Microbiome and Volatile Organic Compounds in Patients With CDH

NCT03787160 | Completed

• 1 other identifier: 28-528 ex 15/16
• Study Type: interventional
• Target: 18
• Locations: 1 country
• Sites: 1

Brief Summary

Despite improved prenatal diagnostics and therapeutic possibilities, congenital diaphragmatic hernia (CDH) represents a cross-disciplinary challenge. With an incidence of 1:2000-1:5000, it is a common disease that effects centres of paediatrics and juvenile medicine. The etiology is still unclear. Patients with this diagnosis are usually affected by other comorbities such as failure to thrive, gastroesophageal reflux, funnel chest, etc. Depending on the extent of CDH, a more or less pronounced lung hypoplasia with functional impairment occurs. The health-relevant importance of the human microbiome is increasingly evident. While it was previously particularly associated with the gastrointestinal tract, other systems such as the pulmonary microbiome have become the focus of scientific interest. Research into changes in the microbiome and volatile organic compounds (VOCs) could provide new insights into the underlying mechanisms and therapeutic measures of this disease.

Conditions

Congenital Diaphragmatic Hernia

Keywords

congenital diaphragmatic hernia; volatile organic compounds; microbiome; pulmonary function; multiple breath washout

Outcome Measures

Primary Outcomes (17)

• Analysis of the pulmonary microbiome in the sputum of CDH group versus control group.

  OTUs (Operational Taxonomic Units) will be visualized as OTU tables, bar charts and PCOA (Principal Coordinates Analysis) plots using the Qiime core microbiome script. For the different groups alpha-diversity (Chao 1 index, Shannon Index etc.) will be compared. Additionally, we will compare beta-diversity by Adonis test. Relative abundances of the bacteria at the different levels (phylum to genus) will be compared between the groups by using Kruskal Wallis Test.

  12 months

• Analysis of VOCs in the respiratory air by needle-trap microextraction (NTME) and stool by solid phase microextraction (SPME) of CDH group versus control group.

  From the results of the patient measurements, those substances and substance concentrations are determined which are specific for study group 1 and group 2, i.e. compounds which are not present in the comparison group or only in significantly lower or higher concentrations. The selected volatile markers, as well as any volatile contaminants that may have been detected in the environment, are stored in an analytical reference database and, after elimination of the contamination, bundled into possibly disease-specific marker profiles. The VOCs are recorded and displayed in the following order. The unit in which the VOCs are measured is pars per billion (ppb). Class (for example carbons) VOCs (ppb) CDHV1 (congenital diaphragmatic hernia group visit 1) CDHK (congenital diaphragmatic hernia - control group visit 1) CDHV2 (congenital diaphragmatic hernia group visit 2) CDHV3 (congenital diaphragmatic hernia group visit 3) p-value

  12 months

• Analysis of the lung function: Lung clearance index (LCI) is derived from multiple breath washout tests of CDH group versus control group.

  The LCI is about 7 (range from 6.45-7.78) for healthy individuals and is a number without a unit.

  12 months

• Analysis of the lung function: Forced expiratory volume in one second (FEV1) measured with spirometry of CDH group versus control group.

  The FEV1 is the forced expiratory volume within the first second (liter/second), generated by a maximal voluntary exhalation after maximum inspiration before, usually described as the Tiffeneau-Index in % of FVC (FEV1/FVC).

  12 months

• Analysis of the cardiopulmonary capacity: Resting ECG of CDH group versus control group.

  A Resting ECG recording the resting heart rate, the rhythm, the PQ duration, the width and height of the QRS complex, the QT duration, and the ST segment is recorded.

  12 months

• Analysis of the cardiopulmonary capacity: Systolic and diastolic blood pressures of CDH group versus control group.

  Noninvasiv systolic and diastolic blood pressures are assessed (Unit: mmHg).

  12 months

• Analysis of the cardiopulmonary capacity: Body height of CDH group versus control group.

  Body height is measured in cm.

  12 months

• Analysis of the cardiopulmonary capacity: Body weight of CDH group versus control group.

  Body weight is measured in kg.

  12 months

• Analysis of the cardiopulmonary capacity: Body mass index (BMI) of CDH group versus control group.

  Body mass index is calculated in kg body weight/body height².

  12 months

• Analysis of the cardiopulmonary capacity: Muscle mass of CDH group versus control group.

  Muscle mass is specified in kg/body height².

  12 months

• Analysis of the cardiopulmonary capacity: Body fat of CDH group versus control group.

  Body fat is specified in percent of body weight.

  12 months

• Analysis of the cardiopulmonary capacity: Aerobic performance of CDH group versus control group.

