Cystic Fibrosis Blood Neutrophils

NCT04970225 | Completed

• 2 other identifiers: APHP1804302018-A03017-48
• Study Type: interventional
• Target: 47
• Locations: 1 country
• Sites: 1

Brief Summary

The purpose of this prospective study is to analyze function and phenotype of blood neutrophils in cystic fibrosis patients and the impact of Pseudomonas aeruginosa chronic infection, treatment with CFTR modulators and acute exacerbation on blood neutrophils phenotype and function.

Conditions

Cystic Fibrosis

Keywords

Blood neutrophils; Pseudomonas aeruginosa; Cystic fibrosis; CFTR modulators; respiratory exacerbation; airway chronic infection

Outcome Measures

Primary Outcomes (5)

• Quantification of blood low density neutrophils in cystic fibrosis (CF)

  Quantitative flow cytometric evaluation of neutrophil membrane markers that differ according to whether they are : * mature neutrophils : CD16high, CD15high, CD33high, CD10high * or Low density neutrophils (LDG) : CD16low, CD15neg, CD33 neg, CD10 neg. Comparison of neutrophil membrane markers profile in CF patients versus control blood-donors.

  Through study completion, an average of 1 year

• Transcriptomic analysis of blood neutrophils in cystic fibrosis (CF)

  Transcriptomic analysis of blood neutrophil proinflammatory or immunomodulatory potential. Comparison of transcriptomic blood neutrophil profile in CF patients versus control blood-donors.

  Through study completion, an average of 1 year

• Effector function analysis of blood neutrophils in CF.

  Comparison of effector function analysis of blood neutrophils of CF patients versus control blood-donors.

  Through study completion, an average of 1 year

• Phagocytosis potential of blood neutrophils in CF.

  Comparison of phagocytosis potential of blood neutrophils of CF patients versus control blood-donors.

  Through study completion, an average of 1 year

• Survival/apoptosis balance analysis in CF

  Survival / apoptosis balance analysis : (PCNA localization) in CF patients blood neutrophils versus control blood-donors.

  Through study completion, an average of 1 year

Secondary Outcomes (6)

• Quantification of blood low density neutrophils in CF vs other chronic inflammatory disorders.

  Through study completion, an average of 1 year

• Quantification of blood low density neutrophils in CF according to different clinical situations.

  Through study completion, an average of 1 year

• Transcriptomic analysis of blood neutrophils in CF according to different clinical situations.

  Through study completion, an average of 1 year

• Effector function analysis of blood neutrophils in CF according to different clinical situations.

  Through study completion, an average of 1 year

• Phagocytosis potential of blood neutrophils in CF according to different clinical situations.

  Through study completion, an average of 1 year

Study Arms (3)

Stable state

EXPERIMENTAL

45 adult cystic fibrosis patients followed in the respiratory medicine department of Cochin hospital, paris, France: * With severe cftr mutations * With or without PA chronic infection * Treated or not with Ivacaftor-Lumacaftor

Other: 1 blood sample

Starting Ivacaftor-Tezacaftor-Elexacaftor

EXPERIMENTAL

40 adult cystic fibrosis patients followed in the respiratory medicine department of Cochin hospital, paris, France: * With at least one severe cftr mutation * With or without PA chronic infection * Initiating Ivacaftor-Tezacaftor-Elexacaftor

Other: 2 blood samples

Exacerbation

EXPERIMENTAL

15 adult cystic fibrosis patients followed in the respiratory medicine department of Cochin hospital, paris, France and hospitalized for respiratory exacerbation

Other: 2 blood samples

Interventions

1 blood sample OTHER

4 tubes of 7 ml per sample (a single sample)

Stable state

2 blood samples OTHER

4 tubes of 7 ml per sample / 2 samples : before / after antibiotic treatment

Exacerbation; Starting Ivacaftor-Tezacaftor-Elexacaftor

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Patient over the age of 18 who is not under legal protection
• Patients with CF according to the diagnostic criteria of the Cystic Fibrosis Foundation including:
• patients with severe mutation but not chronically infected with PA and not treated with lumacaftor / ivacaftor
• patients homozygous phe508del, chronically infected with PA and not treated with lumacaftor / ivacaftor
• patients homozygous phe508del, chronically infected with PA and treated with lumacaftor / ivacaftor
• hospitalized patients for respiratory exacerbation
• patients initiating Ivacaftor-Tezacaftor-Elexacaftor treatment.
• No change in baseline treatment for 15 days (including antibiotic treatment).
• Patient affiliated to a social security system

You may not qualify if:

• Informed consent impossible to obtain

Sponsors & Collaborators

• Assistance Publique - Hôpitaux de Paris: lead
• Institut National de la Santé Et de la Recherche Médicale, France: collaborator
• URC-CIC Paris Descartes Necker Cochin: collaborator

Study Sites (1)

Cochin hospital, AP-HP

Paris, 75014, France

Location

Related Publications (44)

• Wright R, Keller G, Gould SJ, Subramani S, Rine J. Cell-type control of membrane biogenesis induced by HMG-CoA reductase. New Biol. 1990 Oct;2(10):915-21.

