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| ID | Type | Description | Link |
|---|---|---|---|
| 20/PR/0004 | Other Identifier | Health Research Authority |
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In this project the investigators will look for auto-antibodies to relevant proteins both in native form and importantly in post-translationally modified forms. Potential modified auto-antigens are eosinophil proteins (analogous to the cytoplasmic neutrophil proteins identified in vasculitides such as Granulomatosis with Polyangiitis (formerly known as Wegener's granulomatosis) and alternatively structural proteins such as collagen V. As well as advancing the understanding of asthma pathology, identifying a serum auto-antibody that could then be used as a clinical blood test, analogous to anti-cyclic citrullinated peptide (CCP) antibodies in rheumatoid arthritis, may revolutionise diagnosis of severe eosinophilic asthma and Eosinophilic Granulomatosis with Polyangiitis (EGPA). There is a considerable burden of undiagnosed severe eosinophilic asthma in part due to difficulties in definitive diagnosis and a diagnostic blood test would help diagnose these patients, allowing them to receive necessary treatment.
The investigators will approach the research question with parallel agnostic and targeted approaches.
In the agnostic approach the presence of auto-antibodies in patient serum and sputum to inactive and activated eosinophils, with and without post-translational modification, will be examined by indirect immunofluorescence.
In the targeted approach the investigators will examine by enzyme-linked immunoassay (ELISA) the presence/absence of antibodies to pre-selected candidate eosinophil and base membrane proteins both in native form and post-translationally modified. Proteins to examine will be chosen based on literature review (e.g. eosinophil peroxidase and collagen V) and eosinophil-specific proteins identified by FANTOM5 (Functional Annotation of the Mouse/Mammalian Genome) geneset analysis (FANTOM Consortium et al. 2014).
Both blood and sputum samples from highly-characterised patients with severe eosinophilic asthma and/or EGPA will be examined given the possibility of compartment-specific immune responses.
Once candidate auto-antigens have been identified in the selected group of patients with severe eosinophilic asthma and EGPA, the investigators will then examine their prevalence in serum samples from a wider selection of patients with eosinophilic airways diseases including mild-to-moderate asthma, severe eosinophilic asthma, EGPA, nasal polyposis and eosinophilic chronic obstructive pulmonary disease (COPD) as well as healthy controls. Length of disease, atopy, presence/absence nasal polyps, gender, age will be examined as co-variates. Correlations with highest blood eosinophil counts, requirement for oral corticosteroids and presence of other auto-antibodies, e.g. anti-MPO (myeloperoxidase) ANCA (anti-neutrophil cytoplasmic antibody), will be examined. In particular the investigators will look for the presence of novel autoantibodies in specific patient subsets: i) ANCA negative, ii) ANCA positive by immunofluorescence but negative for anti-MPO and anti-PR3 (proteinase-3) antibodies, iii) ANA (anti-nuclear antibody) positive but ANCA and extractable nuclear antigen (ENA) negative; since patients in all three groups may have novel, as yet undetermined autoantibodies. ROC (receiver operator characteristic curve) AUC (area under curve) analyses will be conducted to ascertain the predictive value of blood auto-antibodies for diagnosis of eosinophilic airways disease.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Severe eosinophilic asthma | Patients with eosinophilic asthma meeting ERS/ATS criteria for severe asthma. |
| |
| Other respiratory conditions | Milder asthma, other vasculitides, eosinophilic COPD, and/or eosinophilic oesophagitis |
| |
| Healthy controls | Healthy patients with no chronic lung condition. |
| |
| EGPA | Patients with asthma meeting criteria for a diagnosis of EGPA (eosinophilic granulomatosis with polyangiitis) as per Wechsler et al. [N Engl J Med. 2017 May 18;376(20):1921-1932] |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Autoantibody ELISA | Diagnostic Test | Serum will be tested for novel autoantibodies against candidate auto-antigens by ELISA, such as those previously identified as of importance (e.g. eosinophil peroxidase, EPX) and also novel candidate proteins specific to eosinophils as identified by FANTOM5 geneset analysis. |
| Measure | Description | Time Frame |
|---|---|---|
| Number and Percentage of Patients With a Positive Autoantibody ELISA | Serum tested for novel autoantibodies against candidate auto-antigens by ELISA. Outcome: Positive OD by ELISA (serum samples) to autoantigen panel (MPO, Collagen V, TREM1, IL1R2). | Baseline, at study entry |
| Measure | Description | Time Frame |
|---|---|---|
| Number and Percentage of Patients With Positive Granulocyte Immunofluorescence | FITC anti-IgG immunofluorescence with slides of unstimulated/PMA-stimulated neutrophils (serum samples) | Baseline, at study entry |
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Inclusion Criteria:
Exclusion Criteria:
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Patients will be recruited via Outpatient Clinics conducted at St Bartholomew's (Bart's) Hospital, The Royal London Hospital, and Mile End Hospital (all Bart's Health NHS Trust), as well as from inpatients at these hospitals under the care of the Respiratory Medicine and Rheumatology teams (including those under other services needing inpatient respiratory medicine or rheumatology review).
