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Zielen S, Alemdar O, Wimmers A, Gronau L, Duecker R, Hutter M, Trischler J, de Monchy JG, Schubert R. The Late Asthmatic Reaction Is in Part Independent from the Early Asthmatic Reactions. Int J Mol Sci 2025; 26:2088. [PMID: 40076712 PMCID: PMC11900439 DOI: 10.3390/ijms26052088] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2025] [Revised: 02/19/2025] [Accepted: 02/24/2025] [Indexed: 03/14/2025] Open
Abstract
House dust mites (HDM) are the world's most important cause of allergic asthma. It is unclear why some patients with HDM allergy develop an early asthmatic reaction (EAR) only, whereas others react with a dual asthmatic reaction-EAR plus late asthmatic reaction (LAR). In patients with LAR, the symptoms and bronchial inflammation are more severe, and the current knowledge suggests that the EAR always precedes the LAR. The aim of the present study was to investigate whether a LAR can occur separately even without a significant EAR. In a pilot study of 20 patients with asthma and HDM allergy, a bronchial allergen challenge (BAC) was performed on three separate occasions with a tapered allergen dose. Before and 24 h later, exhaled NO (eNO), eosinophils and miRNAs were measured as markers of bronchial inflammation. Compared to BAC1, at BAC2 there was a significant decrease in the EAR from mean 39.25 ± 13.37% to mean 33.55 ± 5.25% (p < 0.01), whereas the LAR remained unchanged: mean 28.10 ± 10.95% to mean 30.31 ± 7.77% (n.s.). At BAC3, both the EAR and the LAR were significantly attenuated compared to the first and second BAC. In 3 (15%) patients, even the tapered allergen dose induced a dual asthmatic reaction. In 10 (50%) patients, the allergen dose was too low to trigger a significant EAR and LAR. In 7 (35%) patients, there was no EAR, but a significant LAR (mean max fall FEV1 20.5 + 4.7%) recorded. Significant correlations (p < 0.05) were found between distinct miRNAs (miR-15a-5p, miR-15b-5p and miR-374a-p5), eNO, and the decline in lung function and the presence of a LAR (p < 0.01). We can demonstrate that a LAR is induced in some patients without an EAR to low allergen exposure. This leads to a strong inflammatory reaction with an increase in eNO and a decrease in FEV1 and distinct miRNAs. Accordingly, these individuals are at greater risk of asthmatic symptoms and remodeling with loss of lung function than patients who do not have a LAR.
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Affiliation(s)
- Stefan Zielen
- Department of Pediatrics, Division of Pneumology, Allergology, Infectious Diseases and Gastroenterology, Goethe University Frankfurt, 60590 Frankfurt am Main, Germany; (O.A.); (A.W.); (L.G.); (R.D.); (J.T.); (R.S.)
- Respiratory Research Institute, Medaimun GmbH, 60596 Frankfurt am Main, Germany
| | - Oguzhan Alemdar
- Department of Pediatrics, Division of Pneumology, Allergology, Infectious Diseases and Gastroenterology, Goethe University Frankfurt, 60590 Frankfurt am Main, Germany; (O.A.); (A.W.); (L.G.); (R.D.); (J.T.); (R.S.)
- Respiratory Research Institute, Medaimun GmbH, 60596 Frankfurt am Main, Germany
| | - Andreas Wimmers
- Department of Pediatrics, Division of Pneumology, Allergology, Infectious Diseases and Gastroenterology, Goethe University Frankfurt, 60590 Frankfurt am Main, Germany; (O.A.); (A.W.); (L.G.); (R.D.); (J.T.); (R.S.)
- Respiratory Research Institute, Medaimun GmbH, 60596 Frankfurt am Main, Germany
| | - Lucia Gronau
- Department of Pediatrics, Division of Pneumology, Allergology, Infectious Diseases and Gastroenterology, Goethe University Frankfurt, 60590 Frankfurt am Main, Germany; (O.A.); (A.W.); (L.G.); (R.D.); (J.T.); (R.S.)
| | - Ruth Duecker
- Department of Pediatrics, Division of Pneumology, Allergology, Infectious Diseases and Gastroenterology, Goethe University Frankfurt, 60590 Frankfurt am Main, Germany; (O.A.); (A.W.); (L.G.); (R.D.); (J.T.); (R.S.)
| | - Martin Hutter
- Department of Pediatrics, Division of Pneumology, Allergology, Infectious Diseases and Gastroenterology, Goethe University Frankfurt, 60590 Frankfurt am Main, Germany; (O.A.); (A.W.); (L.G.); (R.D.); (J.T.); (R.S.)
| | - Jordis Trischler
- Department of Pediatrics, Division of Pneumology, Allergology, Infectious Diseases and Gastroenterology, Goethe University Frankfurt, 60590 Frankfurt am Main, Germany; (O.A.); (A.W.); (L.G.); (R.D.); (J.T.); (R.S.)
| | - Jan G. de Monchy
- DC Klinieken Lairesse (Amsterdam), Valeriusplein 11, 1075 BG Amsterdam, The Netherlands;
| | - Ralf Schubert
- Department of Pediatrics, Division of Pneumology, Allergology, Infectious Diseases and Gastroenterology, Goethe University Frankfurt, 60590 Frankfurt am Main, Germany; (O.A.); (A.W.); (L.G.); (R.D.); (J.T.); (R.S.)
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Duecker RP, Alemdar O, Wimmers A, Gronau L, Chiocchetti AG, Valesky EM, Donath H, Trischler J, Blumchen K, Zielen S, Schubert R. MicroRNA Profiling of the Inflammatory Response after Early and Late Asthmatic Reaction. Int J Mol Sci 2024; 25:1356. [PMID: 38279356 PMCID: PMC10817008 DOI: 10.3390/ijms25021356] [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: 11/23/2023] [Revised: 01/19/2024] [Accepted: 01/19/2024] [Indexed: 01/28/2024] Open
Abstract
A high proportion of house dust mite (HDM)-allergic asthmatics suffer from both an early asthmatic reaction (EAR) and a late asthmatic reaction (LAR) which follows it. In these patients, allergic inflammation is more relevant. MiRNAs have been shown to play an important role in the regulation of asthma's pathology. The aim of this study was to analyze the miRNA profile in patients with mild asthma and an HDM allergy after bronchial allergen provocation (BAP). Seventeen patients with EAR/no LAR and 17 patients with EAR plus LAR, determined by a significant fall in FEV1 after BAP, were differentially analyzed. As expected, patients with EAR plus LAR showed a more pronounced allergic inflammation and FEV1 delta drop after 24 h. NGS-miRNA analysis identified the down-regulation of miR-15a-5p, miR-15b-5p, and miR-374a-5p after BAP with the highest significance in patients with EAR plus LAR, which were negatively correlated with eNO and the maximum decrease in FEV1. These miRNAs have shared targets like CCND1, VEGFA, and GSK3B, which are known to be involved in airway remodeling, basement membrane thickening, and Extracellular Matrix deposition. NGS-profiling identified miRNAs involved in the inflammatory response after BAP with HDM extract, which might be useful to predict a LAR.
