworth BJ. Oscillometry bronchodilator response in adult moderate to severe eosinophilic asthma patients: A prospective cohort study. Clin Exp Allergy 2022; 52:1118-1120. [PMID: 35707948 PMCID: PMC9540425 DOI: 10.1111/cea.14185] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2022] [Revised: 06/09/2022] [Accepted: 06/11/2022] [Indexed: 11/27/2022]
Affiliation(s)
- Rory Chan
- Scottish Centre for Respiratory Research, Ninewells Hospital and Medical School University of Dundee, Dundee, UK
| | - Brian J Lipworth
- Scottish Centre for Respiratory Research, Ninewells Hospital and Medical School University of Dundee, Dundee, UK
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29
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Hengeveld VS, Lammers N, van der Kamp MR, van der Palen J, Thio BJ. Can the response to a single dose of beclomethasone dipropionate predict the outcome of long-term treatment in childhood exercise-induced bronchoconstriction? Pediatr Allergy Immunol 2022; 33:e13808. [PMID: 35754119 DOI: 10.1111/pai.13808] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/02/2022] [Revised: 05/09/2022] [Accepted: 05/13/2022] [Indexed: 11/28/2022]
Abstract
BACKGROUND Exercise-induced bronchoconstriction (EIB) is a frequent and highly specific symptom of childhood asthma. Inhaled corticosteroids (ICS) are the mainstay of controller therapy for EIB and asthma; however, a proportion of asthmatic children and adolescents is less responsive to ICS. We hypothesized that a single dose response to ICS could function as a predictor for individual long-term efficacy of ICS. OBJECTIVE To assess the predictive value of the bronchoprotective effect of a single-dose beclomethasone dipropionate (BDP) against EIB for the bronchoprotective effect of 4 weeks of treatment, using an exercise challenge test (ECT). METHODS Thirty-two steroid-naïve children and adolescents aged 6 to 18 years with EIB were included in this prospective cohort study. They performed an ECT at baseline, after a single-dose BDP (200µg) and after 4 weeks of BDP treatment (100 µg twice daily) to assess EIB severity. RESULTS The response to a single-dose BDP on exercise-induced fall in FEV1 showed a significant correlation with the response on exercise-induced fall in FEV1 after 4 weeks of BDP treatment (r = .38, p = .004). A reduction in post-exercise fall in FEV1 of more than 8% after a single-dose BDP could predict BDP efficacy against EIB after 4 weeks of treatment with a positive predictive value of 100% (CI: 86.1-100%) and a negative predictive value of 29.4% (CI: 11.7%-53.7%). CONCLUSION We found that the individual response to a single-dose BDP against EIB has a predictive value for the efficacy of long-term treatment with BDP. This could support clinicians in providing personalized management of EIB in childhood asthma.
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Affiliation(s)
- Vera S Hengeveld
- Department of Paediatrics, Medisch Spectrum Twente, Enschede, The Netherlands
| | - Natasja Lammers
- Department of Paediatrics, Medisch Spectrum Twente, Enschede, The Netherlands
| | - Mattienne R van der Kamp
- Department of Paediatrics, Medisch Spectrum Twente, Enschede, The Netherlands.,Department of Biomedical Signals and Systems, University of Twente, Enschede, The Netherlands
| | - Job van der Palen
- Clinical Epidemiology, Medisch Spectrum Twente, Enschede, The Netherlands.,Department of Research Methodology, Measurement and Data Analysis, University of Twente, Enschede, The Netherlands
| | - Bernard J Thio
- Department of Paediatrics, Medisch Spectrum Twente, Enschede, The Netherlands
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30
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Lee EG, Rhee CK. Principles of asthma treatment and appropriate use of new drugs. JOURNAL OF THE KOREAN MEDICAL ASSOCIATION 2022. [DOI: 10.5124/jkma.2022.65.1.44] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
Background: Asthma is the most common chronic respiratory disease, affecting 1% to 18% of the population worldwide. It is characterized by various respiratory symptoms, such as wheezing, shortness of breath, chest tightness and cough, and variable airflow limitation. People with asthma often have periods of worsened symptoms and airway obstruction called exacerbations, which can be fatal. We would like to provide the updated clinical management protocols for patients with asthma.Current Concepts: The goal of asthma treatment is to control symptoms adequately and minimize exacerbations. Anti-inflammatory and bronchodilator therapies are the mainstay of asthma treatment and are recommended as a stepwise approach. The pharmacological treatment of asthma involves evaluating and reviewing the current control status based on the symptoms, future risk of exacerbation, comorbidities, side effects, and patient’s satisfaction. Asthma symptoms in some patients remain uncontrolled despite intensive treatment. The development of biomarkers, evaluation of the patient’s phenotype, and personalized treatment, including biologics, can provide new and effective treatment opportunities.Discussion and Conclusion: Successful asthma management can be achieved through accurate diagnosis of asthma, evaluation of the control stages, correct use of controllers and relievers, adjustment of asthma triggers, personalized approach, and training in self-management.
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31
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Alturaiki W, Mubarak A, Mir SA, Afridi A, Premanathan M, Mickymaray S, Vijayakumar R, Alsagaby SA, Almalki SG, Alghofaili F, Alnemare AK, Flanagan BF. Plasma levels of BAFF and APRIL are elevated in patients with asthma in Saudi Arabia. Saudi J Biol Sci 2021; 28:7455-7459. [PMID: 34867050 PMCID: PMC8626297 DOI: 10.1016/j.sjbs.2021.08.044] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2021] [Revised: 08/11/2021] [Accepted: 08/15/2021] [Indexed: 12/02/2022] Open
Abstract
B-cell activation factor (BAFF) and a proliferation-inducing ligand (APRIL) are members of the tumor necrosis factor superfamily of cytokines and can induce B cell activation, differentiation, and antibody production via interaction with their receptors, including transmembrane activator, calcium modulator, and cyclophilin ligand interactor (TACI), B-cell maturation antigen (BCMA), and B-cell activating factor receptor (BAFF-R). Herein, we assessed the plasma protein levels of BAFF and APRIL in patients with asthma to determine whether their expression is correlated with total IgE production and examined the surface expression of BAFF/APRIL receptors on B cells. Blood samples were collected from 47 patients with controlled asthma symptoms and 20 healthy normal controls, and plasma levels of APRIL, BAFF, and total IgE protein were quantified by corresponding ELISA assays. Furthermore, lymphocytes were isolated and B cells were analyzed for the presence of BAFF-R, BCMA, and TACI receptors using flow cytometry. Our results showed that IgE, BAFF, and APRIL plasma levels were markedly increased in patients with asthma compared with healthy controls. Moreover, expression of BAFF-R and BCMA, but not that of TACI, was significantly increased in patients with asthma compared with healthy controls. Overall, the findings suggest BAFF and APRIL as key mediators of asthma, and determination of their plasma levels may be useful in monitoring asthma symptoms and treatment response.
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Affiliation(s)
- Wael Alturaiki
- Department of Medical Laboratory Sciences, College of Applied Medical Sciences, Majmaah University, Majmaah 11952, Saudi Arabia
| | - Ayman Mubarak
- Department of Botany and Microbiology, College of Science, King Saud University, Riyadh 11451, Saudi Arabia
| | - Sajad Ahmad Mir
- Department of Internal Medicine, Alzulfi General Hospital, Alzulfi 11932, Saudi Arabia
| | - Adnan Afridi
- Department of Internal Medicine, Alzulfi General Hospital, Alzulfi 11932, Saudi Arabia
| | - Mariappan Premanathan
- Department of Biology, College of Science in Zulfi, Majmaah University, Majmaah 11952, Saudi Arabia
| | - Suresh Mickymaray
- Department of Biology, College of Science in Zulfi, Majmaah University, Majmaah 11952, Saudi Arabia
| | - Rajendran Vijayakumar
- Department of Biology, College of Science in Zulfi, Majmaah University, Majmaah 11952, Saudi Arabia
| | - Suliman A Alsagaby
- Department of Medical Laboratory Sciences, College of Applied Medical Sciences, Majmaah University, Majmaah 11952, Saudi Arabia
| | - Sami G Almalki
- Department of Medical Laboratory Sciences, College of Applied Medical Sciences, Majmaah University, Majmaah 11952, Saudi Arabia
| | - Fayez Alghofaili
- Department of Medical Laboratory Sciences, College of Applied Medical Sciences, Majmaah University, Majmaah 11952, Saudi Arabia
| | - Ahmad K Alnemare
- Otolaryngology Department, College of Medicine, Majmaah University, Majmaah 11952, Saudi Arabia
| | - Brian F Flanagan
- Department of Women's and Children's Health, Institute of Translational Medicine, University of Liverpool, Alder Hey Children's NHS Foundation Trust Hospital, Eaton Road, Liverpool L12 2AP, UK
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32
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Khatri SB, Iaccarino JM, Barochia A, Soghier I, Akuthota P, Brady A, Covar RA, Debley JS, Diamant Z, Fitzpatrick AM, Kaminsky DA, Kenyon NJ, Khurana S, Lipworth BJ, McCarthy K, Peters M, Que LG, Ross KR, Schneider-Futschik EK, Sorkness CA, Hallstrand TS. Use of Fractional Exhaled Nitric Oxide to Guide the Treatment of Asthma: An Official American Thoracic Society Clinical Practice Guideline. Am J Respir Crit Care Med 2021; 204:e97-e109. [PMID: 34779751 PMCID: PMC8759314 DOI: 10.1164/rccm.202109-2093st] [Citation(s) in RCA: 61] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022] Open
Abstract
Background: The fractional exhaled nitric oxide (FENO) test is a point-of-care test that is used in the assessment of asthma. Objective: To provide evidence-based clinical guidance on whether FENO testing is indicated to optimize asthma treatment in patients with asthma in whom treatment is being considered. Methods: An international, multidisciplinary panel of experts was convened to form a consensus document regarding a single question relevant to the use of FENO. The question was selected from three potential questions based on the greatest perceived impact on clinical practice and the unmet need for evidence-based answers related to this question. The panel performed systematic reviews of published randomized controlled trials between 2004 and 2019 and followed the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) evidence-to-decision framework to develop recommendations. All panel members evaluated and approved the recommendations. Main Results: After considering the overall low quality of the evidence, the panel made a conditional recommendation for FENO-based care. In patients with asthma in whom treatment is being considered, we suggest that FENO is beneficial and should be used in addition to usual care. This judgment is based on a balance of effects that probably favors the intervention; the moderate costs and availability of resources, which probably favors the intervention; and the perceived acceptability and feasibility of the intervention in daily practice. Conclusions: Clinicians should consider this recommendation to measure FENO in patients with asthma in whom treatment is being considered based on current best available evidence.