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| Name | Affiliation | Role |
|---|---|---|
| Myles J Lewis, MD PhD FRCP | Queen Mary University of London | Study Chair |
| Paul Pfeffer, MD | Barts & The London NHS Trust | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Barts Health NHS Trust, Dept of Rheumatology, Mile End Hospital | London | E1 4DG | United Kingdom | |||
| Barts Health NHS Trust, Dept of Respiratory Medicine, St Bartholomew's Hospital |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 37334358 | Derived | Esposito I, Kontra I, Giacomassi C, Manou-Stathopoulou S, Brown J, Stratton R, Verykokou G, Buccafusca R, Stevens M, Nissim A, Lewis MJ, Pfeffer PE. Identification of autoantigens and their potential post-translational modification in EGPA and severe eosinophilic asthma. Front Immunol. 2023 Jun 2;14:1164941. doi: 10.3389/fimmu.2023.1164941. eCollection 2023. |
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| ID | Title | Description |
|---|---|---|
| FG000 | Severe Eosinophilic Asthma | Patients with eosinophilic asthma meeting ERS/ATS criteria for severe asthma. |
| FG001 | Healthy Controls | Healthy patients with no chronic lung condition. |
| FG002 | EGPA | Patients with asthma meeting criteria for a diagnosis of EGPA (eosinophilic granulomatosis with polyangiitis) |
| FG003 | Other Respiratory Conditions | Mild-to-moderate asthma, other vasculitides, eosinophilic COPD, and/or eosinophilic oesophagitis |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
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| ID | Title | Description |
|---|---|---|
| BG000 | Severe Eosinophilic Asthma | Patients with eosinophilic asthma meeting ERS/ATS criteria for severe asthma. |
| BG001 | Healthy Controls | Healthy patients with no chronic lung condition. |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Age for one healthy control not available. |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Number and Percentage of Patients With a Positive Autoantibody ELISA | Serum tested for novel autoantibodies against candidate auto-antigens by ELISA. Outcome: Positive OD by ELISA (serum samples) to autoantigen panel (MPO, Collagen V, TREM1, IL1R2). | EGPA and Other respiratory conditions arms included as reference populations, with some patients purposefully recruited due to known anti-MPO status (potential selection bias). 17 Severe eosinophilic asthma patients, 5 Healthy control participants, 5 EGPA patients and 3 patients with Other Respiratory Conditions excluded from outcome due to technical errors with ELISA assays (missing data). | Posted | Count of Participants | Participants | Baseline, at study entry |
|
Single study visit for each patient, of an average duration of 10 minutes. No follow-up.