  PMID: 2078559 BACKGROUND

• Bonvillain RW, Painter RG, Adams DE, Viswanathan A, Lanson NA Jr, Wang G. RNA interference against CFTR affects HL60-derived neutrophil microbicidal function. Free Radic Biol Med. 2010 Dec 15;49(12):1872-80. doi: 10.1016/j.freeradbiomed.2010.09.012. Epub 2010 Sep 24.

  PMID: 20870018 BACKGROUND

• Bouayad D, Pederzoli-Ribeil M, Mocek J, Candalh C, Arlet JB, Hermine O, Reuter N, Davezac N, Witko-Sarsat V. Nuclear-to-cytoplasmic relocalization of the proliferating cell nuclear antigen (PCNA) during differentiation involves a chromosome region maintenance 1 (CRM1)-dependent export and is a prerequisite for PCNA antiapoptotic activity in mature neutrophils. J Biol Chem. 2012 Sep 28;287(40):33812-25. doi: 10.1074/jbc.M112.367839. Epub 2012 Jul 30.

  PMID: 22846997 BACKGROUND

• 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.

  PMID: 25977288 BACKGROUND

• Bulloch MN, Hanna C, Giovane R. Lumacaftor/ivacaftor, a novel agent for the treatment of cystic fibrosis patients who are homozygous for the F580del CFTR mutation. Expert Rev Clin Pharmacol. 2017 Oct;10(10):1055-1072. doi: 10.1080/17512433.2017.1378094. Epub 2017 Sep 22.

  PMID: 28891346 BACKGROUND

• Chiara AD, Pederzoli-Ribeil M, Burgel PR, Danel C, Witko-Sarsat V. Targeting cytosolic proliferating cell nuclear antigen in neutrophil-dominated inflammation. Front Immunol. 2012 Oct 9;3:311. doi: 10.3389/fimmu.2012.00311. eCollection 2012.

  PMID: 23181059 BACKGROUND

• Cantin A. Cystic fibrosis lung inflammation: early, sustained, and severe. Am J Respir Crit Care Med. 1995 Apr;151(4):939-41. doi: 10.1164/ajrccm.151.4.7697269. No abstract available.

  PMID: 7697269 BACKGROUND

• Vaz WL, Nisksch A, Jahnig F. Electrostatic interactions at charged lipid membranes. Measurement of surface pH with fluorescent lipoid pH indicators. Eur J Biochem. 1978 Feb 1;83(1):299-305. doi: 10.1111/j.1432-1033.1978.tb12094.x.

  PMID: 23947 BACKGROUND

• Downey DG, Bell SC, Elborn JS. Neutrophils in cystic fibrosis. Thorax. 2009 Jan;64(1):81-8. doi: 10.1136/thx.2007.082388.

  PMID: 19103874 BACKGROUND

• Fadok VA, Bratton DL, Henson PM. Phagocyte receptors for apoptotic cells: recognition, uptake, and consequences. J Clin Invest. 2001 Oct;108(7):957-62. doi: 10.1172/JCI14122. No abstract available.

  PMID: 11581295 BACKGROUND

• Futosi K, Mocsai A. Tyrosine kinase signaling pathways in neutrophils. Immunol Rev. 2016 Sep;273(1):121-39. doi: 10.1111/imr.12455.

  PMID: 27558332 BACKGROUND

• Gilroy DW, Lawrence T, Perretti M, Rossi AG. Inflammatory resolution: new opportunities for drug discovery. Nat Rev Drug Discov. 2004 May;3(5):401-16. doi: 10.1038/nrd1383. No abstract available.

  PMID: 15136788 BACKGROUND

• Hayes E, Pohl K, McElvaney NG, Reeves EP. The cystic fibrosis neutrophil: a specialized yet potentially defective cell. Arch Immunol Ther Exp (Warsz). 2011 Apr;59(2):97-112. doi: 10.1007/s00005-011-0113-6. Epub 2011 Feb 11.