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Brochetti RA, Klein S, Alonso PT, Schapochnik A, Damazo AS, Hamblin MR, de Souza Setubal Destro MF, Lino-Dos-Santos-Franco A. Beneficial effects of infrared light-emitting diode in corticosteroid-resistant asthma. Lasers Med Sci 2021; 37:1963-1971. [PMID: 34743255 DOI: 10.1007/s10103-021-03457-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2021] [Accepted: 10/26/2021] [Indexed: 10/19/2022]
Abstract
Corticosteroid-resistant asthma (CRA) is a severe form of disease and clinically important, since patients do not respond to mainstay corticosteroid therapies. Thus, new therapies are needed. However, a big limiting factor in the understanding of CRA is the existence of different immunological and inflammatory phenotypes, a fact that makes it difficult to reproduce experimentally. Photobiomodulation (PBM) emerges as an alternative therapy based on earlier studies. This study aims to evaluate the effect of PBM using infrared light-emitting diode (ILED) on the development of corticosteroid-resistant asthma. Therefore, groups of rats were sensitized and challenged with ovalbumin plus Freund's adjuvant for the induction of CRA, and treated or not with ILED directly in the respiratory tract on the skin (wavelength 810 nm; power 100 mW; density energy 5 J/cm; total energy 15 J; time 150 s). Our experimental model was capable to induce neutrophilic asthma. Besides that, the corticosteroid treatment did not reverse the lung cell migration as well as the levels of leukotriene B4, and interleukins 17 and 6. The treatment with ILED reduced the lung cell migration; myeloperoxidase activity; mast cell degranulation; and the levels of leukotriene B4, thromboxane B2, prostaglandin E2, tumoral necrosis factor alpha, and interleukins 17 and 6. Still, ILED increased the level of interleukin 10. In conclusion, we showed promisor effects of ILED when irradiated directly in the respiratory tract as adjuvant treatment of corticosteroid-resistant asthma.
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Affiliation(s)
- Robson Alexandre Brochetti
- Post Graduate Program in Biophotonics Applied to Health Sciences, University Nove de Julho (UNINOVE), Rua Vergueiro, 239/245, São Paulo, SP, CEP 01504-000, Brazil
| | - Simone Klein
- Post Graduate Program in Biophotonics Applied to Health Sciences, University Nove de Julho (UNINOVE), Rua Vergueiro, 239/245, São Paulo, SP, CEP 01504-000, Brazil
| | - Paula Tatiane Alonso
- Post Graduate Program in Biophotonics Applied to Health Sciences, University Nove de Julho (UNINOVE), Rua Vergueiro, 239/245, São Paulo, SP, CEP 01504-000, Brazil
| | - Adriana Schapochnik
- Post Graduate Program in Biophotonics Applied to Health Sciences, University Nove de Julho (UNINOVE), Rua Vergueiro, 239/245, São Paulo, SP, CEP 01504-000, Brazil
| | - Amílcar Sabino Damazo
- Department of Basic Science in Health, Faculty of Medical Sciences, Federal University of Cuiabá, Cuiabá, Brazil
| | - Michael R Hamblin
- Laser Research Centre, Faculty of Health Science, University of Johannesburg, Doornfontein, 2028, South Africa
| | - Maria Fernanda de Souza Setubal Destro
- Post Graduate Program in Biophotonics Applied to Health Sciences, University Nove de Julho (UNINOVE), Rua Vergueiro, 239/245, São Paulo, SP, CEP 01504-000, Brazil
| | - Adriana Lino-Dos-Santos-Franco
- Post Graduate Program in Biophotonics Applied to Health Sciences, University Nove de Julho (UNINOVE), Rua Vergueiro, 239/245, São Paulo, SP, CEP 01504-000, Brazil.
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34
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Kim Y, Hou V, Huff RD, Aguiar JA, Revill S, Tiessen N, Cao Q, Miller MS, Inman MD, Ask K, Doxey AC, Hirota JA. Potentiation of long-acting β 2-agonist and glucocorticoid responses in human airway epithelial cells by modulation of intracellular cAMP. Respir Res 2021; 22:266. [PMID: 34666750 PMCID: PMC8527633 DOI: 10.1186/s12931-021-01862-1] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2021] [Accepted: 10/09/2021] [Indexed: 11/10/2022] Open
Abstract
Introduction Over 300 million people in the world live with asthma, resulting in 500,000 annual global deaths with future increases expected. It is estimated that around 50–80% of asthma exacerbations are due to viral infections. Currently, a combination of long-acting beta agonists (LABA) for bronchodilation and glucocorticoids (GCS) to control lung inflammation represent the dominant strategy for the management of asthma, however, it is still sub-optimal in 35–50% of moderate-severe asthmatics resulting in persistent lung inflammation, impairment of lung function, and risk of mortality. Mechanistically, LABA/GCS combination therapy results in synergistic efficacy mediated by intracellular cyclic adenosine monophosphate (cAMP). Hypothesis Increasing intracellular cAMP during LABA/GCS combination therapy via inhibiting phosphodiesterase 4 (PDE4) and/or blocking the export of cAMP by ATP Binding Cassette Transporter C4 (ABCC4), will potentiate anti-inflammatory responses of mainstay LABA/GCS therapy. Methods Expression and localization experiments were performed using in situ hybridization and immunohistochemistry in human lung tissue from healthy subjects, while confirmatory transcript and protein expression analyses were performed in primary human airway epithelial cells and cell lines. Intervention experiments were performed on the human airway epithelial cell line, HBEC-6KT, by pre-treatment with combinations of LABA/GCS with PDE4 and/or ABCC4 inhibitors followed by Poly I:C or imiquimod challenge as a model for viral stimuli. Cytokine readouts for IL-6, IL-8, CXCL10/IP-10, and CCL5/RANTES were quantified by ELISA. Results Using archived human lung and human airway epithelial cells, ABCC4 gene and protein expression were confirmed in vitro and in situ. LABA/GCS attenuation of Poly I:C or imiquimod-induced IL-6 and IL-8 were potentiated with ABCC4 and PDE4 inhibition, which was greater when ABCC4 and PDE4 inhibition was combined. Modulation of cAMP levels had no impact on LABA/GCS modulation of Poly I:C-induced CXCL10/IP-10 or CCL5/RANTES. Conclusion Modulation of intracellular cAMP levels by PDE4 or ABCC4 inhibition potentiates LABA/GCS efficacy in human airway epithelial cells challenged with viral stimuli. The data suggest further exploration of the value of adding cAMP modulators to mainstay LABA/GCS therapy in asthma for potentiated anti-inflammatory efficacy.