The only patient contact in this study was the consent process and the sample donation (venipuncture and collection of blood into sterile containers using standard phlebotomy practice at the recruiting NHS Trust, with/without collection of spontaneously produced sputum). Only events relating to this contact were to be considered for Adverse Events (AE) and Serious Adverse Events (SAE) reporting.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Severe Eosinophilic Asthma | Patients with eosinophilic asthma meeting ERS/ATS criteria for severe asthma. |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Dr Myles Lewis, Dr Paul Pfeffer | Queen Mary University of London | +4420 7882 5555 | myles.lewis@qmul.ac.uk; p.pfeffer@qmul.ac.uk |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Jun 20, 2022 | Dec 13, 2022 | Prot_SAP_000.pdf |
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| ID | Term |
|---|---|
| D015267 | Churg-Strauss Syndrome |
| D011657 | Pulmonary Eosinophilia |
| D057765 | Eosinophilic Esophagitis |
| ID | Term |
|---|---|
| D056648 | Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis |
| D056647 | Systemic Vasculitis |
| D014657 | Vasculitis |
| D014652 | Vascular Diseases |
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Blood samples
|
| Granulocyte Immunofluorescence | Diagnostic Test | The presence of auto-antibodies in patient serum to inactive and activated neutrophils / eosinophils, with and without post-translational modification, will be examined by indirect immunofluorescence. |
|
| London |
| EC1A 7BE |
| United Kingdom |
| BG002 | EGPA | Patients with asthma meeting criteria for a diagnosis of EGPA (eosinophilic granulomatosis with polyangiitis) |
| BG003 | Other Respiratory Conditions | Mild-to-moderate asthma, other vasculitides, eosinophilic COPD, and/or eosinophilic oesophagitis |
| BG004 | Total | Total of all reporting groups |
| Count of Participants |
| Participants |
|
| Age, Continuous | Age for one Healthy control patient not available | Mean | Standard Deviation | years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Race/Ethnicity, Customized | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
| OG001 | Healthy Controls | Healthy patients with no chronic lung condition. |
| OG002 | EGPA | Patients with asthma meeting criteria for a diagnosis of EGPA (eosinophilic granulomatosis with polyangiitis) |
| OG003 | Other Respiratory Conditions | Mild-to-moderate asthma, other vasculitides, eosinophilic COPD, and/or eosinophilic oesophagitis |
|
|
| Secondary | Number and Percentage of Patients With Positive Granulocyte Immunofluorescence | FITC anti-IgG immunofluorescence with slides of unstimulated/PMA-stimulated neutrophils (serum samples) | EGPA and Other respiratory conditions arms included as reference populations, with some patients purposefully recruited due to known anti-MPO status (potential selection bias). 46 Severe eosinophilic asthma patients, 23 Healthy control participants, 12 EGPA patients and 10 patients with Other Respiratory Conditions excluded from outcome due to missing data (only limited samples were tested). | Posted | Count of Participants | Participants | Baseline, at study entry |
|
|
|
| Post-Hoc | Percentage of Total Unique BCR Sequences Being of IgA1 Subclass | Peripheral blood B Cell Receptor (BCR) bulkRNA repertoire sequencing | Peripheral blood samples for sequencing were only available for a proportion of participants. 60 participants were chosen for this post-hoc analysis to represent a range of SEA/EGPA patients and healthy controls. Sequencing from 1 sample did not reach quality control criteria resulting in 59 samples reported. No participants with Other respiratory conditions were analysed for this post-hoc outcome as these were not the population of interest for this post-hoc outcome measure. | Posted | Mean | Standard Deviation | Percentage of unique BCR sequences | Baseline, at study entry |
|
|
|
| Post-Hoc | Percentage of Total Unique BCR Sequences Being of IgA2 Subclass | Peripheral blood B Cell Receptor (BCR) bulkRNA repertoire sequencing | Peripheral blood samples for sequencing were only available for a proportion of participants. 60 participants were chosen for this post-hoc analysis to represent a range of SEA/EGPA patients and healthy controls. Sequencing from 1 sample did not reach quality control criteria resulting in 59 samples reported. No participants with Other respiratory conditions were analysed for this post-hoc outcome as these were not the population of interest for this post-hoc outcome measure. | Posted | Mean | Standard Deviation | Percentage of unique BCR sequences | Baseline, at study entry |
|
|
|
| Post-Hoc | Percentage of Total Unique BCR Sequences Being of IgG1 Subclass | Peripheral blood B Cell Receptor (BCR) bulkRNA repertoire sequencing | Peripheral blood samples for sequencing were only available for a proportion of participants. 60 participants were chosen for this post-hoc analysis to represent a range of SEA/EGPA patients and healthy controls. Sequencing from 1 sample did not reach quality control criteria resulting in 59 samples reported. No participants with Other respiratory conditions were analysed for this post-hoc outcome as these were not the population of interest for this post-hoc outcome measure. | Posted | Mean | Standard Deviation | Percentage of unique BCR sequences | Baseline, at study entry |
