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CompletedNCT03479138ANNEUpdated Jan 11, 2024

Non-Eosinophilic Neutrophilic Asthma

An observational study in Neutrophilic Asthma, sponsored by Fundació Institut de Recerca de l'Hospital de la Santa Creu i Sant Pau. Completed at 2 sites in Spain. Open to participants aged 18 Years to 80 Years. Per ClinicalTrials.gov, last updated 2024-01-11.

Sponsored by Fundació Institut de Recerca de l'Hospital de la Santa Creu i Sant Pau · Observational

Study type
Observational
Model
Cohort
Time perspective
Prospective
Enrollment
10
Ages
18 Years to 80 Years
Sex
All
01

Study summary

Define and characterize the neutrophilic phenotype of severe asthma.

Read the detailed description

Neutrophilic asthma (NA) is the asthma phenotype less known, causes a severe disease and does not have a specific treatment. Research on the neutrophilia mechanisms, new neutrophil (NEU) types and bronchial microbiome, can provide an opportunity to better understand the NA pathogenesis.

OBJECTIVES: 1. To describe the clinical characteristics of NA and its sub-phenotypes (SUBSTUDY 1); 2. To determine the NEU types associated with the NA and its sub-phenotypes (SUBSTUDY 2); and 3. To identify the bronchial microbiological flora of the NA, specifically related to lung microbiome and the immune response against Chlamydia Pneumoniae (SUBSTUDY 3).

METHODS: Multicenter prospective study including 100 patients with severe asthma (GINA/GEMA criteria): 50 with non-neutrophilic asthma (\<65% NEU in induced sputum [IS]); and 50 with NA (> 64% NEU in IS). SUBSTUDY 1: clinical variables (years of evolution, exacerbations, asthma control test, mini asthma quality of life questionnary), comorbidities (GERD, nasal polyposis, obesity, ASS), pulmonary function (FEV1, exhaled fraction of nitric oxide, total lung capacity, Aspergillus), prick-test and CT scan chest; SUBSTUDY 2 (in IS and plasma): apoptotic index by means NE culture and flux cytometer (Annexin-V-FITC), NEU phenotype by surface markers (CD16, CD66b, CD62L, HLADR, CD177, CD11b, CD63, CXCR2, CXCR4) with density gradient study and determination of cytokines (IL-6, IL-8, IL-17, IL-1, IL-22) by ELISA; SUBSTUDY 3 (in IS): bronchial microbiome for 16 subunit rRNA by Phylogenetic Investigation of Communities by Reconstruction of Unobserved States (PICRUSt), and anti-Chlamydia Pneumoniae Immunoglobuling A by ELISA.

02

Conditions studied

  • Neutrophilic Asthma

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Keywords

  • severe asthma
  • induced sputum
  • asthma phenotypes
  • neutrophilic inflammation
  • microbiome
03

Who can participate

Ages eligible
18 Years to 80 Years
Sexes eligible
All
Accepts healthy volunteers
No
Sampling method
Non-probability sample

Study population

Patients bewteen 18-80 years with severe asthma.

Inclusion criteria

  • 18 - 80 years old
  • Confirmed diagnosis of asthma (according to spanish guideline GEMA)
  • Severe persistent asthma (step 5-6 GEMA)
  • Eosinophils\<300/mm3 in peripheral blood

Exclusion criteria

Exclusion Criteria:

  • Respiratory infection during the previous month
  • Significant lung pathology not attributable to asthma (bronchiectasis with Reiff score>3)
04

Study design

Observational model
Cohort
Time perspective
Prospective
Enrollment
10 participants (actual)
Patient registry
No
Biospecimen retention
Samples without dna

Groups and cohorts

  • Neutrophilic asthma

    Patients 18 to 80 years old diagnosed of severe asthma, requiring treatment at least with long acting beta agonists (LABA) + high doses inhaled corticosteroids (ICS) with eosinophil count in blood\<300/mm3. They must be ex-smokers with less than 10 packs-year and no other relevant pulmonary disease.

    Diagnostic Test: Induced sputum

  • Non neutrophilic asthma

    Patients 18 to 80 years old diagnosed of severe asthma, requiring treatment at least with LABA+ high doses ICS, with eosinophil count in blood\<300/mm3. They must be ex-smokers with less than 10 packs-year and no other relevant pulmonary disease.