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Affiliation(s)
- Yechan Kim
- Firestone Institute for Respiratory Health-Division of Respirology, Department of Medicine, McMaster University, Hamilton, ON, L8N 4A6, Canada
| | - Vincent Hou
- Firestone Institute for Respiratory Health-Division of Respirology, Department of Medicine, McMaster University, Hamilton, ON, L8N 4A6, Canada
| | - Ryan D Huff
- Division of Respiratory Medicine, Department of Medicine, University of British Columbia, Vancouver, BC, V6H 3Z, Canada
| | - Jennifer A Aguiar
- Department of Biology, University of Waterloo, Waterloo, ON, N2L 3G1, Canada
| | - Spencer Revill
- Firestone Institute for Respiratory Health-Division of Respirology, Department of Medicine, McMaster University, Hamilton, ON, L8N 4A6, Canada
| | - Nicholas Tiessen
- Firestone Institute for Respiratory Health-Division of Respirology, Department of Medicine, McMaster University, Hamilton, ON, L8N 4A6, Canada
| | - Quynh Cao
- Firestone Institute for Respiratory Health-Division of Respirology, Department of Medicine, McMaster University, Hamilton, ON, L8N 4A6, Canada
| | - Matthew S Miller
- Department of Biochemistry, McMaster University, Hamilton, ON, L8S 4K1, Canada.,McMaster Immunology Research Centre, McMaster University, Hamilton, ON, L8S 4K1, Canada.,Michael G. DeGroote Institute for Infectious Disease Research, McMaster University, Hamilton, ON, L8S 4K1, Canada
| | - Mark D Inman
- Firestone Institute for Respiratory Health-Division of Respirology, Department of Medicine, McMaster University, Hamilton, ON, L8N 4A6, Canada
| | - Kjetil Ask
- Firestone Institute for Respiratory Health-Division of Respirology, Department of Medicine, McMaster University, Hamilton, ON, L8N 4A6, Canada.,McMaster Immunology Research Centre, McMaster University, Hamilton, ON, L8S 4K1, Canada
| | - Andrew C Doxey
- Firestone Institute for Respiratory Health-Division of Respirology, Department of Medicine, McMaster University, Hamilton, ON, L8N 4A6, Canada.,Department of Biology, University of Waterloo, Waterloo, ON, N2L 3G1, Canada
| | - Jeremy A Hirota
- Firestone Institute for Respiratory Health-Division of Respirology, Department of Medicine, McMaster University, Hamilton, ON, L8N 4A6, Canada. .,Division of Respiratory Medicine, Department of Medicine, University of British Columbia, Vancouver, BC, V6H 3Z, Canada. .,Department of Biology, University of Waterloo, Waterloo, ON, N2L 3G1, Canada. .,McMaster Immunology Research Centre, McMaster University, Hamilton, ON, L8S 4K1, Canada.
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35
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Using FeNO Measurement in Clinical Asthma Management. Chest 2021; 161:906-917. [PMID: 34673021 DOI: 10.1016/j.chest.2021.10.015] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2021] [Revised: 09/30/2021] [Accepted: 10/10/2021] [Indexed: 11/24/2022] Open
Abstract
Asthma is a common and heterogeneous disease, characterised by lower airway inflammation and airflow limitation. Critical factors in asthma management include establishing an accurate diagnosis and ensuring appropriate selection and dosage of anti-inflammatory therapies. The majority of asthma patients exhibit type 2 (T2) inflammation, with increased interleukin (IL)-4, IL-5, and IL-13 signalling, often with associated eosinophilia. Identifying lower airway eosinophilia with sputum induction improves asthma outcomes, but is time consuming and costly. Increased T2-inflammation leads to upregulation of nitric oxide (NO) release into the airway, with increasing fractional exhaled NO (FeNO) reflecting greater T2-inflammation. FeNO can be easily and quickly measured in the clinic, offering a point of care surrogate measure of the degree of lower airway inflammation. FeNO testing can be used to help confirm an asthma diagnosis, to guide inhaled corticosteroid therapy, to assess adherence to treatment, and to aid selection of appropriate biologic therapy. However, FeNO levels may also be influenced by a variety of intrinsic and extrinsic factors other than asthma, including nasal polyposis and cigarette smoking, and must be interpreted in the broader clinical context rather than viewed in isolation. This review discusses the clinical application of FeNO measurement in asthma care, from diagnosis to treatment selection, and describes its place in current international expert guidelines.
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36
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Hernandez-Pacheco N, Gorenjak M, Li J, Repnik K, Vijverberg SJ, Berce V, Jorgensen A, Karimi L, Schieck M, Samedy-Bates LA, Tavendale R, Villar J, Mukhopadhyay S, Pirmohamed M, Verhamme KMC, Kabesch M, Hawcutt DB, Turner S, Palmer CN, Tantisira KG, Burchard EG, Maitland-van der Zee AH, Flores C, Potočnik U, Pino-Yanes M. Identification of ROBO2 as a Potential Locus Associated with Inhaled Corticosteroid Response in Childhood Asthma. J Pers Med 2021; 11:jpm11080733. [PMID: 34442380 PMCID: PMC8399629 DOI: 10.3390/jpm11080733] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2021] [Accepted: 07/26/2021] [Indexed: 12/15/2022] Open
Abstract
Inhaled corticosteroids (ICS) are the most common asthma controller medication. An important contribution of genetic factors in ICS response has been evidenced. Here, we aimed to identify novel genetic markers involved in ICS response in asthma. A genome-wide association study (GWAS) of the change in lung function after 6 weeks of ICS treatment was performed in 166 asthma patients from the SLOVENIA study. Patients with an improvement in lung function ≥8% were considered as ICS responders. Suggestively associated variants (p-value ≤ 5 × 10−6) were evaluated in an independent study (n = 175). Validation of the association with asthma exacerbations despite ICS use was attempted in European (n = 2681) and admixed (n = 1347) populations. Variants previously associated with ICS response were also assessed for replication. As a result, the SNP rs1166980 from the ROBO2 gene was suggestively associated with the change in lung function (OR for G allele: 7.01, 95% CI: 3.29–14.93, p = 4.61 × 10−7), although this was not validated in CAMP. ROBO2 showed gene-level evidence of replication with asthma exacerbations despite ICS use in Europeans (minimum p-value = 1.44 × 10−5), but not in admixed individuals. The association of PDE10A-T with ICS response described by a previous study was validated. This study suggests that ROBO2 could be a potential novel locus for ICS response in Europeans.
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Affiliation(s)
- Natalia Hernandez-Pacheco
- Research Unit, Hospital Universitario N.S. de Candelaria, Universidad de La Laguna, Carretera General del Rosario 145, 38010 Santa Cruz de Tenerife, Spain;
- Genomics and Health Group, Department of Biochemistry, Microbiology, Cell Biology and Genetics, Universidad de La Laguna, Avenida Astrofísico Francisco Sánchez s/n, Faculty of Science, Apartado 456, 38200 San Cristóbal de La Laguna, Spain;
- CIBER de Enfermedades Respiratorias, Instituto de Salud Carlos III, Avenida de Monforte de Lemos, 5, 28029 Madrid, Spain;
- Correspondence: (N.H.-P.); (U.P.); Tel.: +46-0702983315 (N.H.-P.); +386-22345854 (U.P.)
| | - Mario Gorenjak
- Center for Human Molecular Genetics and Pharmacogenomics, Faculty of Medicine, University of Maribor, Taborska Ulica 8, 2000 Maribor, Slovenia; (M.G.); (K.R.); (V.B.)
| | - Jiang Li
- The Channing Division of Network Medicine, Department of Medicine, Brigham & Women’s Hospital and Harvard Medical School, 75 Francis St, Boston, MA 02115, USA; (J.L.); (K.G.T.)
| | - Katja Repnik
- Center for Human Molecular Genetics and Pharmacogenomics, Faculty of Medicine, University of Maribor, Taborska Ulica 8, 2000 Maribor, Slovenia; (M.G.); (K.R.); (V.B.)
- Laboratory for Biochemistry, Molecular Biology, and Genomics, Faculty of Chemistry and Chemical Engineering, University of Maribor, Smetanova ulica 17, 2000 Maribor, Slovenia
| | - Susanne J. Vijverberg
- Department of Respiratory Medicine, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands; (S.J.V.); (A.H.M.-v.d.Z.)
- Division of Pharmacoepidemiology and Clinical Pharmacology, Faculty of Science, Utrecht University, Princetonplein 5, 3584 CC Utrecht, The Netherlands
- Department of Pediatric Respiratory Medicine and Allergy, Emma’s Children Hospital, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands
| | - Vojko Berce
- Center for Human Molecular Genetics and Pharmacogenomics, Faculty of Medicine, University of Maribor, Taborska Ulica 8, 2000 Maribor, Slovenia; (M.G.); (K.R.); (V.B.)
- Department of Pediatrics, University Medical Centre Maribor, Ljubljanska Ulica 5, 2000 Maribor, Slovenia
| | - Andrea Jorgensen
- Department of Biostatistics, University of Liverpool, Crown Street, Liverpool L69 3BX, UK;
| | - Leila Karimi
- Department of Medical Informatics, Erasmus University Medical Center, Dr. Molewaterplein 40, 3015 GD Rotterdam, The Netherlands; (L.K.); (K.M.C.V.)
| | - Maximilian Schieck
- Department of Pediatric Pneumology and Allergy, University Children’s Hospital Regensburg (KUNO), Franz-Josef-Strauß-Allee 11, 93053 Regensburg, Germany; (M.S.); (M.K.)