|
|
|
| Post-Hoc | Percentage of Total Unique BCR Sequences Being of IgG2 Subclass | Peripheral blood B Cell Receptor (BCR) bulkRNA repertoire sequencing | Peripheral blood samples for sequencing were only available for a proportion of participants. 60 participants were chosen for this post-hoc analysis to represent a range of SEA/EGPA patients and healthy controls. Sequencing from 1 sample did not reach quality control criteria resulting in 59 samples reported. No participants with Other respiratory conditions were analysed for this post-hoc outcome as these were not the population of interest for this post-hoc outcome measure. | Posted | Mean | Standard Deviation | Percentage of unique BCR sequences | Baseline, at study entry |
|
|
|
| Post-Hoc | Percentage of Total Unique BCR Sequences Being of IgG3 Subclass | Peripheral blood B Cell Receptor (BCR) bulkRNA repertoire sequencing | Peripheral blood samples for sequencing were only available for a proportion of participants. 60 participants were chosen for this post-hoc analysis to represent a range of SEA/EGPA patients and healthy controls. Sequencing from 1 sample did not reach quality control criteria resulting in 59 samples reported. No participants with Other respiratory conditions were analysed for this post-hoc outcome as these were not the population of interest for this post-hoc outcome measure. | Posted | Mean | Standard Deviation | Percentage of unique BCR sequences | Baseline, at study entry |
|
|
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| Post-Hoc | Percentage of Total Unique BCR Sequences Being of IgG4 Subclass | Peripheral blood B Cell Receptor (BCR) bulkRNA repertoire sequencing | Peripheral blood samples for sequencing were only available for a proportion of participants. 60 participants were chosen for this post-hoc analysis to represent a range of SEA/EGPA patients and healthy controls. Sequencing from 1 sample did not reach quality control criteria resulting in 59 samples reported. No participants with Other respiratory conditions were analysed for this post-hoc outcome as these were not the population of interest for this post-hoc outcome measure. | Posted | Mean | Standard Deviation | Percentage of unique BCR sequences | Baseline, at study entry |
|
|
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| Post-Hoc | Percentage of Total Unique BCR Sequences Being of IgE Subclass | Peripheral blood B Cell Receptor (BCR) bulkRNA repertoire sequencing | Peripheral blood samples for sequencing were only available for a proportion of participants. 60 participants were chosen for this post-hoc analysis to represent a range of SEA/EGPA patients and healthy controls. Sequencing from 1 sample did not reach quality control criteria resulting in 59 samples reported. No participants with Other respiratory conditions were analysed for this post-hoc outcome as these were not the population of interest for this post-hoc outcome measure. | Posted | Mean | Standard Deviation | Percentage of unique BCR sequences | Baseline, at study entry |
|
|
|
| 0 |
| 63 |
| 0 |
| 63 |
| 0 |
| 63 |
| EG001 | Healthy Controls | Healthy patients with no chronic lung condition. | 0 | 30 | 0 | 30 | 0 | 30 |
| EG002 | EGPA | Patients with asthma meeting criteria for a diagnosis of EGPA (eosinophilic granulomatosis with polyangiitis) | 0 | 17 | 0 | 17 | 0 | 17 |
| EG003 | Other Respiratory Conditions | Milder asthma, other vasculitides, eosinophilic COPD, and/or eosinophilic oesophagitis | 0 | 9 | 0 | 9 | 0 | 9 |
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| D002318 | Cardiovascular Diseases |
| D006099 | Granuloma |
| D008232 | Lymphoproliferative Disorders |
| D008206 | Lymphatic Diseases |
| D006425 | Hemic and Lymphatic Diseases |
| D017445 | Skin Diseases, Vascular |
| D012871 | Skin Diseases |
| D017437 | Skin and Connective Tissue Diseases |
| D001327 | Autoimmune Diseases |
| D007154 | Immune System Diseases |
| D008171 | Lung Diseases |
| D012140 | Respiratory Tract Diseases |
| D017681 | Hypereosinophilic Syndrome |
| D004802 | Eosinophilia |
| D007960 | Leukocyte Disorders |
| D006402 | Hematologic Diseases |
| D004941 | Esophagitis |
| D004935 | Esophageal Diseases |
| D005767 | Gastrointestinal Diseases |
| D004066 | Digestive System Diseases |
| D005759 | Gastroenteritis |
| D006969 | Hypersensitivity, Immediate |
| D006967 | Hypersensitivity |
| Between 18 and 65 years |
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| >=65 years |
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| Male |
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| Asian |
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| Black |
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| Other / Declined / Not Available |
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