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Affiliation(s)
- Ruth P. Duecker
- Department of Pediatrics, Division of Pneumology, Allergology, Infectious Diseases and Gastroenterology, University Hospital, Goethe University Frankfurt, 60590 Frankfurt am Main, Germany; (O.A.); (A.W.); (L.G.); (H.D.); (J.T.); (K.B.); (S.Z.); (R.S.)
| | - Oguzhan Alemdar
- Department of Pediatrics, Division of Pneumology, Allergology, Infectious Diseases and Gastroenterology, University Hospital, Goethe University Frankfurt, 60590 Frankfurt am Main, Germany; (O.A.); (A.W.); (L.G.); (H.D.); (J.T.); (K.B.); (S.Z.); (R.S.)
- Respiratory Research Institute, Medaimun GmbH, 60596 Frankfurt am Main, Germany
| | - Andreas Wimmers
- Department of Pediatrics, Division of Pneumology, Allergology, Infectious Diseases and Gastroenterology, University Hospital, Goethe University Frankfurt, 60590 Frankfurt am Main, Germany; (O.A.); (A.W.); (L.G.); (H.D.); (J.T.); (K.B.); (S.Z.); (R.S.)
- Respiratory Research Institute, Medaimun GmbH, 60596 Frankfurt am Main, Germany
| | - Lucia Gronau
- Department of Pediatrics, Division of Pneumology, Allergology, Infectious Diseases and Gastroenterology, University Hospital, Goethe University Frankfurt, 60590 Frankfurt am Main, Germany; (O.A.); (A.W.); (L.G.); (H.D.); (J.T.); (K.B.); (S.Z.); (R.S.)
| | - Andreas G. Chiocchetti
- Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, University Hospital, Goethe University Frankfurt, 60590 Frankfurt am Main, Germany;
| | - Eva M. Valesky
- Department of Dermatology, Venerology and Allergology, University Hospital, Goethe University Frankfurt, 60590 Frankfurt am Main, Germany;
| | - Helena Donath
- Department of Pediatrics, Division of Pneumology, Allergology, Infectious Diseases and Gastroenterology, University Hospital, Goethe University Frankfurt, 60590 Frankfurt am Main, Germany; (O.A.); (A.W.); (L.G.); (H.D.); (J.T.); (K.B.); (S.Z.); (R.S.)
| | - Jordis Trischler
- Department of Pediatrics, Division of Pneumology, Allergology, Infectious Diseases and Gastroenterology, University Hospital, Goethe University Frankfurt, 60590 Frankfurt am Main, Germany; (O.A.); (A.W.); (L.G.); (H.D.); (J.T.); (K.B.); (S.Z.); (R.S.)
| | - Katharina Blumchen
- Department of Pediatrics, Division of Pneumology, Allergology, Infectious Diseases and Gastroenterology, University Hospital, Goethe University Frankfurt, 60590 Frankfurt am Main, Germany; (O.A.); (A.W.); (L.G.); (H.D.); (J.T.); (K.B.); (S.Z.); (R.S.)
| | - Stefan Zielen
- Department of Pediatrics, Division of Pneumology, Allergology, Infectious Diseases and Gastroenterology, University Hospital, Goethe University Frankfurt, 60590 Frankfurt am Main, Germany; (O.A.); (A.W.); (L.G.); (H.D.); (J.T.); (K.B.); (S.Z.); (R.S.)
- Respiratory Research Institute, Medaimun GmbH, 60596 Frankfurt am Main, Germany
| | - Ralf Schubert
- Department of Pediatrics, Division of Pneumology, Allergology, Infectious Diseases and Gastroenterology, University Hospital, Goethe University Frankfurt, 60590 Frankfurt am Main, Germany; (O.A.); (A.W.); (L.G.); (H.D.); (J.T.); (K.B.); (S.Z.); (R.S.)
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Agache I, Antolin‐Amerigo D, Blay F, Boccabella C, Caruso C, Chanez P, Couto M, Covar R, Doan S, Fauquert J, Gauvreau G, Gherasim A, Klimek L, Lemiere C, Nair P, Ojanguren I, Peden D, Perez‐de‐Llano L, Pfaar O, Rondon C, Rukhazde M, Sastre J, Schulze J, Silva D, Tarlo S, Toppila‐Salmi S, Walusiak‐Skorupa J, Zielen S, Eguiluz‐Gracia I. EAACI position paper on the clinical use of the bronchial allergen challenge: Unmet needs and research priorities. Allergy 2022; 77:1667-1684. [PMID: 34978085 DOI: 10.1111/all.15203] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2021] [Revised: 12/16/2021] [Accepted: 12/27/2021] [Indexed: 12/22/2022]
Abstract
Allergic asthma (AA) is a common asthma phenotype, and its diagnosis requires both the demonstration of IgE-sensitization to aeroallergens and the causative role of this sensitization as a major driver of asthma symptoms. Therefore, a bronchial allergen challenge (BAC) would be occasionally required to identify AA patients among atopic asthmatics. Nevertheless, BAC is usually considered a research tool only, with existing protocols being tailored to mild asthmatics and research needs (eg long washout period for inhaled corticosteroids). Consequently, existing BAC protocols are not designed to be performed in moderate-to-severe asthmatics or in clinical practice. The correct diagnosis of AA might help select patients for immunomodulatory therapies. Allergen sublingual immunotherapy is now registered and recommended for controlled or partially controlled patients with house dust mite-driven AA and with FEV1 ≥ 70%. Allergen avoidance is costly and difficult to implement for the management of AA, so the proper selection of patients is also beneficial. In this position paper, the EAACI Task Force proposes a methodology for clinical BAC that would need to be validated in future studies. The clinical implementation of BAC could ultimately translate into a better phenotyping of asthmatics in real life, and into a more accurate selection of patients for long-term and costly management pathways.