- Department of Human Genetics, Hannover Medical School, Carl-Neuberg-Straße 1, 30625 Hannover, Germany
| | - Lesly-Anne Samedy-Bates
- Department of Medicine, University of California, San Francisco, CA 94143, USA; (L.-A.S.-B.); (E.G.B.)
- Department of Bioengineering and Therapeutic Sciences, University of California, 533 Parnassus Ave, San Francisco, CA 94143, USA
| | - Roger Tavendale
- Population Pharmacogenetics Group, Biomedical Research Institute, Ninewells Hospital, and Medical School, University of Dundee, Dundee DD1 9SY, UK; (R.T.); (S.M.); (C.N.P.)
| | - Jesús Villar
- CIBER de Enfermedades Respiratorias, Instituto de Salud Carlos III, Avenida de Monforte de Lemos, 5, 28029 Madrid, Spain;
- Multidisciplinary Organ Dysfunction Evaluation Research Network, Research Unit, Hospital Universitario Dr. Negrín, Calle Barranco de la Ballena s/n, 35019 Las Palmas de Gran Canaria, Spain
- Keenan Research Center for Biomedical Science, Li Ka Shing Knowledge Institute, St Michael’s Hospital, 30 Bond St, Toronto, ON M5B 1W8, Canada
| | - Somnath Mukhopadhyay
- Population Pharmacogenetics Group, Biomedical Research Institute, Ninewells Hospital, and Medical School, University of Dundee, Dundee DD1 9SY, UK; (R.T.); (S.M.); (C.N.P.)
- Academic Department of Paediatrics, Brighton and Sussex Medical School, Royal Alexandra Children’s Hospital, 94 N-S Rd, Falmer, Brighton BN2 5BE, UK
| | - Munir Pirmohamed
- Department of Molecular and Clinical Pharmacology, Institute of Translational Medicine, University of Liverpool, 200 London Rd, Liverpool L3 9TA, UK;
| | - Katia M. C. Verhamme
- Department of Medical Informatics, Erasmus University Medical Center, Dr. Molewaterplein 40, 3015 GD Rotterdam, The Netherlands; (L.K.); (K.M.C.V.)
| | - Michael Kabesch
- Department of Pediatric Pneumology and Allergy, University Children’s Hospital Regensburg (KUNO), Franz-Josef-Strauß-Allee 11, 93053 Regensburg, Germany; (M.S.); (M.K.)
| | - Daniel B. Hawcutt
- Department of Women’s and Children’s Health, University of Liverpool, Liverpool L69 3BX, UK;
- Alder Hey Children’s Hospital, E Prescot Rd, Liverpool L14 5AB, UK
| | - Steve Turner
- Child Health, University of Aberdeen, King’s College, Aberdeen AB24 3FX, UK;
| | - Colin N. Palmer
- Population Pharmacogenetics Group, Biomedical Research Institute, Ninewells Hospital, and Medical School, University of Dundee, Dundee DD1 9SY, UK; (R.T.); (S.M.); (C.N.P.)
| | - Kelan G. Tantisira
- The Channing Division of Network Medicine, Department of Medicine, Brigham & Women’s Hospital and Harvard Medical School, 75 Francis St, Boston, MA 02115, USA; (J.L.); (K.G.T.)
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women’s Hospital, and Harvard Medical School, 75 Francis St, Boston, MA 02115, USA
| | - Esteban G. Burchard
- Department of Medicine, University of California, San Francisco, CA 94143, USA; (L.-A.S.-B.); (E.G.B.)
- Department of Bioengineering and Therapeutic Sciences, University of California, 533 Parnassus Ave, San Francisco, CA 94143, USA
| | - Anke H. Maitland-van der Zee
- Department of Respiratory Medicine, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands; (S.J.V.); (A.H.M.-v.d.Z.)
- Division of Pharmacoepidemiology and Clinical Pharmacology, Faculty of Science, Utrecht University, Princetonplein 5, 3584 CC Utrecht, The Netherlands
- Department of Pediatric Respiratory Medicine and Allergy, Emma’s Children Hospital, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands
| | - Carlos Flores
- Research Unit, Hospital Universitario N.S. de Candelaria, Universidad de La Laguna, Carretera General del Rosario 145, 38010 Santa Cruz de Tenerife, Spain;
- CIBER de Enfermedades Respiratorias, Instituto de Salud Carlos III, Avenida de Monforte de Lemos, 5, 28029 Madrid, Spain;
- Genomics Division, Instituto Tecnológico y de Energías Renovables (ITER), Polígono Industrial de Granadilla, 38600 Granadilla, Spain
- Instituto de Tecnologías Biomédicas (ITB), Universidad de La Laguna, Faculty of Health Sciences, Apartado 456, 38200 San Cristóbal de La Laguna, Spain
| | - Uroš Potočnik
- Center for Human Molecular Genetics and Pharmacogenomics, Faculty of Medicine, University of Maribor, Taborska Ulica 8, 2000 Maribor, Slovenia; (M.G.); (K.R.); (V.B.)
- Laboratory for Biochemistry, Molecular Biology, and Genomics, Faculty of Chemistry and Chemical Engineering, University of Maribor, Smetanova ulica 17, 2000 Maribor, Slovenia
- Correspondence: (N.H.-P.); (U.P.); Tel.: +46-0702983315 (N.H.-P.); +386-22345854 (U.P.)
| | - Maria Pino-Yanes
- Genomics and Health Group, Department of Biochemistry, Microbiology, Cell Biology and Genetics, Universidad de La Laguna, Avenida Astrofísico Francisco Sánchez s/n, Faculty of Science, Apartado 456, 38200 San Cristóbal de La Laguna, Spain;
- CIBER de Enfermedades Respiratorias, Instituto de Salud Carlos III, Avenida de Monforte de Lemos, 5, 28029 Madrid, Spain;
- Instituto de Tecnologías Biomédicas (ITB), Universidad de La Laguna, Faculty of Health Sciences, Apartado 456, 38200 San Cristóbal de La Laguna, Spain
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Blais CM, Davis BE, Nair P, Cockcroft DW. Direct and indirect bronchoprovocation tests in dose-response studies of inhaled corticosteroids: Past, present, and future directions. Allergy 2021; 76:1679-1692. [PMID: 33185888 DOI: 10.1111/all.14658] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2020] [Revised: 10/06/2020] [Accepted: 11/03/2020] [Indexed: 11/30/2022]
Abstract
Inhaled corticosteroids (ICS) are a mainstay of treatment in eosinophilic asthma. Many studies have explored the dose-response effect of different formulations of ICS through direct or indirect bronchoprovocation testing. Such studies are important for investigating efficacy and identifying the relative potency between formulations. However, lack of consistency in methods and designs has hindered the comparability of study findings. This review discusses current knowledge of the dose-response, or lack thereof, of different formulations of ICS through direct and indirect bronchoprovocation testing. The strengths and weaknesses of past studies inform recommendations for future methodological considerations in this field, such as utilizing a randomized double-blind crossover design, enrolling participants likely to respond to ICS therapy, and carefully selecting treatment durations and washout periods to assess incremental improvement in airway hyperresponsiveness while reducing the likelihood of a carryover effect.
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Affiliation(s)
- Christianne M. Blais
- Division of Respirology Critical Care and Sleep Medicine Department of Medicine University of Saskatchewan Saskatoon SK Canada
| | - Beth E. Davis
- Division of Respirology Critical Care and Sleep Medicine Department of Medicine University of Saskatchewan Saskatoon SK Canada
| | - Parameswaran Nair
- Firestone Institute for Respiratory Health St. Joseph's Healthcare & Department of Medicine McMaster University Hamilton ON Canada
| | - Donald W. Cockcroft
- Division of Respirology Critical Care and Sleep Medicine Department of Medicine University of Saskatchewan Saskatoon SK Canada
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Diamant N, Amirav I, Armoni-Domany K, Sadot E, Shapira U, Cahal M, Be'er M, Rochman M, Lavie M. High fractional exhaled nitric oxide levels in asthma patients: Does size matter? Pediatr Pulmonol 2021; 56:1449-1454. [PMID: 33730452 DOI: 10.1002/ppul.25333] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/12/2020] [Revised: 02/13/2021] [Accepted: 02/15/2021] [Indexed: 11/07/2022]
Abstract
BACKGROUND Fractional exhaled nitric oxide (FeNO) is a biomarker for eosinophilic inflammation used for diagnosis and monitoring of asthma. High FeNO indicates significant airway eosinophilia and steroid-responsive airway inflammation. Some children with asthma have extremely high FeNO levels, but whether these levels represent a different asthma phenotype compared with those with mildly elevated FeNO is unclear. The objective of this study is to investigate whether the extent of high FeNO levels correlates with clinical phenotype, asthma control, comorbidity, and pulmonary function test (PFT) findings in children with asthma. METHODS Anthropometric data, daytime and nighttime symptoms, controller treatment, comorbidity, and PFT findings were retrieved from the Pediatric Pulmonology Unit database (2014-2020) and correlated with FeNO levels in pediatric asthma patients with high FeNO levels. RESULTS Two-hundred children and adolescents with high FeNO levels (range 36-227 ppb) were included. Within this range, higher FeNO levels positively correlated with increased daytime and nighttime symptoms (p = .013 and p = .01, respectively) and poorly controlled asthma (p = .034). A FeNO level of ≥80 ppb was the cutoff for significantly more severe daytime and nighttime symptoms and very poorly controlled asthma compared with levels <80 ppb (p = .004, p = .005, and p = .036, respectively). No correlation was found between FeNO and controller treatment, comorbidity, and PFT performance. CONCLUSION In pediatric asthma patients, high FeNO levels correlate with increased symptom severity and poor asthma control. A FeNO level of ≥80 ppb may serve as an objective indicator for severe asthma.