  PMID: 21311988 BACKGROUND

• Khan TZ, Wagener JS, Bost T, Martinez J, Accurso FJ, Riches DW. Early pulmonary inflammation in infants with cystic fibrosis. Am J Respir Crit Care Med. 1995 Apr;151(4):1075-82. doi: 10.1164/ajrccm/151.4.1075.

  PMID: 7697234 BACKGROUND

• Koenderman L, Chilvers ER. Future treatment in patients with chronic obstructive pulmonary disease: to reverse or not to reverse steroid resistance-that is the question. J Allergy Clin Immunol. 2014 Aug;134(2):323-4. doi: 10.1016/j.jaci.2014.04.030. Epub 2014 Jun 13. No abstract available.

  PMID: 24934274 BACKGROUND

• Laval J, Touhami J, Herzenberg LA, Conrad C, Taylor N, Battini JL, Sitbon M, Tirouvanziam R. Metabolic adaptation of neutrophils in cystic fibrosis airways involves distinct shifts in nutrient transporter expression. J Immunol. 2013 Jun 15;190(12):6043-50. doi: 10.4049/jimmunol.1201755. Epub 2013 May 20.

  PMID: 23690474 BACKGROUND

• Leliefeld PH, Koenderman L, Pillay J. How Neutrophils Shape Adaptive Immune Responses. Front Immunol. 2015 Sep 14;6:471. doi: 10.3389/fimmu.2015.00471. eCollection 2015.

  PMID: 26441976 BACKGROUND

• Mantovani A, Cassatella MA, Costantini C, Jaillon S. Neutrophils in the activation and regulation of innate and adaptive immunity. Nat Rev Immunol. 2011 Jul 25;11(8):519-31. doi: 10.1038/nri3024.

  PMID: 21785456 BACKGROUND

• Martin C, Ohayon D, Alkan M, Mocek J, Pederzoli-Ribeil M, Candalh C, Thevenot G, Millet A, Tamassia N, Cassatella MA, Thieblemont N, Burgel PR, Witko-Sarsat V. Neutrophil-Expressed p21/waf1 Favors Inflammation Resolution in Pseudomonas aeruginosa Infection. Am J Respir Cell Mol Biol. 2016 May;54(5):740-50. doi: 10.1165/rcmb.2015-0047OC.

  PMID: 26517580 BACKGROUND

• McKeon DJ, Condliffe AM, Cowburn AS, Cadwallader KC, Farahi N, Bilton D, Chilvers ER. Prolonged survival of neutrophils from patients with Delta F508 CFTR mutations. Thorax. 2008 Jul;63(7):660-1. doi: 10.1136/thx.2008.096834. No abstract available.

  PMID: 18587042 BACKGROUND

• Meijer L, Nelson DJ, Riazanski V, Gabdoulkhakova AG, Hery-Arnaud G, Le Berre R, Loaec N, Oumata N, Galons H, Nowak E, Gueganton L, Dorothee G, Prochazkova M, Hall B, Kulkarni AB, Gray RD, Rossi AG, Witko-Sarsat V, Norez C, Becq F, Ravel D, Mottier D, Rault G. Modulating Innate and Adaptive Immunity by (R)-Roscovitine: Potential Therapeutic Opportunity in Cystic Fibrosis. J Innate Immun. 2016;8(4):330-49. doi: 10.1159/000444256. Epub 2016 Mar 18.

  PMID: 26987072 BACKGROUND

• Moriceau S, Kantari C, Mocek J, Davezac N, Gabillet J, Guerrera IC, Brouillard F, Tondelier D, Sermet-Gaudelus I, Danel C, Lenoir G, Daniel S, Edelman A, Witko-Sarsat V. Coronin-1 is associated with neutrophil survival and is cleaved during apoptosis: potential implication in neutrophils from cystic fibrosis patients. J Immunol. 2009 Jun 1;182(11):7254-63. doi: 10.4049/jimmunol.0803312.

  PMID: 19454722 BACKGROUND

• Moriceau S, Lenoir G, Witko-Sarsat V. In cystic fibrosis homozygotes and heterozygotes, neutrophil apoptosis is delayed and modulated by diamide or roscovitine: evidence for an innate neutrophil disturbance. J Innate Immun. 2010;2(3):260-6. doi: 10.1159/000295791. Epub 2010 Mar 10.

  PMID: 20375556 BACKGROUND

• Ohayon D, De Chiara A, Chapuis N, Candalh C, Mocek J, Ribeil JA, Haddaoui L, Ifrah N, Hermine O, Bouillaud F, Frachet P, Bouscary D, Witko-Sarsat V. Cytoplasmic proliferating cell nuclear antigen connects glycolysis and cell survival in acute myeloid leukemia. Sci Rep. 2016 Oct 19;6:35561. doi: 10.1038/srep35561.