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Affiliation(s)
- Ioana Agache
- Faculty of Medicine Transylvania University Brasov Romania
| | - Dario Antolin‐Amerigo
- Servicio de Alergia Hospital Universitario Ramón y Cajal Instituto Ramón y Cajal de Investigación Sanitaria Madrid Spain
| | - Frederic Blay
- ALYATEC Environmental Exposure Chamber Chest Diseases Department Strasbourg University Hospital University of Strasbourg Strasbourg France
| | - Cristina Boccabella
- Department of Cardiovascular and Thoracic Sciences Università Cattolica del Sacro Cuore Fondazione Policlinico Universitario A. Gemelli ‐ IRCCS Rome Italy
| | | | - Pascal Chanez
- Department of Respiratory CIC Nord INSERMINRAE C2VN Aix Marseille University Marseille France
| | - Mariana Couto
- Centro de Alergia Hospital CUF Descobertas Lisboa Portugal
| | - Ronina Covar
- Pediatrics National Jewish Health Denver Colorado USA
| | | | | | - Gail Gauvreau
- Division of Respirology Department of Medicine McMaster University Hamilton Ontario Canada
| | - Alina Gherasim
- ALYATEC Environmental Exposure Chamber Strasbourg France
| | - Ludger Klimek
- Center for Rhinology and Allergology Wiesbaden Germany
| | - Catherine Lemiere
- Research Centre Centre Intégré Universitaire de santé et de services sociaux du Nord‐de‐l'île‐de‐Montréal Montréal Quebec Canada
- Faculty of Medicine Université de Montreal Montreal Quebec Canada
| | - Parameswaran Nair
- Department of Medicine Firestone Institute of Respiratory Health at St. Joseph's Healthcare McMaster University Hamilton Ontario Canada
| | - Iñigo Ojanguren
- Departament de Medicina Servei de Pneumología Hospital Universitari Valld´Hebron Universitat Autònoma de Barcelona (UAB) Institut de Recerca (VHIR) CIBER de Enfermedades Respiratorias (CIBERES) Barcelona Spain
| | - David Peden
- Division of Pediatric Allergy and Immunology Center for Environmental Medicine, Asthma and Lung Biology The School of Medicine The University of North Carolina at Chapel Hill Chapel Hill North Carolina USA
| | - Luis Perez‐de‐Llano
- Department of Respiratory Medicine University Hospital Lucus Augusti Lugo Spain
| | - Oliver Pfaar
- Section of Rhinology and Allergy Department of Otorhinolaryngology, Head and Neck Surgery University Hospital Marburg Philipps‐Universität Marburg Marburg Germany
| | - Carmen Rondon
- Allergy Unit Hospital Regional Universitario de Malaga Instituto de Investigacion Biomedica de Malaga (IBIMA) Malaga Spain
| | - Maia Rukhazde
- Center of Allergy & Immunology Teaching University Geomedi LLC Tbilisi Georgia
| | - Joaquin Sastre
- Allergy Unit Hospital Universitario Fundación Jiménez Díaz Center for Biomedical Network of Respiratory Diseases (CIBERES) Instituto de Salud Carlos III (ISCIII) Madrid Spain
| | - Johannes Schulze
- Department for Children and Adolescents, Division of Allergology Pulmonology and Cystic Fibrosis Goethe‐University Hospital Frankfurt am Main Germany
| | - Diana Silva
- Basic and Clinical Immunology Unit Department of Pathology Faculty of Medicine University of Porto and Serviço de Imunoalergologia Centro Hospitalar São João, EPE Porto Portugal
| | - Susan Tarlo
- Respiratory Division Department of Medicine University Health Network, Toronto Western Hospital University of Toronto Department of Medicine, and Dalla Lana Department of Public Health Toronto Ontario Canada
| | - Sanna Toppila‐Salmi
- Haartman Institute, Medicum, Skin and Allergy Hospital Hospital District of Helsinki and Uusimaa Helsinki University Hospital and University of Helsinki Helsinki Finland
| | - Jolanta Walusiak‐Skorupa
- Department of Occupational Diseases and Environmental Health Nofer Institute of Occupational Medicine Łódź Poland
| | - Stefan Zielen
- Department for Children and Adolescents, Division of Allergology Pulmonology and Cystic Fibrosis Goethe‐University Hospital Frankfurt am Main Germany
| | - Ibon Eguiluz‐Gracia
- Allergy Unit Hospital Regional Universitario de Malaga Instituto de Investigacion Biomedica de Malaga (IBIMA) Malaga Spain
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Dreßler M, Fussbroich D, Böhler L, Herrmann E, Benker N, Tytyk M, Schulze J, Schubert R, Beermann C, Zielen S. Oil supplementation with a special combination of n-3 and n-6 long-chain polyunsaturated fatty acids does not protect for exercise induced asthma: a double-blind placebo-controlled trial. Lipids Health Dis 2020; 19:167. [PMID: 32660564 PMCID: PMC7359229 DOI: 10.1186/s12944-020-01343-2] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2020] [Accepted: 07/03/2020] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Many patients suffering from exercise-induced asthma (EIA) have normal lung function at rest and show symptoms and a decline in FEV1 when they do sports or during exercise-challenge. It has been described that long-chain polyunsaturated fatty acids (LCPUFA) could exert a protective effect on EIA. METHODS In this study the protective effect of supplementation with a special combination of n-3 and n-6 LCPUFA (sc-LCPUFA) (total 1.19 g/ day) were investigated in an EIA cold air provocation model. PRIMARY OUTCOME MEASURE Decrease in FEV1 after exercise challenge and secondary outcome measure: anti-inflammatory effects monitored by exhaled NO (eNO) before and after sc-LCPUFA supplementation versus placebo. RESULTS Ninety-nine patients with exercise-induced symptoms aged 10 to 45 were screened by a standardized exercise challenge in a cold air chamber at 4 °C. Seventy-three patients fulfilled the inclusion criteria of a FEV1 decrease > 15% and were treated double-blind placebo-controlled for 4 weeks either with sc-LCPUFA or placebo. Thirty-two patients in each group completed the study. Mean FEV1 decrease after cold air exercise challenge and eNO were unchanged after 4 weeks sc-LCPUFA supplementation. CONCLUSION Supplementation with sc-LCPUFA at a dose of 1.19 g/d did not have any broncho-protective and anti-inflammatory effects on EIA. TRIAL REGISTRATION Clinical trial registration number: NCT02410096. Registered 7 February 2015 at Clinicaltrial.gov.