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Affiliation(s)
- Nir Diamant
- Pediatric Pulmonology Unit, Dana-Dwek Children's Hospital, Tel-Aviv Sourasky Medical Center, Tel Aviv, Israel, affiliated to The Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Israel Amirav
- Pediatric Pulmonology Unit, Dana-Dwek Children's Hospital, Tel-Aviv Sourasky Medical Center, Tel Aviv, Israel, affiliated to The Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Keren Armoni-Domany
- Pediatric Pulmonology Unit, Dana-Dwek Children's Hospital, Tel-Aviv Sourasky Medical Center, Tel Aviv, Israel, affiliated to The Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Efraim Sadot
- Pediatric Pulmonology Unit, Dana-Dwek Children's Hospital, Tel-Aviv Sourasky Medical Center, Tel Aviv, Israel, affiliated to The Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Udi Shapira
- Pediatric Pulmonology Unit, Dana-Dwek Children's Hospital, Tel-Aviv Sourasky Medical Center, Tel Aviv, Israel, affiliated to The Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Michal Cahal
- Pediatric Pulmonology Unit, Dana-Dwek Children's Hospital, Tel-Aviv Sourasky Medical Center, Tel Aviv, Israel, affiliated to The Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Moria Be'er
- Pediatric Pulmonology Unit, Dana-Dwek Children's Hospital, Tel-Aviv Sourasky Medical Center, Tel Aviv, Israel, affiliated to The Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Mika Rochman
- Pediatric Pulmonology Unit, Dana-Dwek Children's Hospital, Tel-Aviv Sourasky Medical Center, Tel Aviv, Israel, affiliated to The Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Moran Lavie
- Pediatric Pulmonology Unit, Dana-Dwek Children's Hospital, Tel-Aviv Sourasky Medical Center, Tel Aviv, Israel, affiliated to The Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
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Zhou J, Li W, Wen X, Zeng D, Lin J, Chen S, Zang N, Deng Y, Xie X, Ren L, Liu E. Establishing a patient registry study database of dust mite allergic asthma in children: design, methodology and preliminary exploration. ANNALS OF TRANSLATIONAL MEDICINE 2021; 9:993. [PMID: 34277793 PMCID: PMC8267296 DOI: 10.21037/atm-21-2566] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/27/2021] [Accepted: 06/15/2021] [Indexed: 11/17/2022]
Abstract
Background Asthma is a heterogeneous disease with different phenotypes, endotypes and responses to treatment. Dust mite allergic asthma (DMAA) is the most common type in children. Compared with randomized control trials, a patient registry study (PRS) can reflect the real physical condition and clinical diagnosis more comprehensively. Methods Children who visited the asthma clinic of the Children’s Hospital of Chongqing Medical University between August 2018 and August 2020, and met the inclusion criteria and also agreed to participate, were enrolled in the registry study. Clinical information, laboratory tests and peripheral blood samples were collected after informed consent was given by guardians. Results To date, 208 children have been enrolled in the patient registry database of DMAA. They are mainly male, with >50% having a history of allergic rhinitis, cesarean section, positive family history and passive smoking. Eosinophils and total immunoglobulin E levels were all significantly higher than normal. According to results for the childhood asthma control test (c-ACT) and ratio of forced expiratory volume in 1 s to predicted value after inhaled corticosteroid treatment, the uncontrolled group had higher hemoglobin (Hb) levels than the control group. The group exhibiting abnormal pulmonary function was older, and had longer disease duration, higher fractional exhaled nitric oxide and Hb than the group in which pulmonary function was restored. Conclusions We have preliminarily established a registered study database of children with DMAA. By cluster analysis and using blood samples, we can further study the different pathophysiological mechanisms in order to provide more individualized and targeted treatments for all children.
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Affiliation(s)
- Juan Zhou
- Department of Respiratory Medicine, Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing, China.,Chongqing Key Laboratory of Pediatrics, Chongqing, China.,Department of Pediatrics, Guizhou Provincial People's Hospital, Medical College of Guizhou University, Guiyang, China
| | - Weiguo Li
- Department of Respiratory Medicine, Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing, China.,Chongqing Key Laboratory of Pediatrics, Chongqing, China
| | - Xiang Wen
- Department of Respiratory Medicine, Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing, China.,Chongqing Key Laboratory of Pediatrics, Chongqing, China
| | - Dan Zeng
- Department of Respiratory Medicine, Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing, China.,Chongqing Key Laboratory of Pediatrics, Chongqing, China
| | - Jilei Lin
- Department of Respiratory Medicine, Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing, China.,Chongqing Key Laboratory of Pediatrics, Chongqing, China
| | - Shiyi Chen
- Chongqing Key Laboratory of Pediatrics, Chongqing, China.,Pediatric Research Institute Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing, China
| | - Na Zang
- Department of Respiratory Medicine, Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing, China.,Chongqing Key Laboratory of Pediatrics, Chongqing, China
| | - Yu Deng
- Department of Respiratory Medicine, Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing, China.,Chongqing Key Laboratory of Pediatrics, Chongqing, China
| | - Xiaohong Xie
- Department of Respiratory Medicine, Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing, China.,Chongqing Key Laboratory of Pediatrics, Chongqing, China
| | - Luo Ren
- Chongqing Key Laboratory of Pediatrics, Chongqing, China.,Pediatric Research Institute Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing, China
| | - Enmei Liu
- Department of Respiratory Medicine, Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing, China.,Chongqing Key Laboratory of Pediatrics, Chongqing, China
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Sutherland L, Shaw K, Parrish C, Singleton N, McKeever TM, Stewart I, Shaw D, Martin MJ, Harrison T. A low exhaled nitric oxide level excludes a short-term benefit from inhaled corticosteroids in suspected asthma: A randomized placebo-controlled trial. Respirology 2021; 26:666-672. [PMID: 33939245 DOI: 10.1111/resp.14055] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2020] [Revised: 01/29/2021] [Accepted: 02/23/2021] [Indexed: 01/24/2023]
Abstract
BACKGROUND AND OBJECTIVE Fractional exhaled nitric oxide (FeNO) is a non-invasive biomarker that reflects IL-4/IL-13 production and therefore represents T2 allergic inflammation. FeNO has previously been used to guide inhaled corticosteroid (ICS) treatment in asthma. The purpose of this study was to determine if a low FeNO (≤27 ppb) could be used to reliably identify patients with symptoms suggestive of asthma who would not benefit from initiating treatment with an ICS. METHODS A total of 180 steroid-naïve adults with healthcare professional suspected asthma and an FeNO of ≤27 ppb were randomized to receive either 400 mcg of budesonide or placebo daily for 3 months. The primary outcome was the difference in the Asthma Control Questionnaire 7 (ACQ7) between treatment groups and the study was powered to determine equivalence. Secondary outcomes were the difference in FEV1 , Medical Research Council and Leicester Cough Questionnaire scores. RESULTS One hundred and thirty-four patients (68 budesonide and 66 placebo) completed the study and were included in the analysis. The between-group mean difference in ACQ7 from baseline to the end of the study was -0.25 and the 95% CI around this difference was -0.004 to 0.495 confirming equivalence (p < 0.05). Differences in forced expiratory volume over 1 s and other secondary outcomes were also small and clinically unimportant. CONCLUSION The results of this study suggest that steroid-naïve patients with symptoms suggestive of asthma and an FeNO ≤ 27 ppb are unlikely to benefit from initiating treatment with an ICS over 3 months. However, further research is recommended to confirm these findings before withholding ICS treatment.