    Diagnostic Test: Induced sputum

Interventions

  • Diagnostic testInduced sputum

    Characterization with flow cytometry of the phenotype of the neutrophils isolated in the sputum, microbiome

05

What researchers measure

Primary outcomes

  1. Phenotype of neutrophils

    To determine the types of neutrophils (in induced sputum and blood) associated with neutrophilic asthma and its subphenotypes according to flow cytometry

    Time frame: 24 hours

  2. Microbiome analysis

    To analyse the bronchial microbiological flora of neutrophilic asthma

    Time frame: 6 months

Secondary outcomes

  1. Clinical demographic characteristics

    To describe the clinical characteristics and natural history of the neutrophilic asthma and its subphenotypes

    Time frame: 1 year

  2. Demographic characteristics

    To describe demographic characteristics

    Time frame: 1 year

06

Study locations

2 sites
  • Hospital de la Santa Creu i Sant Pau. Carrer Mas Casanovas 90.
    Barcelona, 08041, Spain
  • Hospital de la Santa Creu i Sant Pau
    Barcelona, 08041, Spain
07

References and documents

Publications

  • Nair P, Aziz-Ur-Rehman A, Radford K. Therapeutic implications of 'neutrophilic asthma'. Curr Opin Pulm Med. 2015 Jan;21(1):33-8. doi: 10.1097/MCP.0000000000000120. PubMed 25415406 ↗
  • Wenzel SE, Szefler SJ, Leung DY, Sloan SI, Rex MD, Martin RJ. Bronchoscopic evaluation of severe asthma. Persistent inflammation associated with high dose glucocorticoids. Am J Respir Crit Care Med. 1997 Sep;156(3 Pt 1):737-43. doi: 10.1164/ajrccm.156.3.9610046. PubMed 9309987 ↗
  • Simpson JL, Baines KJ, Ryan N, Gibson PG. Neutrophilic asthma is characterised by increased rhinosinusitis with sleep disturbance and GERD. Asian Pac J Allergy Immunol. 2014 Mar;32(1):66-74. doi: 10.12932/AP0322.32.1.2014. PubMed 24641293 ↗
  • Shaw DE, Berry MA, Hargadon B, McKenna S, Shelley MJ, Green RH, Brightling CE, Wardlaw AJ, Pavord ID. Association between neutrophilic airway inflammation and airflow limitation in adults with asthma. Chest. 2007 Dec;132(6):1871-5. doi: 10.1378/chest.07-1047. Epub 2007 Oct 9. PubMed 17925424 ↗
  • Wenzel SE. Asthma phenotypes: the evolution from clinical to molecular approaches. Nat Med. 2012 May 4;18(5):716-25. doi: 10.1038/nm.2678. PubMed 22561835 ↗
  • Simpson JL, Powell H, Boyle MJ, Scott RJ, Gibson PG. Clarithromycin targets neutrophilic airway inflammation in refractory asthma. Am J Respir Crit Care Med. 2008 Jan 15;177(2):148-55. doi: 10.1164/rccm.200707-1134OC. Epub 2007 Oct 18. PubMed 17947611 ↗
  • Polosa R, Thomson NC. Smoking and asthma: dangerous liaisons. Eur Respir J. 2013 Mar;41(3):716-26. doi: 10.1183/09031936.00073312. Epub 2012 Aug 16. PubMed 22903959 ↗
  • Sutherland ER, Martin RJ. Asthma and atypical bacterial infection. Chest. 2007 Dec;132(6):1962-6. doi: 10.1378/chest.06-2415. PubMed 18079229 ↗
  • Uddin M, Nong G, Ward J, Seumois G, Prince LR, Wilson SJ, Cornelius V, Dent G, Djukanovic R. Prosurvival activity for airway neutrophils in severe asthma. Thorax. 2010 Aug;65(8):684-9. doi: 10.1136/thx.2009.120741. PubMed 20685741 ↗
  • Newcomb DC, Peebles RS Jr. Th17-mediated inflammation in asthma. Curr Opin Immunol. 2013 Dec;25(6):755-60. doi: 10.1016/j.coi.2013.08.002. Epub 2013 Sep 11. PubMed 24035139 ↗
  • Chesne J, Braza F, Mahay G, Brouard S, Aronica M, Magnan A. IL-17 in severe asthma. Where do we stand? Am J Respir Crit Care Med. 2014 Nov 15;190(10):1094-101. doi: 10.1164/rccm.201405-0859PP. PubMed 25162311 ↗
  • Bruijnzeel PL, Uddin M, Koenderman L. Targeting neutrophilic inflammation in severe neutrophilic asthma: can we target the disease-relevant neutrophil phenotype? J Leukoc Biol. 2015 Oct;98(4):549-56. doi: 10.1189/jlb.3VMR1214-600RR. Epub 2015 May 14. PubMed 25977288 ↗