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Affiliation(s)
- M Dreßler
- Department for Children and Adolescents, Division of Allergology, Pulmonology and Cystic fibrosis, Goethe-University, Frankfurt/Main, Germany
| | - D Fussbroich
- Department for Children and Adolescents, Division of Allergology, Pulmonology and Cystic fibrosis, Goethe-University, Frankfurt/Main, Germany.,Department of Food Technology, University of Applied Science, Fulda, Germany.,Faculty of Biological Sciences, Goethe-University, Frankfurt/Main, Germany
| | - L Böhler
- Department for Children and Adolescents, Division of Allergology, Pulmonology and Cystic fibrosis, Goethe-University, Frankfurt/Main, Germany
| | - E Herrmann
- Institute of Biostatistics and Mathematical Modelling, Goethe-University, Frankfurt/Main, Germany
| | - N Benker
- Department for Children and Adolescents, Division of Allergology, Pulmonology and Cystic fibrosis, Goethe-University, Frankfurt/Main, Germany
| | - M Tytyk
- Department of Food Technology, University of Applied Science, Fulda, Germany
| | - J Schulze
- Department for Children and Adolescents, Division of Allergology, Pulmonology and Cystic fibrosis, Goethe-University, Frankfurt/Main, Germany
| | - R Schubert
- Department for Children and Adolescents, Division of Allergology, Pulmonology and Cystic fibrosis, Goethe-University, Frankfurt/Main, Germany
| | - C Beermann
- Department of Food Technology, University of Applied Science, Fulda, Germany
| | - S Zielen
- Department for Children and Adolescents, Division of Allergology, Pulmonology and Cystic fibrosis, Goethe-University, Frankfurt/Main, Germany.
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Fischl A, Eckrich J, Passlack V, Klenke SK, Hartmann D, Herrmann E, Schulze J, Zielen S. Comparison of bronchial and nasal allergen provocation in children and adolescents with bronchial asthma and house dust mite sensitization. Pediatr Allergy Immunol 2020; 31:143-149. [PMID: 31660641 DOI: 10.1111/pai.13147] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/29/2019] [Revised: 10/09/2019] [Accepted: 10/10/2019] [Indexed: 01/10/2023]
Abstract
BACKGROUND Bronchial allergen provocation (BAP) is an established tool for the diagnosis of allergy in patients with asthma, but its use is limited by the potential risk of severe asthmatic reactions. Nasal provocation testing (NPT) may be an alternative safe method and does not require sophisticated equipment. OBJECTIVE The aim of this prospective study was to evaluate the concordance of both methods in patients with asthma and house dust mite (HDM) sensitization. METHODS A total of 112 patients with HDM sensitization underwent BAP and had the following parameters analysed: decrease in FEV1, exhaled NO, and total and specific IgE. Within 12 weeks, NPT with HDM was performed in 74 patients with a median age of 9 years (range, 5-16 years). The results were evaluated using the Lebel score which quantifies major symptoms like rhinorrhea, nasal obstruction, sneezes and minor symptoms, such as pruritus, conjunctivitis and pharyngitis. RESULTS Fifty-seven of 74 patients had an early asthmatic reaction, of which 41 were identified using the Lebel score. The Lebel score had a sensitivity of 71.9% and a positive predictive value (PPV) of 89.1%. In addition, an eNO ≥ 10 ppb (AUC 0.78), a specific IgE Dermatophagoïdes pteronyssinus ≥ 25.6 kU/L (AUC 0.76) and a specific IgE Dermatophagoïdes farinae ≥ 6.6 kU/L (AUC 0.78) were good predictors of an early asthmatic reaction. CONCLUSION A sequential use of NPT prior to BAP is justified to establish the relevance of HDM allergy. In patients with a negative NPT, BAP is still recommended to rule out a HDM-induced asthmatic reaction.
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Affiliation(s)
- Anna Fischl
- Department for Children and Adolescents, Division of Pediatric Allergy, Pulmonology, and Cystic fibrosis, Goethe University, Frankfurt, Germany
| | - Jonas Eckrich
- Department of Otolaryngology, Head and Neck Surgery, School of Medicine, University of Mainz, Mainz, Germany
| | - Vanessa Passlack
- Department for Children and Adolescents, Division of Pediatric Allergy, Pulmonology, and Cystic fibrosis, Goethe University, Frankfurt, Germany
| | - Sara-Kristin Klenke
- Department for Children and Adolescents, Division of Pediatric Allergy, Pulmonology, and Cystic fibrosis, Goethe University, Frankfurt, Germany
| | - Desiree Hartmann
- Department for Children and Adolescents, Division of Pediatric Allergy, Pulmonology, and Cystic fibrosis, Goethe University, Frankfurt, Germany
| | - Eva Herrmann
- Institute of Biostatistics and Mathematical Modelling, Goethe University, Frankfurt, Germany
| | - Johannes Schulze
- Department for Children and Adolescents, Division of Pediatric Allergy, Pulmonology, and Cystic fibrosis, Goethe University, Frankfurt, Germany
| | - Stefan Zielen
- Department for Children and Adolescents, Division of Pediatric Allergy, Pulmonology, and Cystic fibrosis, Goethe University, Frankfurt, Germany
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6
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Eickmeier O, Zissler UM, Wittschorek J, Unger F, Schmitt-Grohé S, Schubert R, Herrmann E, Zielen S. Clinical relevance of Aspergillus fumigatus sensitization in cystic fibrosis. Clin Exp Allergy 2020; 50:325-333. [PMID: 31886564 DOI: 10.1111/cea.13557] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2019] [Revised: 12/04/2019] [Accepted: 12/12/2019] [Indexed: 12/12/2022]
Abstract
RATIONALE The clinical relevance of sensitization to Aspergillus (A) fumigatus in cystic fibrosis (CF) is unclear. Some researchers propose that specific A fumigatus IgE is an innocent bystander, whereas others describe it as the major cause of TH-2-driven asthma-like disease. OBJECTIVES Lung function parameters in mild CF patients may be different in patients with and without A fumigatus sensitization. We aimed to ascertain whether allergen exposure to A fumigatus by bronchial allergen provocation (BAP) induces TH-2 inflammation comparable to an asthma-like disease. METHODS A total of 35 patients, aged 14.8 ± 8.5 years, and 20 healthy controls were investigated prospectively. The patients were divided into two groups: group 1 (n = 18): specific (s)IgE negative, and group 2 (n = 17): sIgE positive (≥0.7 KU/L) for A fumigatus. Lung function, exhaled NO, and induced sputum were analysed. All sensitized patients with an FEV1 > 75% (n = 13) underwent BAP with A fumigatus, and cell counts, and the expression of IL-5, IL-13, INF-γ, and IL-8 as well as transcription factors T-bet, GATA-3, and FoxP3, were measured. RESULTS Lung function parameters decreased significantly compared to controls, but not within the CF patient group. After BAP, 8 of 13 patients (61%) had a significant asthmatic response and increased eNO 24 hours later. In addition, marked TH-2-mediated inflammation involving eosinophils, IL-5, IL-13, and FoxP3 became apparent in induced sputum cells. CONCLUSION Our study demonstrated the clinical relevance of A fumigatus for the majority of sensitized CF patients. A distinct IgE/TH-2-dominated inflammation was found in induced sputum after A fumigatus exposure.
