Study of the Sex Differences in Inflammatory Diseases in Children (SepsiX)

Sexual differences in innate immune response have been demonstrated and were mainly attributed to the influence of the sex steroids (1-18). However, recent clinical data revealed significant differences in inflammatory markers between boys and girls suffering from acute and chronic inflammatory diseases (19-23). Sex hormone levels in prepubertal children are particularly low and insufficient to explain the gender differences observed in inflammatory conditions from neonates to the elderly, suggesting the contribution of another mechanism, such as the influence of genes situated on the sex chromosomes and involved in the inflammatory response.

The aim of this work is to evaluate the role of the X chromosome in the sex differences in inflammatory diseases in children. In order to discriminate more precisely the role of the X chromosome relatively to the sex steroids in the sex-specific inflammatory response, some innate immune functions related to X-linked genes will be evaluated in whole blood from prepubertal children of both sexes, suffering from acute inflammatory processes such as pyelonephritis caused by Escherichia coli, pneumonia with pleural effusion caused by Streptococcus pneumoniae or sepsis

Study Overview

• Status: Recruiting
• Conditions: Sex Differences in Immune Response; Acute Inflammatory Diseases in Children
• Intervention / Treatment: Other: Blood collection; Other: Stool collection

Detailed Description

Many studies demonstrated immune differences between men and women suffering from acute and chronic inflammatory processes. In cases of acute inflammatory diseases, such as sepsis, females have better prognosis comparing to males (1,24-28).

On the contrary, worse prognosis for women is observed in chronic inflammatory diseases such as asthma or cystic fibrosis (8-10,12,13,29).

Sex-depended inflammatory response was attributed to the influence of sex hormones on the immune system. (2,15-18). However recent studies revealed differences in the clinical outcome but also in inflammatory markers between boys and girls suffering from acute and chronic inflammatory diseases (19-23). Sex hormone levels in prepubertal children are particularly low and insufficient to explain the gender differences observed in inflammatory conditions from neonates to the elderly, suggesting the contribution of another mechanism, such as the influence of genes situated on the sex chromosomes and involved in the inflammatory response.

The aim of this work is to identify the potential X-linked mechanisms responsible for some of the differences between boys and girls in the inflammatory response, making the girls more at risk of developing complications in chronic inflammatory diseases and the boys more at risk of lethal complications in severe acute inflammatory diseases like sepsis. Several genes coding for innate immunity components are linked to the X chromosome such as diapedesis molecule CD99 or TLR pathway proteins genes. (30-33). X chromosome is also highly enriched in genes encoding micro RNAs (miRNAs) involved in the post-transcriptional regulation of gene expression which play a critical role in immune inflammatory response (34-36).

Thus, in order to discriminate more precisely the role of the X chromosome relatively to the sex steroids in the sex-specific inflammatory response, some innate immune functions related to X-linked genes will be evaluated in whole blood from prepubertal children of both sexes, suffering from acute inflammatory processes such as pyelonephritis caused by Escherichia coli, pneumonia with pleural effusion caused by Streptococcus pneumoniae or sepsis. We will also study the correlations between inflammatory and clinical markers of the disease activity to identify prognosis indicators depending on the sex. Additionally, to delineate microbiome contribution, we will study the gut microbiota in stool samples obtained from the recruited patients.

• Study Type: Interventional
• Enrollment (Anticipated): 160
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Alexandros Popotas, MD; Phone Number: +32 2 477 24 24; Email: alexandros.popotas@ulb.be
• Study Contact Backup: Name: Nicolas Lefevre, MD, PhD; Phone Number: +32 2 477 23 41; Email: nicolas.lefevre@huderf.be

Study Locations

• Belgium
  • Brussels, Belgium, 1020
    • Recruiting
    • Huderf
    • Contact: Alexandros Popotas, MD; Phone Number: +32 2 477 24 24; Email: alexandros.popotas@ulb.be
    • Contact: Georges Casimir, MD, PhD; Phone Number: + 32 2 477 29 45; Email: georges.casimir@huderf.be
    • Principal Investigator: Alexandros Popotas, MD
    • Sub-Investigator: Francis Corazza, MD, PhD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 6 months to 7 years (CHILD)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria of Experimental group :

• Male (XY) and female (XX) aged from 6 months to 7 years old.