  • Pillay J, Ramakers BP, Kamp VM, Loi AL, Lam SW, Hietbrink F, Leenen LP, Tool AT, Pickkers P, Koenderman L. Functional heterogeneity and differential priming of circulating neutrophils in human experimental endotoxemia. J Leukoc Biol. 2010 Jul;88(1):211-20. doi: 10.1189/jlb.1209793. Epub 2010 Apr 16. PubMed 20400675 ↗
  • Beyrau M, Bodkin JV, Nourshargh S. Neutrophil heterogeneity in health and disease: a revitalized avenue in inflammation and immunity. Open Biol. 2012 Nov;2(11):120134. doi: 10.1098/rsob.120134. PubMed 23226600 ↗
  • Green BJ, Wiriyachaiporn S, Grainge C, Rogers GB, Kehagia V, Lau L, Carroll MP, Bruce KD, Howarth PH. Potentially pathogenic airway bacteria and neutrophilic inflammation in treatment resistant severe asthma. PLoS One. 2014 Jun 23;9(6):e100645. doi: 10.1371/journal.pone.0100645. eCollection 2014. PubMed 24955983 ↗
  • Kiley JP, Caler EV. The lung microbiome. A new frontier in pulmonary medicine. Ann Am Thorac Soc. 2014 Jan;11 Suppl 1(Suppl 1):S66-70. doi: 10.1513/AnnalsATS.201308-285MG. No abstract available. PubMed 24437410 ↗
  • Marri PR, Stern DA, Wright AL, Billheimer D, Martinez FD. Asthma-associated differences in microbial composition of induced sputum. J Allergy Clin Immunol. 2013 Feb;131(2):346-52.e1-3. doi: 10.1016/j.jaci.2012.11.013. Epub 2012 Dec 23. PubMed 23265859 ↗
  • Huang YJ, Nariya S, Harris JM, Lynch SV, Choy DF, Arron JR, Boushey H. The airway microbiome in patients with severe asthma: Associations with disease features and severity. J Allergy Clin Immunol. 2015 Oct;136(4):874-84. doi: 10.1016/j.jaci.2015.05.044. Epub 2015 Jul 26. PubMed 26220531 ↗
  • Martin RJ, Kraft M, Chu HW, Berns EA, Cassell GH. A link between chronic asthma and chronic infection. J Allergy Clin Immunol. 2001 Apr;107(4):595-601. doi: 10.1067/mai.2001.113563. PubMed 11295645 ↗
  • Brusselle GG, Vanderstichele C, Jordens P, Deman R, Slabbynck H, Ringoet V, Verleden G, Demedts IK, Verhamme K, Delporte A, Demeyere B, Claeys G, Boelens J, Padalko E, Verschakelen J, Van Maele G, Deschepper E, Joos GF. Azithromycin for prevention of exacerbations in severe asthma (AZISAST): a multicentre randomised double-blind placebo-controlled trial. Thorax. 2013 Apr;68(4):322-9. doi: 10.1136/thoraxjnl-2012-202698. Epub 2013 Jan 3. PubMed 23291349 ↗
  • Blasi F. Atypical pathogens and respiratory tract infections. Eur Respir J. 2004 Jul;24(1):171-81. doi: 10.1183/09031936.04.00135703. PubMed 15293621 ↗
  • Frehn L, Jansen A, Bennek E, Mandic AD, Temizel I, Tischendorf S, Verdier J, Tacke F, Streetz K, Trautwein C, Sellge G. Distinct patterns of IgG and IgA against food and microbial antigens in serum and feces of patients with inflammatory bowel diseases. PLoS One. 2014 Sep 12;9(9):e106750. doi: 10.1371/journal.pone.0106750. eCollection 2014. PubMed 25215528 ↗
  • Tuuminen T, Edelstein I, Punin A, Kislova N, Stratchounski L. Use of quantitative and objective enzyme immunoassays to investigate the possible association between Chlamydia pneumoniae and Mycoplasma pneumoniae antibodies and asthma. Clin Microbiol Infect. 2004 Apr;10(4):345-8. doi: 10.1111/j.1198-743X.2004.00822.x. PubMed 15059128 ↗

Individual participant data

Plan to share: Undecided

08

Registry details

Key details

Study ID
NCT03479138
Lead sponsor
Fundació Institut de Recerca de l'Hospital de la Santa Creu i Sant Pau
Collaborators
Spanish Clinical Research Network - SCReN
Responsible party
Sponsor
First posted
Mar 27, 2018
Start date
Feb 21, 2018
Primary completion
Jun 30, 2023
Completion
Jul 30, 2023
Last update
Jan 11, 2024

Oversight

Data monitoring committee
No
FDA-regulated drug
No
FDA-regulated device
No
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