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Affiliation(s)
- Olaf Eickmeier
- Department for Children and Adolescents, Division of Allergology, Pulmonology and Cystic fibrosis, Goethe University, Frankfurt, Germany
| | - Ulrich M Zissler
- Center of Allergy & Environment (ZAUM), Technical University of Munich and Helmholtz Center Munich, German Research Center for Environmental Health, Member of the German Center for Lung Research (DZL), CPC-M, Munich, Germany
| | - Julia Wittschorek
- Department for Children and Adolescents, Division of Allergology, Pulmonology and Cystic fibrosis, Goethe University, Frankfurt, Germany
| | - Frederike Unger
- Department for Children and Adolescents, Division of Allergology, Pulmonology and Cystic fibrosis, Goethe University, Frankfurt, Germany
| | - Sabina Schmitt-Grohé
- Department for Children and Adolescents, Division of Allergology, Pulmonology and Cystic fibrosis, Goethe University, Frankfurt, Germany
| | - Ralf Schubert
- Department for Children and Adolescents, Division of Allergology, Pulmonology and Cystic fibrosis, Goethe University, Frankfurt, Germany
| | - Eva Herrmann
- Institute of Biostatistics and Mathematical Modeling, Goethe University, Frankfurt, Germany
| | - Stefan Zielen
- Department for Children and Adolescents, Division of Allergology, Pulmonology and Cystic fibrosis, Goethe University, Frankfurt, Germany
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7
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Hartmann D, Fischl A, Herrmann E, Schulze J, Schubert R, Zielen S. Prospective comparison of a nonmodified and a modified mite extract for immunotherapy in children and adolescents. Immunotherapy 2019; 11:1015-1029. [PMID: 31319714 DOI: 10.2217/imt-2019-0015] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
Aim: This prospective study compares nonmodified and modified house dust mite extracts for allergen immunotherapy (AIT) in pediatric patients with allergic asthma. Materials & methods: Total 95 patients underwent bronchial allergen provocation (BAP). AIT was recommended to 62 patients. Complete datasets of 54 subjects were obtained. Primary aim was the comparison of treatment success defined by BAP between two extracts after 1 year. Secondary parameters were laboratory parameters and clinical symptoms. Results: Significant improvement (p < 0.001) was measured by BAP in both treatment groups. No change was seen in the controls. Both extracts exerted comparable effects on all parameters. Conclusion: After 1 year of AIT, the extracts were equally efficient, with significant improvements in 70.0% (nonmodified) and 72.2% (modified) of patients.
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Affiliation(s)
- Desireé Hartmann
- Department for Children & Adolescents, Division of Allergology, Pulmonology & Cystic fibrosis, Goethe University, 60590 Frankfurt am Main, Germany
| | - Anna Fischl
- Department for Children & Adolescents, Division of Allergology, Pulmonology & Cystic fibrosis, Goethe University, 60590 Frankfurt am Main, Germany
| | - Eva Herrmann
- Department of Biostatistics, Goethe University, 60590 Frankfurt am Main, Germany
| | - Johannes Schulze
- Department for Children & Adolescents, Division of Allergology, Pulmonology & Cystic fibrosis, Goethe University, 60590 Frankfurt am Main, Germany
| | - Ralf Schubert
- Department for Children & Adolescents, Division of Allergology, Pulmonology & Cystic fibrosis, Goethe University, 60590 Frankfurt am Main, Germany
| | - Stefan Zielen
- Department for Children & Adolescents, Division of Allergology, Pulmonology & Cystic fibrosis, Goethe University, 60590 Frankfurt am Main, Germany
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Popescu FD, Vieru M. Precision medicine allergy immunoassay methods for assessing immunoglobulin E sensitization to aeroallergen molecules. World J Methodol 2018; 8:17-36. [PMID: 30519536 PMCID: PMC6275558 DOI: 10.5662/wjm.v8.i3.17] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/08/2018] [Revised: 08/17/2018] [Accepted: 10/09/2018] [Indexed: 02/06/2023] Open
Abstract
Molecular-based allergy diagnosis for the in vitro assessment of a patient immunoglobulin E (IgE) sensitization profile at the molecular level uses allergen molecules (also referred to as allergen components), which may be well-defined, highly purified, natural allergen components or recombinant allergens. Modern immunoassay methods used for the detection of specific IgE against aeroallergen components are either singleplex (such as the fluorescence enzyme immunoassay with capsulated cellulose polymer solid-phase coupled allergens, the enzyme-enhanced chemiluminescence immunoassay and the reversed enzyme allergosorbent test, with liquid-phase allergens), multiparameter (such as the line blot immunoassay for defined partial allergen diagnostics with allergen components coating membrane strips) or multiplex (such as the microarray-based immunoassay on immuno solid-phase allergen chip, and the two new multiplex nanotechnology-based immunoassays: the patient-friendly allergen nano-bead array, and the macroarray nanotechnology-based immunoassay used as a molecular allergy explorer). The precision medicine diagnostic work-up may be organized as an integrated “U-shape” approach, with a “top-down” approach (from symptoms to molecules) and a “bottom-up” approach (from molecules to clinical implications), as needed in selected patients. The comprehensive and accurate IgE sensitization molecular profiling, with identification of the relevant allergens, is indicated within the framework of a detailed patient’s clinical history to distinguish genuine IgE sensitization from sensitization due to cross-reactivity (especially in polysensitized patients), to assess unclear symptoms and unsatisfactory response to treatment, to reveal unexpected sensitizations, and to improve assessment of severity and risk aspects in some patients. Practical approaches, such as anamnesis molecular thinking, laboratory molecular thinking and postmolecular anamnesis, are sometimes applied. The component-resolved diagnosis of the specific IgE repertoire has a key impact on optimal decisions making for prophylactic and specific immunotherapeutic strategies tailored for the individual patient.