• Subject hospitalized either for:

  (1) Urinary tract infection caused by Escherichia Coli, with:

• Temperature ≥ to 38,5°C

• Urinalysis

  • Leukocyte esterase +
  • AND/OR Nitrites +
  • AND/OR pyuria (≥ 100WBC/mm³)
  • AND/OR bacteriuria.

• Urinalysis

  • Clean catch voided urine: > 10^4 Escherichia Coli colony form unit (CFU)/mm (urine collection method for children >3 years old or toilet trained children or by stimulation for children <3 years old)
  • Transurethral bladder catheterisation: > 10^4 Escherichia Coli colony form unit (CFU)/mm³ (urine collection method for children <3 years old).

  • Suprapubic aspiration: > 1 Escherichia Coli colony form unit (CFU)/mm³ (urine collection method for children <3 years old).

    (2) Pneumonia with pleural effusion with :

• Temperature ≥ 38,5°C
• Chest radiography/ultrasound: Pleural effusion

• Streptococcus pneumoniae identified on blood or pleural fluid culture or by PCR

  (3) Sepsis with:

• Documented or suspected infection
• Temperature < 36° or > 38.3°C

• Heart rhythm:

  • 2 SD above normal for age
  • 6-23 months: >180/min
  • 24-71 months: >140/min
  • 72-84 months: >130/min

• Respiratory Rate:

  • 6-23 months: >35/min
  • 24 - 71 months: >30/min
  • 72-84 months: >20/min

• WBC:

  • 6-23 months: >17500/µL or <5000/µL
  • 24-71 months: >15500/µL or <6000/µL
  • 72-84 months: >13500/µL or <4500/µL
  • and/or CRP (blood) > 2SD above normal

• And at least two of the following:

  • PaO2/FiO2 <300
  • Proven need for >50% FiO2 to maintain saturation ≥ 92%
  • Need for mechanical ventilation
  • Glasgow score < 11
  • Urine output < 0,5mL/kg/h for at least 2h

  • Creatinine:

    • 6-11 months: >0,4mg/dL
    • 12-23 months: >0,5mg/dL
    • 24-59 months: >0,8mg/dL
    • 60-84 months: >1mg/dL
    • Or creatinine increase more than 0,5 mg/dL
  • Platelet count <100000/mL
  • Bilirubin >2 mg/dL

  • Mean arterial pressure (MAP)

    • 6-11 months: <55 mmHg
    • 12 -23 months: <60 mmHg
    • 24-59 months: <62 mmHg
    • 60-84 months: <65 mmHg
  • SBP less than two SD below normal for age
  • Prolonged capillary refill: > 5 sec

Inclusion Criteria of Control group :

• Male (XY) and female (XX) aged from 6 months to 7 years old.
• Scheduled surgical intervention for a non-infectious pathology.

Exclusion Criteria:

• Use of antithrombotic drugs (acetylsalicylic acid, thienopyridines, dipyridamol, glycoprotein IIb / IIIa antagonists, vitamin K antagonists, heparins).
• Congenital or acquired immunodeficiency: immunosuppressive drugs, hematopoietic stem cells transplantation, immunoglobulin therapy, extracorporeal membrane oxygenation (ECMO).
• Hemodialysis.
• 48h following cardiac operation of any type.
• Malignant cancer.
• HIV.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: BASIC_SCIENCE
• Allocation: NON_RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Children suffering from acute inflammatory processes.; The study population will consist of male and female children, aged from 6 months to 7 years old, admitted to the hospital for one of the three following types of acute inflammatory processes: Urinary tract infection caused by Escherichia coli; Pneumonia with pleural effusion caused by Streptococcus pneumoniae; Sepsis	Other: Blood collection; Blood samples collections to evaluation of the potential role of the sex chromosomes in the innate immune response by analyzing inflammatory cytokine production (IL-1β, IL-6, IL-8, IL-10, TNF-α and IFN-α), studying the cell diapedesis receptor CD99 on PMNs, monocytes, and lymphocytes, analyzing the contribution of X-linked genes of the TLR pathways and the influence of X-linked miRNAs.; Other: Stool collection; Fecal sample collection to delineate microbiome contribution, we will study the gut microbiota in faecal samples obtained from the recruited patients.
OTHER: Control group; Male and female children, aged from 6 months to 7 years old, admitted to the hospital for a scheduled operation for a non-inflammatory pathology.	Other: Blood collection; Blood samples collections to evaluation of the potential role of the sex chromosomes in the innate immune response by analyzing inflammatory cytokine production (IL-1β, IL-6, IL-8, IL-10, TNF-α and IFN-α), studying the cell diapedesis receptor CD99 on PMNs, monocytes, and lymphocytes, analyzing the contribution of X-linked genes of the TLR pathways and the influence of X-linked miRNAs.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Whole blood production of cytokine IL-6	The production of IL6 is measured by multiplex techniques.	within 24 hours of hospital admission (Day 0)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Whole blood production of cytokine IL-1β		within 24 hours of hospital admission (Day 0)
Whole blood production of cytokine IL-8		within 24 hours of hospital admission (Day 0)
Whole blood production of cytokine IL-10		within 24 hours of hospital admission (Day 0)
Whole blood production of cytokine TNF-α		within 24 hours of hospital admission (Day 0)
Whole blood production of cytokine interferon-α		within 24 hours of hospital admission (Day 0)
Intracellular quantity of the phosphorylated forms of NF-κB p65 in leukocyte population.		within 24 hours of hospital admission (Day 0)
Intracellular quantity of the phosphorylated forms of ERK1/2 in leukocyte population.		within 24 hours of hospital admission (Day 0)
Intracellular quantity of the phosphorylated forms of p38 MAPK in leukocyte population.		within 24 hours of hospital admission (Day 0)
Expression of the cell diapedesis receptor CD99 on PMNs	Measurements of cell diapedesis receptor CD99 on leukocytes will be performed by flow cytometry	within 24 hours of hospital admission (Day 0)
Expression of the cell diapedesis receptor CD99 on monocytes	Measurements of cell diapedesis receptor CD99 on leukocytes will be performed by flow cytometry	within 24 hours of hospital admission (Day 0)
Expression of the cell diapedesis receptor CD99 on lymphocytes	Measurements of cell diapedesis receptor CD99 on leukocytes will be performed by flow cytometry	within 24 hours of hospital admission (Day 0)
Expression of TLR2 on PMNs	Measurements of intracellular phosphorylated forms of TLR pathway proteins as well as the expression of TLR2 and TLR4 will be performed by flow cytometry	within 24 hours of hospital admission (Day 0)
Expression of TLR2 on monocytes	Measurements of intracellular phosphorylated forms of TLR pathway proteins as well as the expression of TLR2 and TLR4 will be performed by flow cytometry	within 24 hours of hospital admission (Day 0)
Expression of TLR2 on lymphocytes	Measurements of intracellular phosphorylated forms of TLR pathway proteins as well as the expression of TLR2 and TLR4 will be performed by flow cytometry	within 24 hours of hospital admission (Day 0)
