Evaluation of Bronchial Inflammation in Allergic Bronchopulmonary Aspergillosis (ABPA) - Full Text View

Sponsor:	Johann Wolfgang Goethe University Hospitals
Information provided by:	Johann Wolfgang Goethe University Hospitals
ClinicalTrials.gov Identifier:	NCT00906568

Purpose

Chronic bronchial inflammation is an important clinical feature in cystic fibrosis. Approximately 10% of patients with cystic fibrosis suffer from Allergic Bronchopulmonary Aspergillosis. In addition airway inflammation in patients with cystic fibrosis (CF) plays a major role in progression of CF lung disease. In patients with mild disease (Vital capacity >75%) airway inflammation is often under diagnosed.

Severity of allergy against Aspergillus fumigatus will be examined using radioallergosorbent test and skin Prick-test. Subsequently, in patients with established sensitization (RAST ≥ 0.35 IU/mL) a specific bronchial provocation with Aspergillus will be performed. In addition, exhaled nitric oxide,carbon monoxide, exhaled air temperature and inflammatory cells in sputum is measured. 24 hours after bronchial allergen provocation, exhaled NO, CO, air temperature, and bronchial responsiveness is determined and a second sputum obtained.

This study is designed to characterize patients with CF and sensitization against Aspergillus fumigatus in an early stage to prevent pulmonary complications of ABPA. In addition sputum cytokine profiles in CF patients with mild and moderate disease may be different in patients without and with involvement of small airway disease (SAD).

Condition
Cystic Fibrosis,

Study Type:	Observational
Study Design:	Observational Model: Case-Only Time Perspective: Cross-Sectional
Official Title:	Clinical Presentation and Bronchial Inflammation of Allergic Bronchopulmonary Aspergillosis (ABPA) in Patients With Cystic Fibrosis

Resource links provided by NLM:

MedlinePlus related topics: Aspergillosis Cystic Fibrosis

U.S. FDA Resources

Further study details as provided by Johann Wolfgang Goethe University Hospitals:

Primary Outcome Measures:

The characterization of patients with CF and sensitization to Aspergillus fumigatus, and analyzing involvement of small airway disease (SAD) [ Time Frame: 1 year ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:

Aspergillus-induced inflammation in sputum using new mediators (IL-8, IL-13, TLR2 and TLR4, LBP and Chitinasen) with the quantitative PCR and protein assay analysis. [ Time Frame: 1 year ] [ Designated as safety issue: No ]
In addition planned data analyze: CF-patients will be divided according to their involvement of small airway disease (SAD) into 2 groups: Group 1 without SAD with MEF25 > 50%, Group 2 with SAD with MEF25 < 50% and cell counts and pro-inflammatory cytokines (IL-5, IL-6, IL-8, IL-13, IL-17, INF) measured by quantitative RT-PCR and protein assay will be analyzed.

Biospecimen Retention: Samples With DNA

serum: total Ig-E and RAST, sputum

Enrollment:	40
Study Start Date:	April 2009
Study Completion Date:	August 2010
Primary Completion Date:	May 2010 (Final data collection date for primary outcome measure)

Groups/Cohorts
Sensitized vs non-sensitized CF with and without SAD defined by MEF25 <50%

Detailed Description:

Since symptoms of Bronchopulmonary Aspergillosis are often identical to bacterial infections, the diagnosis is difficult to make. The disease presents with wheezing, pulmonary infiltrates, and bronchiectasis. The most important diagnostic parameters are asthmatic symptoms with obstruction, positive prick test, elevated total IgE, specific IgE and IgG to Aspergillus fumigatus, eosinophilia and radiological findings. Aspergillus fumigatus acts as an allergen Ig-E mediated allergy. Pathophysiological it is assumed that there are two different mechanisms of allergic inflammation. First, there is a direct effect of Aspergillus fumigatus proteases in the alveolar and bronchial epithelium with release of proinflammatory cytokines (IL-8, IL6, MCP-1) and consecutive chemotaxis of inflammatory cells. Second a CD4+ Th2 response with release of IL-4, IL-5 and IL-13. Recently published studies suggest that Aspergillus spores cause the TH2-dependent inflammation directly. So-called Chitinases (part of innate immunity) induce massive IL-13 stimulation. Induction of chitinase activity (CHIT1) leads to an increased remodeling of the lung. It is currently unclear, to which extent Aspergillus-triggered bronchial inflammation in patients with CF is relevant.

Eligibility

Ages Eligible for Study:	4 Years to 45 Years
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No
Sampling Method:	Non-Probability Sample

Study Population

Outpatients of Department of cystic fibrosis, Goethe University, Frankfurt, Germany

Criteria

Inclusion Criteria:

informed consent
age between 4 and 45 years
well-known Cystic fibrosis
Lung function: FEV1 (% pred.) ≥ 70%

Exclusion Criteria:

age < 4 and > 45 years
lung function: FEV1 (% pred.)< 70%
other chronic diseases or infections (e.g., HIV, tuberculosis, malignancy)
pregnancy
known alcohol, drug and/or drug abuse
inability to capture the scale and scope of the study
participation in another study

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00906568

Locations

Germany
Goethe-University Hospital
Frankfurt, Hesse, Germany, 60590

Sponsors and Collaborators

Johann Wolfgang Goethe University Hospitals

Investigators

Principal Investigator:

Stefan Zielen, MD

Cooperative Weichteilsarkom Study Group

More Information

Publications:

de Oliveira E, Giavina-Bianchi P, Fonseca LA, França AT, Kalil J. Allergic bronchopulmonary aspergillosis' diagnosis remains a challenge. Respir Med. 2007 Nov;101(11):2352-7. Epub 2007 Aug 3.