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Affiliation(s)
- Florin-Dan Popescu
- Department of Allergology, “Carol Davila” University of Medicine and Pharmacy, Bucharest 022441, Romania
- Department of Allergology and Clinical Immunology, “Nicolae Malaxa” Clinical Hospital, Bucharest 022441, Romania
| | - Mariana Vieru
- Department of Allergology, “Carol Davila” University of Medicine and Pharmacy, Bucharest 022441, Romania
- Department of Allergology and Clinical Immunology, “Nicolae Malaxa” Clinical Hospital, Bucharest 022441, Romania
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Schulze J, Leberkuehne L, Salzmann-Manrique E, Schubert R, Zielen S, Rosewich M. Comparison of two different assays and the predictive value of allergen components in house dust mite allergy. Immunotherapy 2018; 9:1253-1262. [PMID: 29130795 DOI: 10.2217/imt-2017-0084] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
AIM In house dust mite (HDM) allergy diagnostics, the IMMULITE, ImmunoCAP and assays for allergen components (nDer p 1 and rDer p 2) are available. METHODS Serum sIgE levels were compared and the predictive values for the detection of an early asthmatic response (EAR) were calculated with receiver operating characteristics and a log-logistic regression model. RESULTS sIgE levels of IMMULITE and ImmunoCAP were similar (Dermatophagoides pteronyssinus [D. pter.] 47.3 ± 35.7 and 42.9 ± 34.4 kU.l-1; p = 0.23). ImmunoCAP slgEs exhibited similar accuracy in detecting an EAR, area under the curves (AUCs): D. pter. (0.76); Dermatophagoides farinae (0.79); nDer p 1 (0.69); and rDer p 2 (0.72). At low sIgE concentrations (3.5 kU.l-1), rDer p 2 was more specific and better predicted an EAR (probability rDer p 2: 62%; D. pter.: 19%).
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Affiliation(s)
- Johannes Schulze
- Department of Allergy, Pulmonology & Cystic Fibrosis, Children's Hospital, Goethe University, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany
| | | | - Emilia Salzmann-Manrique
- Institute of Biostatistics & Mathematical Modeling, Department of Medicine, Goethe University, Frankfurt, Germany
| | - Ralf Schubert
- Department of Allergy, Pulmonology & Cystic Fibrosis, Children's Hospital, Goethe University, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany
| | - Stefan Zielen
- Department of Allergy, Pulmonology & Cystic Fibrosis, Children's Hospital, Goethe University, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany
| | - Martin Rosewich
- Department of Allergy, Pulmonology & Cystic Fibrosis, Children's Hospital, Goethe University, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany
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10
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Zhang W, Lin C, Sampath V, Nadeau K. Impact of allergen immunotherapy in allergic asthma. Immunotherapy 2018; 10:579-593. [PMID: 29569506 DOI: 10.2217/imt-2017-0138] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Although traditional pharmacological approaches improve outcomes in disease management for allergic asthma, these fail to modify the underlying immune responses. Allergen immunotherapy remains the only etiological therapy for the treatment of respiratory allergies for which clinical efficacy has been demonstrated through several well-controlled studies. In this review, we examine evidence from the past 5 years regarding the impact of allergen immunotherapy on allergic asthma to inform practitioners and stimulate further discussion and research.
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Affiliation(s)
- Wenming Zhang
- Sean N. Parker Center for Allergy & Asthma Research, Stanford University, Stanford, CA 94305, USA
| | - Chunrong Lin
- Sean N. Parker Center for Allergy & Asthma Research, Stanford University, Stanford, CA 94305, USA
| | - Vanitha Sampath
- Sean N. Parker Center for Allergy & Asthma Research, Stanford University, Stanford, CA 94305, USA
| | - Kari Nadeau
- Sean N. Parker Center for Allergy & Asthma Research, Stanford University, Stanford, CA 94305, USA
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11
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Rosewich M, Girod K, Zielen S, Schubert R, Schulze J. Induction of Bronchial Tolerance After 1 Cycle of Monophosphoryl-A-Adjuvanted Specific Immunotherapy in Children With Grass Pollen Allergies. ALLERGY, ASTHMA & IMMUNOLOGY RESEARCH 2016; 8:257-63. [PMID: 26922936 PMCID: PMC4773214 DOI: 10.4168/aair.2016.8.3.257] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/29/2015] [Revised: 08/14/2015] [Accepted: 08/28/2015] [Indexed: 12/27/2022]
Abstract
PURPOSE Subcutaneous allergen-specific immunotherapy (SCIT) is a well-established and clinically effective method to treat allergic diseases, such as rhinitis and asthma. It remains unclear how soon after initiation of an ultra-short course of grass pollen immunotherapy adjuvanted with monophosphoryl lipid A (MPL)-specific bronchial tolerance can be induced. METHODS In a prospective study of 69 children double-sensitized to birch and grass pollens (51 males, average age 11.1 years), development of bronchial tolerance after 1 cycle of SCIT for grass was evaluated. In all the patients, the bronchial allergen provocation test (BAP) was performed before and after treatment. According to the results of the first BAP, the patients were divided into 2 groups: those showing a negative BAP with a decrease in FEV1 of <20% (seasonal allergic rhinitis [SAR] group, n=47); and those showing a positive BAP with a decrease in FEV1 of ≥20% (SAR with allergic asthma [SAR and Asthma] group, n=22). All the patients received MPL-adjuvanted, ultra-short course immunotherapy for birch, but only those with a positive BAP to grass received MPL-SCIT for grass. RESULTS After the pollen season, the BAP in the SAR group remained unchanged, while it was improved in the SAR and Asthma group (decrease in FEV1 of 28.8% vs 12.5%, P<0.01). The IgG4 levels increased after SCIT (median before SCIT 0.34 to 11.4 after SCIT), whereas the total and specific IgE levels remained unchanged. CONCLUSIONS After 1 cycle of MPL-SCIT, specific bronchial tolerance may be significantly induced, whereas in patients without SCIT, bronchial hyperactivity may remain unchanged.
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Affiliation(s)
- Martin Rosewich
- Children's Hospital, Department of Allergy, Pneumology and Cystic Fibrosis, Goethe-University, Frankfurt/Main, Germany.
