Markers of Pulmonary Dysbiosis Associated With Exacerbation in Patients Followed for Cystic Fibrosis

Cystic Fibrosis Pulmonary Exacerbation Clinical Trial

— DYSBIOSE-CF  

Official title:

Markers of Pulmonary Dysbiosis Associated With Exacerbation in Patients Followed for Cystic Fibrosis

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT03569904
• Other study ID #: 38RC17.317
• Status: Recruiting
• Start date: October 2, 2018
• Est. completion date: December 2021

Study information

• Verified date: March 2020
• Source: University Hospital, Grenoble
• Contact: Boubou CAMARA, Dr
• Phone: +33(0)4 76 76 58 46
• Email: BCamara[@]chu-grenoble.fr
• Is FDA regulated: No
• Study type: Observational

Clinical Trial Summary

The aim objective is to identify markers of bacterial, viral and fungal pulmonary dysbiosis, associated with the occurrence of exacerbation in patients followed for cystic fibrosis.

The primary endpoint is the association between a modification of at least 10% of the relative abundance of a bacterial phylum (Proteobacteria, Firmicutes, Actinobacteria, Bacteroidetes, Fusobacteria) or fungal (ascomycetes / hemiascomycetes, basidiomycetes, zygomycetes), or viral, and the occurrence of exacerbations over a period of 12 months.

Description:

Therapeutic advances and the organization of care within the "CRCM" have led to an overall improvement in the management of cystic fibrosis. The protein therapies that have marked this progression only target certain genes and concern a small number of patients. The morbidity, mortality and social cost of cystic fibrosis are still considerable. Exacerbations modulate the prognosis of the disease.

We are interested in dysbiosis, which is the association of an imbalance in the composition and functions of commensal complex microbial communities and an alteration of the immune response of the host. It is involved in the development of chronic pulmonary pathologies such as cystic fibrosis Pulmonary microbiota and host responses mutually influence each other, and evidence suggests that changes in microbiota-host interactions play a major role in the evolution of chronic respiratory diseases. The response of the host may be partially measured by protein markers of inflammation or metabolites regulating inflammation (tryptophan metabolites).

Most microbiome studies focus on the bacterial microbiota, while other microorganisms such as fungi and viruses represent an important cofactor in the degradation of respiratory function. Viral dysbiosis probably plays a role in the appearance of exacerbation.

Among the few studies incorporating fungal risk, very few have considered the role of Pneumocystis jirovecii (PCJ). This non-culturable species was found in 12.5% of patients with cystic fibrosis and possibly associated with exacerbations. We will prospectively follow a cohort of cystic fibrosis patients by collecting clinical and microbiological data on various samples (exhaled air condensate (EAC), sputum and serum) on a quarterly basis and during episodes of exacerbations.

Our project will verify the hypothesis of a correlation between the microbiota, inflammation, and the production of metabolites regulating inflammation (dysbiosis), but also to determine what is the initial biological process leading to the exacerbation: dysbiosis induced by variation of the microbiota or dysbiosis induced by modification of host defense systems. In addition, unlike studies in this area, we will be interested in the bacterial, viral and fungal microbiota.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 30
• Est. completion date: December 2021
• Est. primary completion date: September 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: 12 Years and older

Eligibility

Inclusion Criteria:

• Patients with cystic fibrosis

• Patient agreeing to participate in the study

• Patient with at least 2 exacerbations in the year prior to inclusion (2 antimicrobial treatments at home or in hospital during the last 12 months)

• Patient or legal guardian of the patient able to read and understand the procedure and able to express his / her consent for the study protocol

• Stable patients, away from exacerbation (at 4 weeks from the beginning of exacerbation, found to be resolved by the investigator)

• Patient affiliated to the social security scheme

Exclusion Criteria:

• Patients who can not read

• Patients opposing the use of their medical data

• Unstable patients, less than one month from the beginning of the exacerbation

• Pregnant or lactating women

• Adult patient under curatorship or tutorship, person deprived of liberty

• Patient awaiting transplant or non-invasive ventilation in chronic

• Patient can not be contacted in case of emergency

Related Conditions & MeSH terms

• Cystic Fibrosis
• Cystic Fibrosis Pulmonary Exacerbation
• Dysbiosis
• Fibrosis
• Pulmonary Fibrosis

Locations

Country	Name	City	State
France	University Hospital Grenoble	Grenoble

Sponsors (1)