  Aerobic performance is specified in percent of normal values of the Austrian cardiological society.

  12 months

• Analysis of the cardiopulmonary capacity: Maximal oxygen uptake of CDH group versus control group.

  Measurements by spiroergometry: Maximal oxygen uptake in ml/kg/min.

  12 months

• Analysis of the cardiopulmonary capacity: Ventilation of CDH group versus control group.

  Measurements by spiroergometry: Ventilation in liter/min.

  12 months

• Analysis of the cardiopulmonary capacity: Oxygen pulse of CDH group versus control group.

  Measurements by spiroergometry: Oxygen pulse in ml/beats per minute.

  12 months

• Analysis of the cardiopulmonary capacity: Oxygen uptake of CDH group versus control group.

  Respiratory exchange ratio = oxygen uptake in ml/carbon dioxide release in ml.

  12 months

• Analysis of the cardiopulmonary capacity: Breathing reserve of CDH group versus control group.

  Unit: Percent of FEV1 x 35.

  12 months

Secondary Outcomes (15)

• Alterations of pulmonary microbiome after probiotic treatment for a period of 3 months in patients with CDH.

  12 months

• Alterations of VOCs in the respiratory air after probiotic treatment for a period of 3 months in patients with CDH.

  12 months

• Analysis of the lung function: Forced expiratory flow (FEF25-75).

  12 months

• Analysis of the lung function: Forced expiratory flow (FEF25).

  12 months

• Analysis of the lung function: Forced expiratory flow (FEF50).

  12 months

Study Arms (2)

CDH Group

ACTIVE COMPARATOR

10 patients after surgical closure of CDH will undergo VOC profile analysis (2 breath samples) (initial VOC), fecal sampling for 16S rDNA based pyrosequencing (initial fecal microbiome) and deep induced sputum sampling for 16S rDNA pyrosequencing (initial pulmonary microbiome), bicycle spiroergometry to determine the maximum oxygen uptake (maximum oxygen uptake), body plethysmography, spirometry and N2-multiple breath washout testing to determine the functional residual capacity (functional residual capacity). Thereafter patients will receive probiotic treatment with OmniBiotic6 (R) (Allergosan, Graz, Austria) 1 sachet daily for 3 months (probiotic treatment). Three months after discontinuing probiotic treatment VOC testing (VOC probiotics), fecal microbiome sampling (fecal microbiome probiotics) and deep induced sputum testing (pulmonary microbiome probiotics) will be repeated and compared to the results of the initial tests.

Diagnostic Test: initial VOC; Diagnostic Test: initial fecal microbiome; Diagnostic Test: initial pulmonary microbiome; Diagnostic Test: Maximum oxygen uptake; Diagnostic Test: Functional residual capacity; Dietary Supplement: Probiotic treatment; Diagnostic Test: VOC probiotic; Diagnostic Test: Fecal microbiome probiotic; Diagnostic Test: Pulmonary microbiome probiotic

Control Group

OTHER

10 healthy controls (age and sex matched) will undergo VOC profile analysis (2 breath samples) (initial VOC), fecal sampling for 16S rDNA based pyrosequencing (initial fecal microbiome) and deep induced sputum sampling for 16S rDNA pyrosequencing (initial pulmonary microbiome), bicycle spiroergometry to determine the maximum oxygen uptake (maximum oxygen uptake), body plethysmography, spirometry and N2-multiple breath washout testing to determine the functional residual capacity (functional residual capacity).

Diagnostic Test: initial VOC; Diagnostic Test: initial fecal microbiome; Diagnostic Test: initial pulmonary microbiome; Diagnostic Test: Maximum oxygen uptake; Diagnostic Test: Functional residual capacity

Interventions

initial VOC DIAGNOSTIC_TEST

Difference in VOC profile between patients with CDH and healthy controls (2 samples per patient will be obtained after obtaining informed consent).

CDH Group; Control Group

initial fecal microbiome DIAGNOSTIC_TEST

Difference of alpha and beta diversity and relative fecal bacterial abundance between patients with CDH and healthy controls (1 stool sample will be taken per patient after obtaining informed consent)

CDH Group; Control Group

initial pulmonary microbiome DIAGNOSTIC_TEST

Difference of alpha and beta diversity and relative pulmonary bacterial abundance between patients with CDH and healthy controls (1 deep induced sputum sample will be taken per patient after obtaining informed consent)

CDH Group; Control Group

Maximum oxygen uptake DIAGNOSTIC_TEST

Comparison of the maximum oxygen uptake (corrected for body weight and gender) as determined by bicycle spiroergometry between patients with CDH and healthy controls

CDH Group; Control Group

Functional residual capacity DIAGNOSTIC_TEST

FRC will be determined by spirometry, bodyplethysmography and N2-breath wash out method. FRC will be compared between patients after CDH and healthy controls.