| | - Katharina Girod
- Children's Hospital, Department of Allergy, Pneumology and Cystic Fibrosis, Goethe-University, Frankfurt/Main, Germany
| | - Stefan Zielen
- Children's Hospital, Department of Allergy, Pneumology and Cystic Fibrosis, Goethe-University, Frankfurt/Main, Germany
| | - Ralf Schubert
- Children's Hospital, Department of Allergy, Pneumology and Cystic Fibrosis, Goethe-University, Frankfurt/Main, Germany
| | - Johannes Schulze
- Children's Hospital, Department of Allergy, Pneumology and Cystic Fibrosis, Goethe-University, Frankfurt/Main, Germany
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12
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Buslau A, Voss S, Herrmann E, Schubert R, Zielen S, Schulze J. Can we predict allergen-induced asthma in patients with allergic rhinitis? Clin Exp Allergy 2015; 44:1494-502. [PMID: 25270425 DOI: 10.1111/cea.12427] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2014] [Revised: 09/16/2014] [Accepted: 09/22/2014] [Indexed: 11/30/2022]
Abstract
BACKGROUND A high percentage of patients with allergic rhinitis (AR) exhibit signs of bronchial hyperreactivity (BHR), and approximately 30% may develop asthma later in life. OBJECTIVE The aim of this study was to identify predictors for allergen-induced asthma in patients with AR. METHODS Hundred patients with AR selected by public posting and 20 healthy controls were enrolled. Twenty-three patients with concomitant physician-diagnosed asthma and four with a negative allergy test were excluded from further analysis. The remaining 73 subjects with AR underwent bronchial allergen provocation (BAP), which is considered the gold standard for the diagnosis of clinically relevant allergen-specific asthma. The following parameters were measured to explore predictors for an early and late asthmatic response (EAR and LAR): standardised questionnaire, skin prick test (SPT), total IgE, specific IgE to grass pollen, FEV1, PD20FEV1 methacholine, exhaled nitric oxide (eNO) and eosinophils. RESULTS Early asthmatic reaction was equally distributed between patients with and without signs of possible asthma by questionnaire (56.8% vs. 48.3%). The following cut-off values showed the best combination of sensitivity and specificity for an EAR: specific IgE grass pollen 18.5 kU/L (AUC 0.83), SPT 8.5 mm (AUC 0.76), total IgE 95.5 kU/L (AUC 0.73), FEV1 102.4% (AUC 0.69), PD20FEV1 methacholine 1.67 mg (AUC 0.74), eNO 18.05 ppB (AUC 0.64) and eosinophils 115/mm(3) (AUC 0.58). CONCLUSIONS AND CLINICAL RELEVANCE There is a considerable discordance between reported asthma signs and diagnosed disease by BAP. Simple measurement of allergen-specific IgE for grass pollen was the best predictor of allergen-induced asthma in patients with AR.
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Affiliation(s)
- A Buslau
- Department of Pediatric Pulmonology, Allergy and Cystic fibrosis, Children's Hospital, Goethe-University, Frankfurt, Germany
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13
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14
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Zielen S, Trischler J, Schubert R. Lipopolysaccharide challenge: immunological effects and safety in humans. Expert Rev Clin Immunol 2015; 11:409-18. [DOI: 10.1586/1744666x.2015.1012158] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023]
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15
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Soliman M, North ML, Steacy LM, Thiele J, Adams DE, Ellis AK. Nasal allergen challenge studies of allergic rhinitis: a guide for the practicing clinician. Ann Allergy Asthma Immunol 2014; 113:250-6. [PMID: 25168223 DOI: 10.1016/j.anai.2014.06.018] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2014] [Revised: 06/18/2014] [Accepted: 06/24/2014] [Indexed: 11/27/2022]
Affiliation(s)
- Mena Soliman
- Department of Biomedical and Molecular Sciences, Queen's University, Kingston, Ontario
| | - Michelle L North
- Department of Biomedical and Molecular Sciences, Queen's University, Kingston, Ontario
| | - Lisa M Steacy
- Allergy Research Unit, Kingston General Hospital, Kingston, Ontario
| | - Jenny Thiele
- Department of Biomedical and Molecular Sciences, Queen's University, Kingston, Ontario
| | - Daniel E Adams
- Allergy Research Unit, Kingston General Hospital, Kingston, Ontario
| | - Anne K Ellis
- Department of Biomedical and Molecular Sciences, Queen's University, Kingston, Ontario; Allergy Research Unit, Kingston General Hospital, Kingston, Ontario; Department of Medicine, Queen's University, Kingston, Ontario.
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16
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Rosewich M, Arendt S, El Moussaoui S, Schulze J, Schubert R, Zielen S. Bronchial allergen provocation: a useful method to assess the efficacy of specific immunotherapy in children. Pediatr Allergy Immunol 2013; 24:434-40. [PMID: 23578317 DOI: 10.1111/pai.12068] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 02/17/2013] [Indexed: 11/30/2022]
Abstract
BACKGROUND The clinical efficacy of subcutaneous allergen-specific immunotherapy (SCIT) varies between patients. New preparations are under development, and an objective tool with which to evaluate their efficacies in individual patients has become necessary. Our primary research question is whether bronchial allergen provocation (BAP) can be used to assess the efficacy of SCIT. METHODS In 42 house dust mite (HDM) allergic children (average age: 8.6 yr) with asthma, we analysed the clinical and objective improvements of a standardised HDM allergoid. All patients underwent two BAPs, one before SCIT and another 1 yr after SCIT. Fourteen patients who were recommended but chose not to undergo SCIT represented the control group. The total and specific IgE were analysed before SCIT; in addition, after SCIT, specific IgG and IgG4 were analysed. RESULTS After SCIT, the patients' allergen-specific bronchial hyper-reactivity (BHR) was significantly improved; specifically, their PD(20) FEV(1) was 34.4 AU before and 63.3 AU after SCIT (p < 0.01). The PD(20) FEV(1) of the control group remained unchanged. Although BHR improved significantly in the treatment group, we were able to differentiate between the responders (n = 17, 60.7%) and non-responders (n = 11, no improvement in BAP). The patients in both groups stated that SCIT had led to a subjective improvement in their symptoms, in contrast to the untreated control group, but only the responders required less medication after SCIT (p < 0.01). CONCLUSIONS After 1 yr of SCIT against HDM, 60.7% of the patients observed in this study exhibited significant improvements, as defined by BAP. However, BAP was also able to identify the non-responders to treatment. Thus, BAP is a useful and objective method of estimating the effectiveness of SCIT and is not influenced by a placebo effect.
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Affiliation(s)
- Martin Rosewich
- Children's Hospital, Department of Allergy, Pneumology and Cystic fibrosis, Goethe University, Frankfurt/Main, Germany.