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Affiliation(s)
- Lissa Sutherland
- School of Life Sciences, NIHR BRC University of Nottingham, University of Nottingham, Nottingham City Hospital, Nottingham, UK
| | - Karen Shaw
- School of Medicine, NIHR BRC University of Nottingham, University of Nottingham, Nottingham City Hospital, Nottingham, UK
| | - Clair Parrish
- School of Medicine, NIHR BRC University of Nottingham, University of Nottingham, Nottingham City Hospital, Nottingham, UK
| | - Nicola Singleton
- School of Medicine, NIHR BRC University of Nottingham, University of Nottingham, Nottingham City Hospital, Nottingham, UK
| | - Tricia M McKeever
- School of Medicine, NIHR BRC University of Nottingham, University of Nottingham, Nottingham City Hospital, Nottingham, UK
| | - Iain Stewart
- School of Medicine, NIHR BRC University of Nottingham, University of Nottingham, Nottingham City Hospital, Nottingham, UK
| | - Dominick Shaw
- School of Medicine, NIHR BRC University of Nottingham, University of Nottingham, Nottingham City Hospital, Nottingham, UK
| | - Matthew J Martin
- School of Medicine, NIHR BRC University of Nottingham, University of Nottingham, Nottingham City Hospital, Nottingham, UK
| | - Tim Harrison
- School of Medicine, NIHR BRC University of Nottingham, University of Nottingham, Nottingham City Hospital, Nottingham, UK
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Drug Repurposing to Treat Glucocorticoid Resistance in Asthma. J Pers Med 2021; 11:jpm11030175. [PMID: 33802355 PMCID: PMC7999884 DOI: 10.3390/jpm11030175] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2021] [Revised: 02/17/2021] [Accepted: 02/25/2021] [Indexed: 12/26/2022] Open
Abstract
Corticosteroid resistance causes significant morbidity in asthma, and drug repurposing may identify timely and cost-effective adjunctive treatments for corticosteroid resistance. In 95 subjects from the Childhood Asthma Management Program (CAMP) and 19 subjects from the Severe Asthma Research Program (SARP), corticosteroid response was measured by the change in percent predicted forced expiratory volume in one second (FEV1). In each cohort, differential gene expression analysis was performed comparing poor (resistant) responders, defined as those with zero to negative change in FEV1, to good responders, followed by Connectivity Map (CMap) analysis to identify inversely associated (i.e., negatively connected) drugs that reversed the gene expression profile of poor responders to resemble that of good responders. Mean connectivity scores weighted by sample size were calculated. The top five drug compound candidates underwent in vitro validation in NF-κB-based luciferase reporter A549 cells stimulated by IL-1β ± dexamethasone. In CAMP and SARP, 134 and 178 respective genes were differentially expressed in poor responders. CMap analysis identified 46 compounds in common across both cohorts with connectivity scores < −50. γ-linolenic acid, ampicillin, exemestane, brinzolamide, and INCA-6 were selected for functional validation. γ-linolenic acid, brinzolamide, and INCA-6 significantly reduced IL-1β induced luciferase activity and potentiated the anti-inflammatory effect of dexamethasone in A549/NF-κB-luc reporter cells. These results demonstrate how existing drugs, including γ-linolenic acid, brinzolamide, and INCA-6, may be repurposed to improve corticosteroid response in asthmatics.
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Abstract
Eosinophils are a type of granulocyte with eosinophilic granules in the cytoplasm that play an important role in allergic and parasitic diseases. Eosinophils are important in the pathogenesis of asthma, and many studies have examined the relationship between them. In allergic eosinophilic asthma, eosinophils act not only as important effector cells but also as antigen-presenting cells in allergic inflammatory reactions. In nonallergic eosinophilic asthma, type 2 innate lymphoid cells in the airways play an important role in eosinophil activation. Direct methods, including bronchial biopsy, bronchoalveolar lavage, and the induced sputum test, are used to evaluate eosinophilic inflammatory reactions in patients with asthma, however, because of difficulty with their implementation, they are sometimes replaced by measurements of blood eosinophils, fraction of exhaled nitric oxide, and serum periostin level. However, these tests are less accurate than direct methods. For the treatment of patients with severe eosinophilic asthma, anti-interleukin-5 preparations such as mepolizumab, reslizumab, and benralizumab have recently been introduced and broadened the scope of asthma treatment. Although eosinophils are already known to play an important role in asthma, we expect that further studies will reveal more details of their action.
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Affiliation(s)
- Bong Seok Choi
- Department of Pediatrics, School of Medicine, Kyungpook National University, Daegu, Korea
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Abstract
PURPOSE OF REVIEW Asthma is a common disease worldwide, however, its pathogenesis has not been fully elucidated. Emerging evidence suggests that epigenetic modifications may play a role in the development and natural history of asthma. The aim of this review is to highlight recent progress in research on epigenetic mechanisms in asthma. RECENT FINDINGS Over the past years, epigenetic studies, in particular DNA methylation studies, have added to the growing body of evidence supporting a link between epigenetic regulation of gene expression and asthma. Recent studies demonstrate that epigenetic mechanisms also play a role in asthma remission. Although most existing studies in this field have been conducted on blood cells, recent evidence suggests that epigenetic signatures are also crucial for the regulation of airway epithelial cells. Studies conducted on nasal epithelium revealed highly replicable epigenetic patterns that could be used for diagnostic purposes. SUMMARY Further research is needed to explore the diagnostic and therapeutic potential of epigenetic modifications in asthma. Multiomics studies on asthma will become increasingly important for a better understanding of etiology, heterogeneity, and severity of asthma, as well as establishing molecular biomarkers that could be combined with clinical information to improve the management of asthma patients.
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Edris A, de Roos EW, McGeachie MJ, Verhamme KMC, Brusselle GG, Tantisira KG, Iribarren C, Lu M, Wu AC, Stricker BH, Lahousse L. Pharmacogenetics of inhaled corticosteroids and exacerbation risk in adults with asthma. Clin Exp Allergy 2021; 52:33-45. [PMID: 33428814 DOI: 10.1111/cea.13829] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2020] [Revised: 12/21/2020] [Accepted: 01/05/2021] [Indexed: 12/12/2022]
Abstract
BACKGROUND Inhaled corticosteroids (ICS) are a cornerstone of asthma treatment. However, their efficacy is characterized by wide variability in individual responses. OBJECTIVE We investigated the association between genetic variants and risk of exacerbations in adults with asthma and how this association is affected by ICS treatment. METHODS We investigated the pharmacogenetic effect of 10 single nucleotide polymorphisms (SNPs) selected from the literature, including SNPs previously associated with response to ICS (assessed by change in lung function or exacerbations) and novel asthma risk alleles involved in inflammatory pathways, within all adults with asthma from the Dutch population-based Rotterdam study with replication in the American GERA cohort. The interaction effects of the SNPs with ICS on the incidence of asthma exacerbations were assessed using hurdle models adjusting for age, sex, BMI, smoking and treatment step according to the GINA guidelines. Haplotype analyses were also conducted for the SNPs located on the same chromosome. RESULTS rs242941 (CRHR1) homozygotes for the minor allele (A) showed a significant, replicated increased risk for frequent exacerbations (RR = 6.11, P < 0.005). In contrast, rs1134481 T allele within TBXT (chromosome 6, member of a family associated with embryonic lung development) showed better response with ICS. rs37973 G allele (GLCCI1) showed a significantly poorer response on ICS within the discovery cohort, which was also significant but in the opposite direction in the replication cohort. CONCLUSION rs242941 in CRHR1 was associated with poor ICS response. Conversely, TBXT variants were associated with improved ICS response. These associations may reveal specific endotypes, potentially allowing prediction of exacerbation risk and ICS response.
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Affiliation(s)
- Ahmed Edris
- Department of Bioanalysis, Ghent University, Ghent, Belgium.,Department of Epidemiology, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - Emmely W de Roos
- Department of Respiratory Medicine, Ghent University Hospital, Ghent, Belgium.,Department of Epidemiology, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - Michael J McGeachie
- Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, MA, USA
| | - Katia M C Verhamme
- Department of Epidemiology, Erasmus University Medical Center, Rotterdam, The Netherlands.,Department of Medical Informatics, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - Guy G Brusselle
- Department of Respiratory Medicine, Ghent University Hospital, Ghent, Belgium.,Department of Epidemiology, Erasmus University Medical Center, Rotterdam, The Netherlands.,Department of Respiratory Medicine, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - Kelan G Tantisira
- Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, MA, USA.,University of California San Diego, CA, USA
| | - Carlos Iribarren
- Division of Research, Kaiser Permanente Northern California, Oakland, CA, USA
| | - Meng Lu
- Division of Research, Kaiser Permanente Northern California, Oakland, CA, USA
| | - Ann Chen Wu
- Department of Population Medicine, Precision Medicine Translational Research (PROMoTeR) Center, Harvard Pilgrim Health Care Institute and Harvard Medical School, Boston, MA, USA
| | - Bruno H Stricker
- Department of Epidemiology, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - Lies Lahousse
- Department of Bioanalysis, Ghent University, Ghent, Belgium.,Department of Epidemiology, Erasmus University Medical Center, Rotterdam, The Netherlands
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Mäki-Heikkilä R, Karjalainen J, Parkkari J, Valtonen M, Lehtimäki L. Asthma in Competitive Cross-Country Skiers: A Systematic Review and Meta-analysis. Sports Med 2020; 50:1963-1981. [PMID: 32915429 PMCID: PMC7575483 DOI: 10.1007/s40279-020-01334-4] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/30/2023]
Abstract
INTRODUCTION In cross-country skiing, the repetitive ventilation of large amounts of cold and dry air strains the airways. The aim of this systematic review was to establish an overview of the current literature on asthma in cross-country skiers, biathletes and ski-orienteers. METHODS Six databases were searched on August 29, 2019. The search yielded 2161 articles. Thirty articles fulfilled the search criteria and were pooled together for a qualitative synthesis. Eight articles were included in the meta-analysis on the prevalence of asthma and the use of asthma medication. RESULTS According to the meta-analysis, the prevalence of self-reported physician-diagnosed asthma in skiers was 21% (95% CI 14-28%). The onset age of asthma was higher in skiers than in non-skiers with asthma. The prevalence of asthma medication use was on average 23% (CI 95% 19-26%). Several studies reported that asthma was underdiagnosed in skiers, as previously healthy skiers without a prior asthma diagnosis or medication use were frequently found to fulfill diagnostic criteria for asthma according to lung function tests. Studies using bronchial biopsy demonstrated that eosinophilic asthma is not detected in skiers with asthma as often as it is in non-skiers with asthma and that there are signs of airway inflammation even in non-asthmatic skiers. CONCLUSION Our findings suggest that the accuracy and coverage of diagnosing asthma in skiers has improved over the recent decades. However, the optimal treatment and natural course of asthma in this population remain unclear. Future research should investigate how the intensity of training, airway infections and their treatment affect the development of asthma among skiers. PRD REGISTRATION NUMBER CRD42017070940.