CDH Group; Control Group

Probiotic treatment DIETARY_SUPPLEMENT

CDH patients will receive OmniBiotic 6(R) (Allergosan, Graz, Austria) probiotic supplementation 1 sachet daily for 3 months.

CDH Group

VOC probiotic DIAGNOSTIC_TEST

Determination of the VOC profile 3 months after discontinuing probiotic treatment. Comparison to the profiles before the treatment.

CDH Group

Fecal microbiome probiotic DIAGNOSTIC_TEST

Determination of the fecal microbiome from 1 sample per patient (alpha and beta diversity, relative bacterial abundance at the genus level) 3 months after discontinuing probiotic treatment. Comparison to the profiles before the treatment.

CDH Group

Pulmonary microbiome probiotic DIAGNOSTIC_TEST

Determination of the fecal microbiome from 1 deep induced sputum sample per patient (alpha and beta diversity, relative bacterial abundance at the genus level) 3 months after discontinuing probiotic treatment. Comparison to the profiles before the treatment.

CDH Group

Eligibility Criteria

• Age: 6 Years - 16 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Child (0-17)

You may qualify if:

• Age from 6-16 years
• Age 0-6 months at time of CDH-OP (except control group)
• reliable diagnosis of congenital diaphragmatic hernia (except control group)
• surgical occlusion with patch (except control group)
• surgical occlusion without patch (except control group)
• given approval

You may not qualify if:

• chronic pulmonary diseases
• Infection within 4 weeks before the test date
• unaccepted consent

Sponsors & Collaborators

• Medical University of Graz: lead
• University of Rostock: collaborator

Study Sites (1)

Department of Department of Pediatric and Adolescent Surgery, Medical University of Graz

Graz, Styria, 8036, Austria

Location

Related Publications (16)

• Kotecha S, Barbato A, Bush A, Claus F, Davenport M, Delacourt C, Deprest J, Eber E, Frenckner B, Greenough A, Nicholson AG, Anton-Pacheco JL, Midulla F. Congenital diaphragmatic hernia. Eur Respir J. 2012 Apr;39(4):820-9. doi: 10.1183/09031936.00066511. Epub 2011 Oct 27.

  PMID: 22034651 BACKGROUND

• Tracy M, Cogen J, Hoffman LR. The pediatric microbiome and the lung. Curr Opin Pediatr. 2015 Jun;27(3):348-55. doi: 10.1097/MOP.0000000000000212.

  PMID: 25888147 BACKGROUND

• Caverly LJ, Zhao J, LiPuma JJ. Cystic fibrosis lung microbiome: opportunities to reconsider management of airway infection. Pediatr Pulmonol. 2015 Oct;50 Suppl 40:S31-8. doi: 10.1002/ppul.23243.

  PMID: 26335953 BACKGROUND

• Bergmann A, Trefz P, Fischer S, Klepik K, Walter G, Steffens M, Ziller M, Schubert JK, Reinhold P, Kohler H, Miekisch W. In Vivo Volatile Organic Compound Signatures of Mycobacterium avium subsp. paratuberculosis. PLoS One. 2015 Apr 27;10(4):e0123980. doi: 10.1371/journal.pone.0123980. eCollection 2015.

  PMID: 25915653 BACKGROUND

• Fischer S, Trefz P, Bergmann A, Steffens M, Ziller M, Miekisch W, Schubert JS, Kohler H, Reinhold P. Physiological variability in volatile organic compounds (VOCs) in exhaled breath and released from faeces due to nutrition and somatic growth in a standardized caprine animal model. J Breath Res. 2015 May 14;9(2):027108. doi: 10.1088/1752-7155/9/2/027108.

  PMID: 25971714 BACKGROUND

• Pereira J, Porto-Figueira P, Cavaco C, Taunk K, Rapole S, Dhakne R, Nagarajaram H, Camara JS. Breath analysis as a potential and non-invasive frontier in disease diagnosis: an overview. Metabolites. 2015 Jan 9;5(1):3-55. doi: 10.3390/metabo5010003.

  PMID: 25584743 BACKGROUND

• Amann A, Costello Bde L, Miekisch W, Schubert J, Buszewski B, Pleil J, Ratcliffe N, Risby T. The human volatilome: volatile organic compounds (VOCs) in exhaled breath, skin emanations, urine, feces and saliva. J Breath Res. 2014 Sep;8(3):034001. doi: 10.1088/1752-7155/8/3/034001. Epub 2014 Jun 19.