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17
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Schulze J, Reinmüller W, Herrmann E, Rosewich M, Rose MA, Zielen S. Bronchial allergen challenges in children - safety and predictors. Pediatr Allergy Immunol 2013; 24:19-27. [PMID: 23331526 DOI: 10.1111/pai.12031] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 10/30/2012] [Indexed: 01/03/2023]
Abstract
BACKGROUND In allergic asthma, the diagnosis of house dust mite (HDM) allergy is mainly based on the patient's history, allergy testing by the skin prick test (SPT) or the levels of allergen-specific IgE. We retrospectively analysed data from 350 bronchial provocations with HDM and related it to the following parameters: specific IgE, bronchial hyperresponsiveness (BHR) to methacholine testing (MCT) and exhaled NO (eNO). METHODS Approximately 350 patients (5-18 yr of age) with allergic asthma and a positive SPT to HDMs were included. To define the sensitivity and specificity for the detection method of an early asthmatic response (EAR), a receiver-operating characteristic (ROC) curve was plotted. The accuracy was measured by the area under the ROC curve (AUC). A logistic regression model was used to predict the individual probability of a positive challenge. The results of the regression model were validated in a prospective group of n = 75 patients. RESULTS The following cut-off values showed the best combination of sensitivity and specificity: specific IgE Dermatophagoides farinae 19.6 kU/l (AUC, 0.88), PD(20) FEV(1) 0.13 mg methacholine (AUC, 0.73) and eNO 20.1 ppb (AUC, 0.71). The following equation predicted the individual probability of a positive challenge in the retrospective and prospective group: p = 1(.) [1 + exp[-(-1.78 + 2.46.(10) log D. far - 1.25(.10) logPD(20) metha)]](-1) , (AUC = 0.88). CONCLUSIONS The value of using the specific IgE and MCT as predictors was confirmed in a large number of patients. We also showed, for the first time, that the eNO predicted the EAR. The logistic regression model is repeatable with a good accuracy.
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Affiliation(s)
- Johannes Schulze
- Department of Allergy, Pulmonology, and Cystic Fibrosis, Children's Hospital, Goethe-University, Frankfurt, Germany.
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18
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Schulze J, Voss S, Zissler U, Rose MA, Zielen S, Schubert R. Airway responses and inflammation in subjects with asthma after four days of repeated high-single-dose allergen challenge. Respir Res 2012; 13:78. [PMID: 22989372 PMCID: PMC3445853 DOI: 10.1186/1465-9921-13-78] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2011] [Accepted: 06/27/2012] [Indexed: 01/09/2023] Open
Abstract
BACKGROUND Both standard and low-dose allergen provocations are an established tool in asthma research to improve our understanding of the pathophysiological mechanism of allergic asthma. However, clinical symptoms are less likely to be induced. Therefore, we designed a protocol for repetitive high-dose bronchial allergen challenges to generate clinical symptoms and airway inflammation. METHODS A total of 27 patients aged 18 to 40 years with positive skin-prick tests and mild asthma underwent repetitive high-dose allergen challenges with household dust mites for four consecutive days. Pulmonary function and exhaled NO were measured at every visit. Induced sputum was analysed before and after the allergen challenges for cell counts, ECP, IL-5, INF-γ, IL-8, and the transcription factor Foxp3. RESULTS We found a significant decrease in pulmonary function, an increased use of salbutamol and the development of a late asthmatic response and bronchial hyperresponsiveness, as well as a significant induction of eNO, eosinophils, and Th-2 cytokines. Repeated provocation was feasible in the majority of patients. Two subjects had severe adverse events requiring prednisolone to cope with nocturnal asthma symptoms. CONCLUSIONS Repeated high-dose bronchial allergen challenges resulted in severe asthma symptoms and marked Th-2-mediated allergic airway inflammation. The high-dose challenge model is suitable only in an attenuated form in diseased volunteers for proof-of-concept studies and in clinical settings to reduce the risk of severe asthma exacerbations. TRIAL REGISTRATION ClinicalTrials.govNCT00677209.
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Affiliation(s)
- Johannes Schulze
- Department of Allergy, Pulmonology, and Cystic Fibrosis, Children's Hospital, Goethe-University, Frankfurt, Germany
| | - Sandra Voss
- Department of Allergy, Pulmonology, and Cystic Fibrosis, Children's Hospital, Goethe-University, Frankfurt, Germany
| | - Ulrich Zissler
- Department of Allergy, Pulmonology, and Cystic Fibrosis, Children's Hospital, Goethe-University, Frankfurt, Germany
| | - Markus A Rose
- Department of Allergy, Pulmonology, and Cystic Fibrosis, Children's Hospital, Goethe-University, Frankfurt, Germany
| | - Stefan Zielen
- Department of Allergy, Pulmonology, and Cystic Fibrosis, Children's Hospital, Goethe-University, Frankfurt, Germany
| | - Ralf Schubert
- Department of Allergy, Pulmonology, and Cystic Fibrosis, Children's Hospital, Goethe-University, Frankfurt, Germany
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Zielen S, Lieb A, De La Motte S, Wagner F, de Monchy J, Fuhr R, Munzu C, Koehne-Voss S, Rivière GJ, Kaiser G, Erpenbeck VJ. Omalizumab protects against allergen- induced bronchoconstriction in allergic (immunoglobulin E-mediated) asthma. Int Arch Allergy Immunol 2012; 160:102-10. [PMID: 22948442 DOI: 10.1159/000339243] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2011] [Accepted: 05/02/2012] [Indexed: 11/19/2022] Open
Abstract
BACKGROUND Omalizumab has been shown to suppress responses to inhaled allergens in allergic asthma patients with pretreatment immunoglobulin E (IgE) ≤700 IU/ml. To extend current dosing tables, we evaluated the potential of high omalizumab doses to block allergen-induced bronchoconstriction in patients with higher IgE levels. METHODS Asthmatic adults (18-65 years; body weight 40-150 kg) were divided into groups according to screening IgE (group 1: 30-300 IU/ml; group 2: 700-2,000 IU/ml) and randomized 2:1 to omalizumab/placebo every 2 or 4 weeks for 12-14 weeks. Allergen bronchoprovocation (ABP) testing was performed before treatment and at weeks 8 and 16. The primary efficacy endpoint, the early-phase allergic response (EAR), was defined as the maximum percentage drop in forced expiratory volume in 1 s during the first 30 min after ABP. Serum free IgE was determined as a pharmacodynamic endpoint, and the exhaled fractional concentration of nitric oxide (FE(NO)) was an exploratory endpoint. RESULTS Fifty patients were included in the study. Omalizumab improved EAR; at week 8, EAR was 23.1% for placebo, 9.3% in group 1 (p = 0.018 versus placebo) and 5.6% in group 2 (p < 0.001). At week 16, EAR was 20%, 11.8% (p = 0.087) and 5.1% (p < 0.001), respectively. Free IgE decreased in groups 1 and 2 and remained <50 ng/ml in all patients during weeks 6-16. Omalizumab completely suppressed FE(NO) increases after ABP in both groups. CONCLUSIONS Omalizumab blocked early asthmatic responses over a broad range of IgE/body weight combinations. Extending the dosing tables enables omalizumab to benefit a wider range of patients.
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Affiliation(s)
- Stefan Zielen
- Department of Pediatric Allergy, Pneumology and Cystic Fibrosis, University Children's Hospital, J.W. Goethe University, Frankfurt, Germany.
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