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Affiliation(s)
| | - Jussi Karjalainen
- Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
- Allergy Centre, Tampere University Hospital, Tampere, Finland
| | - Jari Parkkari
- Tampere Research Center of Sports Medicine, UKK Institute, Tampere, Finland
| | - Maarit Valtonen
- KIHU, Research Institute for Olympic Sports, Jyväskylä, Finland
| | - Lauri Lehtimäki
- Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland.
- Allergy Centre, Tampere University Hospital, Tampere, Finland.
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Abstract
Bronchial asthma is characterized by chronic airway inflammation, which manifests clinically as variable airway narrowing (wheezes and dyspnea) and cough. Long-standing asthma may induce airway remodeling and become intractable. The prevalence of asthma has increased; however, the number of patients who die from it has decreased (1.3 per 100,000 patients in 2018). The goal of asthma treatment is to control symptoms and prevent future risks. A good partnership between physicians and patients is indispensable for effective treatment. Long-term management with therapeutic agents and the elimination of the triggers and risk factors of asthma are fundamental to its treatment. Asthma is managed by four steps of pharmacotherapy, ranging from mild to intensive treatments, depending on the severity of disease; each step includes an appropriate daily dose of an inhaled corticosteroid, which may vary from low to high. Long-acting β2-agonists, leukotriene receptor antagonists, sustained-release theophylline, and long-acting muscarinic antagonists are recommended as add-on drugs, while anti-immunoglobulin E antibodies and other biologics, and oral steroids are reserved for very severe and persistent asthma related to allergic reactions. Bronchial thermoplasty has recently been developed for severe, persistent asthma, but its long-term efficacy is not known. Inhaled β2-agonists, aminophylline, corticosteroids, adrenaline, oxygen therapy, and other approaches are used as needed during acute exacerbations, by selecting treatment steps for asthma based on the severity of the exacerbations. Allergic rhinitis, eosinophilic chronic rhinosinusitis, eosinophilic otitis, chronic obstructive pulmonary disease, aspirin-exacerbated respiratory disease, and pregnancy are also important conditions to be considered in asthma therapy.
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Chang YD, Li CH, Tsai CH, Cheng YW, Kang JJ, Lee CC. Aryl hydrocarbon receptor deficiency enhanced airway inflammation and remodeling in a murine chronic asthma model. FASEB J 2020; 34:15300-15313. [PMID: 32959404 DOI: 10.1096/fj.202001529r] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2020] [Revised: 08/25/2020] [Accepted: 09/08/2020] [Indexed: 01/05/2023]
Abstract
The aryl hydrocarbon receptor (AhR) is a ligand-dependent-activated transcriptional factor that regulates the metabolism of xenobiotic and endogenous compounds. Recent studies have shown that AhR is a novel master regulator of the mucosal immune system, including lungs and intestine. To elucidate the role of AhR in chronic severe asthma, AhR wild-type and knockout mice (AhR-/- ) were sensitized and challenged with ovalbumin for 4 weeks. To uncover the underlying mechanisms, inflammatory cells profile and cytokines production were analyzed in bronchial lavage fluid (BALF) and lung tissue. Compared to wild-type mice, AhR-/- mice had exacerbated asthma symptoms, including airway inflammation, mucus production, airway hyperresponsiveness, and airway remodeling. BALF monocytes, neutrophils, eosinophils, and lymphocytes were all enhanced in OVA-immunized AhR-/- mice. In OVA-immunized AhR-/- mice, T helper (Th) 17 cell-specific cytokine IL-17A, as well as airway remodeling factors, including epithelial-mesenchymal transition (EMT) markers and vascular endothelial growth factor (VEGF), were all enhanced in lung tissue. Moreover, human cohort studies showed that AhR gene expression in bronchial epithelial cells decreases in severe asthma patients. Loss of AhR leads to worsening of allergic asthma symptoms, indicating its importance in maintaining normal lung function and mediating disease severity.
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Affiliation(s)
- Yu-Di Chang
- Department of Microbiology and Immunology, School of Medicine, China Medicine University, Taichung, Taiwan
| | - Ching-Hao Li
- Department of Physiology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
| | - Chi-Hao Tsai
- School of Pharmaceutical Sciences, National Yang-Ming University, Taipei, Taiwan
| | - Yu-Wen Cheng
- School of Pharmacy, Taipei Medical University, Taipei, Taiwan
| | - Jaw-Jou Kang
- School of Pharmaceutical Sciences, National Yang-Ming University, Taipei, Taiwan
| | - Chen-Chen Lee
- Department of Microbiology and Immunology, School of Medicine, China Medicine University, Taichung, Taiwan
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Truong-Thanh T, Vo-Thi-Kim A, Vu-Minh T, Truong-Viet D, Tran-Van H, Duong-Quy S. The beneficial role of FeNO in association with GINA guidelines for titration of inhaled corticosteroids in adult asthma: A randomized study. Adv Med Sci 2020; 65:244-251. [PMID: 32276003 DOI: 10.1016/j.advms.2020.03.001] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2019] [Revised: 11/16/2019] [Accepted: 03/19/2020] [Indexed: 12/16/2022]
Abstract
PURPOSE This study aimed to demonstrate the role of fractional concentration of exhaled nitric oxide (FeNO) in association with Global Initiative for Asthma (GINA) guidelines for treatment of adult patients with asthma. METHODS It was a prospective and randomized study. The symptomatic asthmatic patients were randomly divided into two groups: GINA group (followed GINA guidelines; N = 86) or GINA + FeNO group (followed GINA guidelines + FeNO for titration of inhaled corticosteroids - ICS; N = 90). They were followed-up for 9 months. RESULTS In GINA group, 37.2% patients had no treatment and 62.8% patients discontinued treatment vs. 40.0% and 60.0% in GINA + FeNO, respectively. After 3, 6 and 9 months of treatment, the percentage of mild, moderate and severe asthma showed no significant difference between the two groups. At 9th month, Δ moderate asthma (reduction) in GINA + FeNO group was significantly higher than in the GINA group (-22.0% vs. -11.6%; P = 0.018). The improvement of asthma control test (ACT) score was not different between the groups at 9th month (12 ± 6 vs. 10 ± 5; P > 0.05); the level of FeNO reduction in GINA + FeNO group was significantly higher than that in GINA group (-42 ± 11 vs. -35 ± 9; P = 0.022). The daily dose of ICS in GINA + FeNO group was significantly lower than that in GINA group (397 ± 171 vs. 482 ± 240 mcg and 375 ± 203 vs. 424 ± 221 mcg; respectively) at the end of 6 and 9 months. CONCLUSION The use of FeNO in association with GINA guidelines has a beneficial role for accurate daily dose of ICS in adult patients with asthma.