Lead Sponsor	Collaborator
University Hospital, Grenoble

Country where clinical trial is conducted

France, 

References & Publications (14)

Beaumier L, Chanoine S, Camara B, Pison C, Bedouch P. Alemtuzumab and de novo pulmonary arterial hypertension: A potential association? J Heart Lung Transplant. 2017 Mar;36(3):370-371. doi: 10.1016/j.healun.2016.10.013. Epub 2016 Oct 29. — View Citation

Bosc C, Clement M, Deroux A, Mammar A, Pison C, Camara B. [Severe pneumonia due to cytomegalovirus in chronic obstructive pulmonary disease]. Rev Mal Respir. 2014 May;31(5):435-8. doi: 10.1016/j.rmr.2013.09.013. Epub 2013 Dec 2. French. — View Citation

Bouvaist H, Thony F, Jondot M, Camara B, Jais X, Pison C. Balloon pulmonary angioplasty in a patient with chronic thromboembolic pulmonary hypertension. Eur Respir Rev. 2014 Sep;23(133):393-5. doi: 10.1183/09059180.00000514. — View Citation

Camara B, Reymond E, Saint-Raymond C, Roth H, Brenier-Pinchart MP, Pinel C, Cadranel J, Ferretti G, Pelloux H, Pison C; Grenoble Aspergillus Committee. Characteristics and outcomes of chronic pulmonary aspergillosis: a retrospective analysis of a tertiary hospital registry. Clin Respir J. 2015 Jan;9(1):65-73. doi: 10.1111/crj.12105. Epub 2014 Feb 17. — View Citation

Claustre J, Brion JP, Quétant S, Bedouch P, Pison C, Camara B. Favorable Evolution of Cryptococcal Meningitis in the Context of Flucytosine Resistance. Exp Clin Transplant. 2018 Feb;16(1):110-113. doi: 10.6002/ect.2015.0217. Epub 2016 Apr 26. — View Citation

Claustre J, Quétant S, Camara B, France M, Schummer G, Bedouch P, Pavese P, Saint Raymond C, Bardy B, Masson D, Roth H, Pison C; Grenoble Lung Transplantation group. Nonspecific immunoglobulin replacement in lung transplantation recipients with hypogammaglobulinemia: a cohort study taking into account propensity score and immortal time bias. Transplantation. 2015 Feb;99(2):444-50. doi: 10.1097/TP.0000000000000339. — View Citation

Decorte N, Gruet M, Camara B, Quetant S, Mely L, Vallier JM, Verges S, Wuyam B. Absence of calf muscle metabolism alterations in active cystic fibrosis adults with mild to moderate lung disease. J Cyst Fibros. 2017 Jan;16(1):98-106. doi: 10.1016/j.jcf.2016.05.010. Epub 2016 Jun 15. — View Citation

Dumollard C, Bailly S, Perriot S, Brenier-Pinchart MP, Saint-Raymond C, Camara B, Gangneux JP, Persat F, Valot S, Grenouillet F, Pelloux H, Pinel C, Cornet M. Prospective Evaluation of a New Aspergillus IgG Enzyme Immunoassay Kit for Diagnosis of Chronic and Allergic Pulmonary Aspergillosis. J Clin Microbiol. 2016 May;54(5):1236-42. doi: 10.1128/JCM.03261-15. Epub 2016 Feb 17. — View Citation

Godet C, Laurent F, Béraud G, Toper C, Camara B, Philippe B, Germaud P, Cottin V, Beigelman-Aubry C, Khalil A, Blouin P, Pouriel M, Roblot F, Bergeron A, Cadranel J; ACHROSCAN study group. Phenotyping chronic pulmonary aspergillosis by cluster analysis. Eur Respir J. 2015 Nov;46(5):1509-12. doi: 10.1183/13993003.00869-2015. Epub 2015 Sep 17. — View Citation

Godet C, Laurent F, Bergeron A, Ingrand P, Beigelman-Aubry C, Camara B, Cottin V, Germaud P, Philippe B, Pison C, Toper C, Carette MF, Frat JP, Béraud G, Roblot F, Cadranel J; ACHROSCAN Study Group. CT Imaging Assessment of Response to Treatment in Chronic Pulmonary Aspergillosis. Chest. 2016 Jul;150(1):139-47. doi: 10.1016/j.chest.2016.02.640. Epub 2016 Feb 19. — View Citation