  PMID: 24946087 BACKGROUND

• Barker M, Hengst M, Schmid J, Buers HJ, Mittermaier B, Klemp D, Koppmann R. Volatile organic compounds in the exhaled breath of young patients with cystic fibrosis. Eur Respir J. 2006 May;27(5):929-36. doi: 10.1183/09031936.06.00085105. Epub 2006 Feb 2.

  PMID: 16455833 BACKGROUND

• Miekisch W, Schubert JK, Noeldge-Schomburg GF. Diagnostic potential of breath analysis--focus on volatile organic compounds. Clin Chim Acta. 2004 Sep;347(1-2):25-39. doi: 10.1016/j.cccn.2004.04.023.

  PMID: 15313139 BACKGROUND

• Forton J. Induced sputum in young healthy children with cystic fibrosis. Paediatr Respir Rev. 2015 Oct;16 Suppl 1:6-8. doi: 10.1016/j.prrv.2015.07.007. Epub 2015 Sep 26.

  PMID: 26410282 BACKGROUND

• Planting NS, Visser GL, Nicol MP, Workman L, Isaacs W, Zar HJ. Safety and efficacy of induced sputum in young children hospitalised with suspected pulmonary tuberculosis. Int J Tuberc Lung Dis. 2014 Jan;18(1):8-12. doi: 10.5588/ijtld.13.0132.

  PMID: 24365546 BACKGROUND

• 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.

  PMID: 23265859 BACKGROUND

• Gorkiewicz G, Thallinger GG, Trajanoski S, Lackner S, Stocker G, Hinterleitner T, Gully C, Hogenauer C. Alterations in the colonic microbiota in response to osmotic diarrhea. PLoS One. 2013;8(2):e55817. doi: 10.1371/journal.pone.0055817. Epub 2013 Feb 8.

  PMID: 23409050 BACKGROUND

• Trefz P, Rosner L, Hein D, Schubert JK, Miekisch W. Evaluation of needle trap micro-extraction and automatic alveolar sampling for point-of-care breath analysis. Anal Bioanal Chem. 2013 Apr;405(10):3105-15. doi: 10.1007/s00216-013-6781-9. Epub 2013 Feb 7.

  PMID: 23388692 BACKGROUND

• Miller MR, Hankinson J, Brusasco V, Burgos F, Casaburi R, Coates A, Crapo R, Enright P, van der Grinten CP, Gustafsson P, Jensen R, Johnson DC, MacIntyre N, McKay R, Navajas D, Pedersen OF, Pellegrino R, Viegi G, Wanger J; ATS/ERS Task Force. Standardisation of spirometry. Eur Respir J. 2005 Aug;26(2):319-38. doi: 10.1183/09031936.05.00034805. No abstract available.

  PMID: 16055882 BACKGROUND

• Wanger J, Clausen JL, Coates A, Pedersen OF, Brusasco V, Burgos F, Casaburi R, Crapo R, Enright P, van der Grinten CP, Gustafsson P, Hankinson J, Jensen R, Johnson D, Macintyre N, McKay R, Miller MR, Navajas D, Pellegrino R, Viegi G. Standardisation of the measurement of lung volumes. Eur Respir J. 2005 Sep;26(3):511-22. doi: 10.1183/09031936.05.00035005. No abstract available.

  PMID: 16135736 BACKGROUND

MeSH Terms

Conditions

Hernias, Diaphragmatic, Congenital

Interventions

Functional Residual Capacity

Condition Hierarchy (Ancestors)

Congenital Abnormalities; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Hernia, Diaphragmatic; Internal Hernia; Hernia; Pathological Conditions, Anatomical; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Total Lung Capacity; Lung Volume Measurements; Respiratory Function Tests; Diagnostic Techniques, Respiratory System; Diagnostic Techniques and Procedures; Diagnosis; Respiratory Physiological Phenomena; Circulatory and Respiratory Physiological Phenomena

Study Officials

• Till Holger, MD

  Department of Pediatric and Adolescent Surgery, Medical University of Graz

  STUDY DIRECTOR

• Ernst Eber, MD

  Department of Pediatric and Adolescent Medicine, Medical University of Graz

  PRINCIPAL INVESTIGATOR

• Gert Warncke, MD

  Department of Pediatric and Adolescent Surgery, Medical University of Graz

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: INVESTIGATOR
• Purpose: BASIC SCIENCE
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: July 10, 2018
• First Posted: December 26, 2018
• Study Start: March 22, 2018
• Primary Completion: October 1, 2019
• Study Completion: October 1, 2019
• Last Updated: April 28, 2020

Record last verified: 2020-04

Data Sharing

• IPD Sharing: Will not share

Locations

AU (1)