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Wu Y, Chen H, Xuan N, Zhou L, Wu Y, Zhu C, Li M, Weng Q, Shen J, Zhang H, Zhang B, Lan F, Xia L, Xiong X, Li Z, Zhao Y, Wu M, Ying S, Li W, Shen H, Chen Z. Induction of ferroptosis-like cell death of eosinophils exerts synergistic effects with glucocorticoids in allergic airway inflammation. Thorax 2020; 75:918-927. [PMID: 32759385 DOI: 10.1136/thoraxjnl-2020-214764] [Citation(s) in RCA: 52] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2020] [Revised: 06/16/2020] [Accepted: 06/24/2020] [Indexed: 12/16/2022]
Abstract
INTRODUCTION Eosinophils are critical in allergic disorders, and promoting eosinophil death effectively attenuates allergic airway inflammation. Ferroptosis is a recently described novel form of cell death; however, little is known about ferroptosis in eosinophils and related diseases. This study aimed to investigate the effects of ferroptosis-inducing agents (FINs) on eosinophil death and allergic airway inflammation, and to explore their potential synergistic effect with glucocorticoids (GCs). METHODS Eosinophils isolated from the peripheral blood of humans or mice were incubated with FINs, and eosinophil ferroptosis was assessed. The in vivo effects of FINs alone or in combination with dexamethasone (DXMS) were examined in a mouse model of allergic airway inflammation. Bronchoalveolar lavage fluid and lung tissue were collected to examine airway inflammation. RESULTS Treatment with FINs time and dose dependency induced cell death in human and mouse eosinophils. Interestingly, FINs induced non-canonical ferroptosis in eosinophils, which generated morphological characteristics unique to ferroptosis and was iron dependent but was independent of lipid peroxidation. The antioxidants glutathione and N-acetylcysteine significantly attenuated FIN-induced cell death. Treatment with FINs triggered eosinophil death in vivo and eventually relieved eosinophilic airway inflammation in mice. Furthermore, FINs exerted a synergistic effect with DXMS to induce eosinophil death in vitro and to alleviate allergic airway inflammation in vivo. CONCLUSIONS FINs induced ferroptosis-like cell death of eosinophils, suggesting their use as a promising therapeutic strategy for eosinophilic airway inflammation, especially due to the advantage of their synergy with GCs in the treatment of allergic disorders.
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Affiliation(s)
- Yanping Wu
- Key Laboratory of Respiratory Disease of Zhejiang Province, Department of Respiratory and Critical Care Medicine, Zhejiang University School of Medicine Second Affiliated Hospital, Hangzhou, Zhejiang, China
| | - Haixia Chen
- Key Laboratory of Respiratory Disease of Zhejiang Province, Department of Respiratory and Critical Care Medicine, Zhejiang University School of Medicine Second Affiliated Hospital, Hangzhou, Zhejiang, China
| | - Nanxia Xuan
- Key Laboratory of Respiratory Disease of Zhejiang Province, Department of Respiratory and Critical Care Medicine, Zhejiang University School of Medicine Second Affiliated Hospital, Hangzhou, Zhejiang, China
| | - Lingren Zhou
- Key Laboratory of Respiratory Disease of Zhejiang Province, Department of Respiratory and Critical Care Medicine, Zhejiang University School of Medicine Second Affiliated Hospital, Hangzhou, Zhejiang, China
| | - Yinfang Wu
- Key Laboratory of Respiratory Disease of Zhejiang Province, Department of Respiratory and Critical Care Medicine, Zhejiang University School of Medicine Second Affiliated Hospital, Hangzhou, Zhejiang, China
| | - Chen Zhu
- Key Laboratory of Respiratory Disease of Zhejiang Province, Department of Respiratory and Critical Care Medicine, Zhejiang University School of Medicine Second Affiliated Hospital, Hangzhou, Zhejiang, China
| | - Miao Li
- Key Laboratory of Respiratory Disease of Zhejiang Province, Department of Respiratory and Critical Care Medicine, Zhejiang University School of Medicine Second Affiliated Hospital, Hangzhou, Zhejiang, China
| | - Qingyu Weng
- Key Laboratory of Respiratory Disease of Zhejiang Province, Department of Respiratory and Critical Care Medicine, Zhejiang University School of Medicine Second Affiliated Hospital, Hangzhou, Zhejiang, China
| | - Jiaxin Shen
- Key Laboratory of Respiratory Disease of Zhejiang Province, Department of Respiratory and Critical Care Medicine, Zhejiang University School of Medicine Second Affiliated Hospital, Hangzhou, Zhejiang, China
| | - Hao Zhang
- Key Laboratory of Respiratory Disease of Zhejiang Province, Department of Respiratory and Critical Care Medicine, Zhejiang University School of Medicine Second Affiliated Hospital, Hangzhou, Zhejiang, China
| | - Bin Zhang
- Key Laboratory of Respiratory Disease of Zhejiang Province, Department of Respiratory and Critical Care Medicine, Zhejiang University School of Medicine Second Affiliated Hospital, Hangzhou, Zhejiang, China
| | - Fen Lan
- Key Laboratory of Respiratory Disease of Zhejiang Province, Department of Respiratory and Critical Care Medicine, Zhejiang University School of Medicine Second Affiliated Hospital, Hangzhou, Zhejiang, China
| | - Lixia Xia
- Key Laboratory of Respiratory Disease of Zhejiang Province, Department of Respiratory and Critical Care Medicine, Zhejiang University School of Medicine Second Affiliated Hospital, Hangzhou, Zhejiang, China
| | - Xuefang Xiong
- Department of Respiratory Medicine, Central Hospital of Lishui City, Lishui, Zhejiang, China
| | - Zhouyang Li
- Key Laboratory of Respiratory Disease of Zhejiang Province, Department of Respiratory and Critical Care Medicine, Zhejiang University School of Medicine Second Affiliated Hospital, Hangzhou, Zhejiang, China
| | - Yun Zhao
- Key Laboratory of Respiratory Disease of Zhejiang Province, Department of Respiratory and Critical Care Medicine, Zhejiang University School of Medicine Second Affiliated Hospital, Hangzhou, Zhejiang, China
| | - Mindan Wu
- Key Laboratory of Respiratory Disease of Zhejiang Province, Department of Respiratory and Critical Care Medicine, Zhejiang University School of Medicine Second Affiliated Hospital, Hangzhou, Zhejiang, China
| | - Songmin Ying
- Key Laboratory of Respiratory Disease of Zhejiang Province, Department of Respiratory and Critical Care Medicine, Zhejiang University School of Medicine Second Affiliated Hospital, Hangzhou, Zhejiang, China
| | - Wen Li
- Key Laboratory of Respiratory Disease of Zhejiang Province, Department of Respiratory and Critical Care Medicine, Zhejiang University School of Medicine Second Affiliated Hospital, Hangzhou, Zhejiang, China
| | - Huahao Shen
- Key Laboratory of Respiratory Disease of Zhejiang Province, Department of Respiratory and Critical Care Medicine, Zhejiang University School of Medicine Second Affiliated Hospital, Hangzhou, Zhejiang, China .,State Key Lab for Respiratory Diseases, National Clinical Research Centre for Respiratory Disease, Guangzhou, Guangdong, China
| | - Zhihua Chen
- Key Laboratory of Respiratory Disease of Zhejiang Province, Department of Respiratory and Critical Care Medicine, Zhejiang University School of Medicine Second Affiliated Hospital, Hangzhou, Zhejiang, China
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Lazova S, Velikova T, Priftis S, Petrova G. Identification of Specific IgE Antibodies and Asthma Control Interaction and Association Using Cluster Analysis in a Bulgarian Asthmatic Children Cohort. Antibodies (Basel) 2020; 9:E31. [PMID: 32640522 PMCID: PMC7551616 DOI: 10.3390/antib9030031] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2020] [Revised: 06/22/2020] [Accepted: 07/01/2020] [Indexed: 02/05/2023] Open
Abstract
(1) Background: Asthma is a complex heterogeneous disease that likely comprises several distinct disease phenotypes, where the clustering approach has been used to classify the heterogeneous asthma population into distinct phenotypes; (2) Methods: For a period of 1 year, we evaluated medical history data of 71 children with asthma aged 3 to 17 years, performing pulmonary function tests, drew blood for IgE antibodies against inhalation and food allergies detection, and Asthma Control Questionnaire (ACQ); (3) Results: Five distinct phenotypes were determined. Cluster 1 (n = 10): (non-atopic) the lowest IgE level, very low ACQ, and median age of diagnosis. Cluster 2 (n = 28): (mixed) the highest Body mass index (BMI) with the latest age of diagnosis and high ACQ and bronchodilator response (BDR) levels and median and IgE levels. Cluster 3 (n = 19) (atopic) early diagnosis, highest BDR, highest ACQ score, highest total, and high specific IgE levels among the clusters. Cluster 4 (n = 9): (atopic) the highest specific IgE result, relatively high BMI, and IgE with median ACQ score among clusters. Cluster 5 (n = 5): (non-atopic) the earliest age for diagnosis, with the lowest BMI, the lowest ACQ score, and specific IgE levels, with high BDR and the median level of IgE among clusters; (4) Conclusions: We identified asthma phenotypes in Bulgarian children according to IgE levels, ACQ score, BDR, and age of diagnosis.
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Affiliation(s)
- Snezhina Lazova
- Pediatric Department, UMHATEM “N. I. Pirogov”, 21 Totleben blvd, 1606 Sofia, Bulgaria
| | - Tsvetelina Velikova
- Sofia University—Medical Faculty, University Hospital Lozenets, 1 Kozyak str, 1407 Sofia, Bulgaria;
| | - Stamatios Priftis
- Faculty of Public Health, Medical University of Sofia, Health Technology Assessment Department, 8 Bialo more str., 1527 Sofia, Bulgaria;
| | - Guergana Petrova
- Medical University, Pediatric clinic, UMHAT Alexandrovska, 1 Georgi Sofiyski blvd., 1431 Sofia, Bulgaria;
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