  PMID: 27759041 BACKGROUND

• Peranzoni E, Zilio S, Marigo I, Dolcetti L, Zanovello P, Mandruzzato S, Bronte V. Myeloid-derived suppressor cell heterogeneity and subset definition. Curr Opin Immunol. 2010 Apr;22(2):238-44. doi: 10.1016/j.coi.2010.01.021. Epub 2010 Feb 17.

  PMID: 20171075 BACKGROUND

• Pillay J, Kamp VM, van Hoffen E, Visser T, Tak T, Lammers JW, Ulfman LH, Leenen LP, Pickkers P, Koenderman L. A subset of neutrophils in human systemic inflammation inhibits T cell responses through Mac-1. J Clin Invest. 2012 Jan;122(1):327-36. doi: 10.1172/JCI57990. Epub 2011 Dec 12.

  PMID: 22156198 BACKGROUND

• 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.

  PMID: 20400675 BACKGROUND

• Pillay J, Tak T, Kamp VM, Koenderman L. Immune suppression by neutrophils and granulocytic myeloid-derived suppressor cells: similarities and differences. Cell Mol Life Sci. 2013 Oct;70(20):3813-27. doi: 10.1007/s00018-013-1286-4. Epub 2013 Feb 20.

  PMID: 23423530 BACKGROUND

• Rossi AG, Sawatzky DA, Walker A, Ward C, Sheldrake TA, Riley NA, Caldicott A, Martinez-Losa M, Walker TR, Duffin R, Gray M, Crescenzi E, Martin MC, Brady HJ, Savill JS, Dransfield I, Haslett C. Cyclin-dependent kinase inhibitors enhance the resolution of inflammation by promoting inflammatory cell apoptosis. Nat Med. 2006 Sep;12(9):1056-64. doi: 10.1038/nm1468. Epub 2006 Sep 3.

  PMID: 16951685 BACKGROUND

• Scapini P, Marini O, Tecchio C, Cassatella MA. Human neutrophils in the saga of cellular heterogeneity: insights and open questions. Immunol Rev. 2016 Sep;273(1):48-60. doi: 10.1111/imr.12448.

  PMID: 27558327 BACKGROUND

• Uhel F, Azzaoui I, Gregoire M, Pangault C, Dulong J, Tadie JM, Gacouin A, Camus C, Cynober L, Fest T, Le Tulzo Y, Roussel M, Tarte K. Early Expansion of Circulating Granulocytic Myeloid-derived Suppressor Cells Predicts Development of Nosocomial Infections in Patients with Sepsis. Am J Respir Crit Care Med. 2017 Aug 1;196(3):315-327. doi: 10.1164/rccm.201606-1143OC.

  PMID: 28146645 BACKGROUND

• Warbrick E. A functional analysis of PCNA-binding peptides derived from protein sequence, interaction screening and rational design. Oncogene. 2006 May 11;25(20):2850-9. doi: 10.1038/sj.onc.1209320.

  PMID: 16407840 BACKGROUND

• Witko-Sarsat V. Neutrophils in the innate immunity conundrum of cystic fibrosis: a CFTR-related matter? J Innate Immun. 2013;5(3):195-6. doi: 10.1159/000350215. Epub 2013 Mar 23. No abstract available.

  PMID: 23548924 BACKGROUND

• Witko-Sarsat V, Allen RC, Paulais M, Nguyen AT, Bessou G, Lenoir G, Descamps-Latscha B. Disturbed myeloperoxidase-dependent activity of neutrophils in cystic fibrosis homozygotes and heterozygotes, and its correction by amiloride. J Immunol. 1996 Sep 15;157(6):2728-35.

  PMID: 8805680 BACKGROUND

• Witko-Sarsat V, Cramer EM, Hieblot C, Guichard J, Nusbaum P, Lopez S, Lesavre P, Halbwachs-Mecarelli L. Presence of proteinase 3 in secretory vesicles: evidence of a novel, highly mobilizable intracellular pool distinct from azurophil granules. Blood. 1999 Oct 1;94(7):2487-96.

  PMID: 10498622 BACKGROUND

• Witko-Sarsat V, Halbwachs-Mecarelli L, Sermet-Gaudelus I, Bessou G, Lenoir G, Allen RC, Descamps-Latscha B. Priming of blood neutrophils in children with cystic fibrosis: correlation between functional and phenotypic expression of opsonin receptors before and after platelet-activating factor priming. J Infect Dis. 1999 Jan;179(1):151-62. doi: 10.1086/314532.