Knutsen AP, Bellone C, Kauffman H. Immunopathogenesis of allergic bronchopulmonary aspergillosis in cystic fibrosis. J Cyst Fibros. 2002 Jun;1(2):76-89. Review.

Stevens DA, Moss RB, Kurup VP, Knutsen AP, Greenberger P, Judson MA, Denning DW, Crameri R, Brody AS, Light M, Skov M, Maish W, Mastella G; Participants in the Cystic Fibrosis Foundation Consensus Conference. Allergic bronchopulmonary aspergillosis in cystic fibrosis--state of the art: Cystic Fibrosis Foundation Consensus Conference. Clin Infect Dis. 2003 Oct 1;37 Suppl 3:S225-64. Review. Erratum in: Clin Infect Dis. 2004 Jan 1;38(1):158.

Almeida MB, Bussamra MH, Rodrigues JC. ABPA diagnosis in cystic fibrosis patients: the clinical utility of IgE specific to recombinant Aspergillus fumigatus allergens. J Pediatr (Rio J). 2006 May-Jun;82(3):215-20. Epub 2006 May 26.

Skov M, Pressler T, Jensen HE, Høiby N, Koch C. Specific IgG subclass antibody pattern to Aspergillus fumigatus in patients with cystic fibrosis with allergic bronchopulmonary aspergillosis (ABPA). Thorax. 1999 Jan;54(1):44-50.

D'Amato G. Role of anti-IgE monoclonal antibody (omalizumab) in the treatment of bronchial asthma and allergic respiratory diseases. Eur J Pharmacol. 2006 Mar 8;533(1-3):302-7. Epub 2006 Feb 7. Review.

Kauffman HF. Immunopathogenesis of allergic bronchopulmonary aspergillosis and airway remodeling. Front Biosci. 2003 Jan 1;8:e190-6. Review.

Mall MA, Harkema JR, Trojanek JB, Treis D, Livraghi A, Schubert S, Zhou Z, Kreda SM, Tilley SL, Hudson EJ, O'Neal WK, Boucher RC. Development of chronic bronchitis and emphysema in beta-epithelial Na+ channel-overexpressing mice. Am J Respir Crit Care Med. 2008 Apr 1;177(7):730-42. Epub 2007 Dec 13.

Reese TA, Liang HE, Tager AM, Luster AD, Van Rooijen N, Voehringer D, Locksley RM. Chitin induces accumulation in tissue of innate immune cells associated with allergy. Nature. 2007 May 3;447(7140):92-6. Epub 2007 Apr 22.

Seibold MA, Donnelly S, Solon M, Innes A, Woodruff PG, Boot RG, Burchard EG, Fahy JV. Chitotriosidase is the primary active chitinase in the human lung and is modulated by genotype and smoking habit. J Allergy Clin Immunol. 2008 Nov;122(5):944-950.e3. Epub 2008 Oct 9.

Zhu Z, Zheng T, Homer RJ, Kim YK, Chen NY, Cohn L, Hamid Q, Elias JA. Acidic mammalian chitinase in asthmatic Th2 inflammation and IL-13 pathway activation. Science. 2004 Jun 11;304(5677):1678-82.

Responsible Party:	Prof. Dr. Stefan Zielen, Children´s Hospital, Department of Allergy, Pulmunology and Cystic Fibrosis, Goethe University, Frankfurt, Germany
ClinicalTrials.gov Identifier:	NCT00906568 History of Changes
Other Study ID Numbers:	KGU-32/09
Study First Received:	May 20, 2009
Last Updated:	February 15, 2011
Health Authority:	Germany: Ethics Commission

Keywords provided by Johann Wolfgang Goethe University Hospitals:

Cystic fibrosis
Sensitization to Aspergillus
Bronchial allergen challenge

Induced Sputum
Bronchial inflammation
Small airways disease (SAD)

Additional relevant MeSH terms:

Aspergillosis
Aspergillosis, Allergic Bronchopulmonary
Cystic Fibrosis
Fibrosis
Inflammation
Pulmonary Aspergillosis
Mycoses
Lung Diseases, Fungal
Lung Diseases
Respiratory Tract Diseases

Respiratory Hypersensitivity
Respiratory Tract Infections
Hypersensitivity, Immediate
Hypersensitivity
Immune System Diseases
Pancreatic Diseases
Digestive System Diseases
Genetic Diseases, Inborn
Infant, Newborn, Diseases
Pathologic Processes

ClinicalTrials.gov processed this record on May 23, 2012