Gruet M, Decorte N, Mely L, Vallier JM, Camara B, Quetant S, Wuyam B, Verges S. Skeletal muscle contractility and fatigability in adults with cystic fibrosis. J Cyst Fibros. 2016 Jan;15(1):e1-8. doi: 10.1016/j.jcf.2015.05.004. Epub 2015 May 29. — View Citation

Roca A, Oluwalana C, Bojang A, Camara B, Kampmann B, Bailey R, Demba A, Bottomley C, D'Alessandro U. Oral azithromycin given during labour decreases bacterial carriage in the mothers and their offspring: a double-blind randomized trial. Clin Microbiol Infect. 2016 Jun;22(6):565.e1-9. doi: 10.1016/j.cmi.2016.03.005. Epub 2016 Mar 26. — View Citation

Wintenberger C, Maubon D, Charpentier E, Rendu J, Pavese P, Augier C, Malvezzi P, Camara B, Mallaret MR, Bouillet L, Epaulard O. Grouped Cases of Pulmonary Pneumocystosis After Solid Organ Transplantation: Advantages of Coordination by an Infectious Diseases Unit for Overall Management and Epidemiological Monitoring. Infect Control Hosp Epidemiol. 2017 Feb;38(2):179-185. doi: 10.1017/ice.2016.274. Epub 2016 Nov 28. — View Citation

Zhao Y, Garnaud C, Brenier-Pinchart MP, Thiébaut-Bertrand A, Saint-Raymond C, Camara B, Hamidfar R, Cognet O, Maubon D, Cornet M, Perlin DS. Direct Molecular Diagnosis of Aspergillosis and CYP51A Profiling from Respiratory Samples of French Patients. Front Microbiol. 2016 Jul 29;7:1164. doi: 10.3389/fmicb.2016.01164. eCollection 2016. — View Citation

* Note: There are 14 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Identification of markers of bacterial fungal and viral dysbiosis associated with the occurrence of exacerbation in patients followed for cystic fibrosis.	Association between a modification of at least 10% of the relative abundance of a bacterial phylum (Proteobacteria, Firmicutes, Actinobacteria, Bacteroidetes, Fusobacteria) or fungal (ascomycetes / hemiascomycetes, basidiomycetes, zygomycetes), or viral and the occurrence of exacerbations over a period of 12 months.	One year
Secondary	Evaluation of the influence of the modification of the relative abundance of different bacterial, viral and fungal taxa, on the occurrence of exacerbations	Association between a change of at least 10% in the relative abundance of a bacterial or fungal taxum, and the occurrence of exacerbations over a 12-month period	One year
Secondary	Evaluation of the influence of the global biodiversity of the bacterial and fungal pulmonary microbiome on the occurrence of exacerbations.	Association between a modification of two indices (Faith's Phylogenetic Diversity and Shannon's B H index) and the occurrence of exacerbations over a 12-month period	One year
Secondary	Association between markers of respiratory function and the relative abundance of different bacterial, viral and fungal phyla and taxa	Correlation between FEV1 on the one hand, and changes in the relative abundance of bacterial, viral and fungal phyla and taxa on the other hand	One year
Secondary	Evaluation of the link between an increase in inflammatory markers and the occurrence of exacerbations	Association between serum concentrations of serum inflammatory cytokines and the occurrence of exacerbations over a period of 12 months	One year
Secondary	Association between markers of respiratory function and serum inflammatory markers	Correlation between FEV 1 and CV on the one hand, and different serum inflammatory serum cytokines	One year
Secondary	Comparison of two types of sputum samples versus expired air condensate to evaluate the pulmonary microbiome in patients with cystic fibrosis	Comparison of relative abundance of phyla of interest in sputum vs exhaled air condensate	One year
Secondary	Evaluation of the interactions between the different taxa of the pulmonary microbiome of patients with cystic fibrosis	Network co-occurrence (network interference) of the relative abundance of different bacterial and fungal taxa	One year
Secondary	Evaluation of the impact of treatments administered during exacerbations on the pulmonary microbiome, in particular on changes in the relative abundance and diversity of different bacterial, viral and fungal taxa	Comparison of the relative abundance of the phyla of interest and the diversity of the microbiome (Faith's Phylogenetic Diversity and Shannon B H index) in the presence or absence of antimicrobial and anti-inflammatory steroid treatments	One year