  PMID: 9841834 BACKGROUND

• Witko-Sarsat V, Mocek J, Bouayad D, Tamassia N, Ribeil JA, Candalh C, Davezac N, Reuter N, Mouthon L, Hermine O, Pederzoli-Ribeil M, Cassatella MA. Proliferating cell nuclear antigen acts as a cytoplasmic platform controlling human neutrophil survival. J Exp Med. 2010 Nov 22;207(12):2631-45. doi: 10.1084/jem.20092241. Epub 2010 Oct 25.

  PMID: 20975039 BACKGROUND

• Witko-Sarsat V, Ohayon D. Proliferating cell nuclear antigen in neutrophil fate. Immunol Rev. 2016 Sep;273(1):344-56. doi: 10.1111/imr.12449.

  PMID: 27558345 BACKGROUND

• Witko-Sarsat V, Pederzoli-Ribeil M, Hirsch E, Sozzani S, Cassatella MA. Regulating neutrophil apoptosis: new players enter the game. Trends Immunol. 2011 Mar;32(3):117-24. doi: 10.1016/j.it.2011.01.001. Epub 2011 Feb 12.

  PMID: 21317039 BACKGROUND

• Witko-Sarsat V, Rieu P, Descamps-Latscha B, Lesavre P, Halbwachs-Mecarelli L. Neutrophils: molecules, functions and pathophysiological aspects. Lab Invest. 2000 May;80(5):617-53. doi: 10.1038/labinvest.3780067. No abstract available.

  PMID: 10830774 BACKGROUND

• Witko-Sarsat V, Sermet-Gaudelus I, Lenoir G, Descamps-Latscha B. Inflammation and CFTR: might neutrophils be the key in cystic fibrosis? Mediators Inflamm. 1999;8(1):7-11. doi: 10.1080/09629359990658.

  PMID: 10704083 BACKGROUND

• Worlitzsch D, Tarran R, Ulrich M, Schwab U, Cekici A, Meyer KC, Birrer P, Bellon G, Berger J, Weiss T, Botzenhart K, Yankaskas JR, Randell S, Boucher RC, Doring G. Effects of reduced mucus oxygen concentration in airway Pseudomonas infections of cystic fibrosis patients. J Clin Invest. 2002 Feb;109(3):317-25. doi: 10.1172/JCI13870.

  PMID: 11827991 BACKGROUND

• Wright HL, Makki FA, Moots RJ, Edwards SW. Low-density granulocytes: functionally distinct, immature neutrophils in rheumatoid arthritis with altered properties and defective TNF signalling. J Leukoc Biol. 2017 Feb;101(2):599-611. doi: 10.1189/jlb.5A0116-022R. Epub 2016 Sep 6.

  PMID: 27601627 BACKGROUND

• Heijerman HGM, McKone EF, Downey DG, Van Braeckel E, Rowe SM, Tullis E, Mall MA, Welter JJ, Ramsey BW, McKee CM, Marigowda G, Moskowitz SM, Waltz D, Sosnay PR, Simard C, Ahluwalia N, Xuan F, Zhang Y, Taylor-Cousar JL, McCoy KS; VX17-445-103 Trial Group. Efficacy and safety of the elexacaftor plus tezacaftor plus ivacaftor combination regimen in people with cystic fibrosis homozygous for the F508del mutation: a double-blind, randomised, phase 3 trial. Lancet. 2019 Nov 23;394(10212):1940-1948. doi: 10.1016/S0140-6736(19)32597-8. Epub 2019 Oct 31.

  PMID: 31679946 BACKGROUND

MeSH Terms

Conditions

Cystic Fibrosis; Pseudomonas Infections

Condition Hierarchy (Ancestors)

Pancreatic Diseases; Digestive System Diseases; Lung Diseases; Respiratory Tract Diseases; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Infant, Newborn, Diseases; Gram-Negative Bacterial Infections; Bacterial Infections; Bacterial Infections and Mycoses; Infections

Study Officials

• Pierre-Régis BURGEL, MD PHD

  APHP

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: BASIC SCIENCE
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 17, 2019
• First Posted: July 21, 2021
• Study Start: July 8, 2021
• Primary Completion: April 6, 2023
• Study Completion: January 8, 2025
• Last Updated: September 12, 2025

Record last verified: 2025-09

Data Sharing

• IPD Sharing: Will not share

Locations

FR (1)