Expression of TLR4 on PMNs	Measurements of intracellular phosphorylated forms of TLR pathway proteins as well as the expression of TLR2 and TLR4 will be performed by flow cytometry	within 24 hours of hospital admission (Day 0)
Expression of TLR4 on monocytes	Measurements of intracellular phosphorylated forms of TLR pathway proteins as well as the expression of TLR2 and TLR4 will be performed by flow cytometry	within 24 hours of hospital admission (Day 0)
Expression of TLR4 on lymphocytes	Measurements of intracellular phosphorylated forms of TLR pathway proteins as well as the expression of TLR2 and TLR4 will be performed by flow cytometry	within 24 hours of hospital admission (Day 0)
BTK gene expression	Measurements will be performed using the Quantitect Reverse Transcription Kit (Qiagen, Manchester, UK) for quantitative PCR (qPCR) on leucocytes.	within 24 hours of hospital admission (Day 0)
IRAK1 gene expression	Measurements will be performed using the Quantitect Reverse Transcription Kit (Qiagen, Manchester, UK) for quantitative PCR (qPCR) on leucocytes.	within 24 hours of hospital admission (Day 0)
NEMO gene expression	Measurements will be performed using the Quantitect Reverse Transcription Kit (Qiagen, Manchester, UK) for quantitative PCR (qPCR) on leucocytes.	within 24 hours of hospital admission (Day 0)
Expression of X-linked miRNAs in leucocytes	Expression of X-linked miRNAs is measured by sequencing and qRT-PCR on leucocytes and/or plasma samples.	within 24 hours of hospital admission (Day 0)
Expression of X-linked miRNAs in plasma	Expression of X-linked miRNAs is measured by sequencing and qRT-PCR on leucocytes and/or plasma samples.	within 24 hours of hospital admission (Day 0)
Leukocyte population	White blood cell count including neutrophils, monocytes, monocytes subtypes and lymphocytes.	within 24 hours of hospital admission (Day 0)
Leukocyte population	White blood cell count including neutrophils, monocytes, monocytes subtypes and lymphocytes. Only applicable for the sepsis sub-group	Day 1
Leukocyte population	White blood cell count including neutrophils, monocytes, monocytes subtypes and lymphocytes. Only applicable for the sepsis sub-group	Day 2
Leukocyte population	White blood cell count including neutrophils, monocytes, monocytes subtypes and lymphocytes. Only applicable for the sepsis sub-group	Day 3
CRP		within 24 hours of hospital admission (Day 0)
CRP	Only applicable for the sepsis sub-group	Day 1
CRP	Only applicable for the sepsis sub-group	Day 2
CRP	Only applicable for the sepsis sub-group	Day 3
Total 17β-estradiol		within 24 hours of hospital admission (Day 0)
Testosterone		within 24 hours of hospital admission (Day 0)
IGF1		within 24 hours of hospital admission (Day 0)
Microbiome analysis		During subject hospitalisation
pSOFA score	Only applicable for the sepsis sub-group. The pSOFA will be evaluated every 24 hours in order to compare laboratory and clinical data. The score will be based on the PaO2: FiO2 or SpO2: FiO2 ratio, the platelet count, the bilirubin level, the Mean Arterial Pressure (MAP), the Glasgow score and the creatinine level.	within 24 hours of hospital admission (Day 0)
pSOFA score	Only applicable for the sepsis sub-group. The pSOFA will be evaluated every 24 hours in order to compare laboratory and clinical data. The score will be based on the PaO2: FiO2 or SpO2: FiO2 ratio, the platelet count, the bilirubin level, the Mean Arterial Pressure (MAP), the Glasgow score and the creatinine level.	Day 1
pSOFA score	Only applicable for the sepsis sub-group. The pSOFA will be evaluated every 24 hours in order to compare laboratory and clinical data. The score will be based on the PaO2: FiO2 or SpO2: FiO2 ratio, the platelet count, the bilirubin level, the Mean Arterial Pressure (MAP), the Glasgow score and the creatinine level.	Day 2
pSOFA score	Only applicable for the sepsis sub-group. The pSOFA will be evaluated every 24 hours in order to compare laboratory and clinical data. The score will be based on the PaO2: FiO2 or SpO2: FiO2 ratio, the platelet count, the bilirubin level, the Mean Arterial Pressure (MAP), the Glasgow score and the creatinine level.	Day 3

Collaborators and Investigators

• Sponsor: Queen Fabiola Children's University Hospital
• Collaborators: Belgium Kid's Fund
• Investigators: Principal Investigator: Alexandros Popotals, MD, Huderf

Publications and helpful links

General Publications

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• Schoeneberg C, Kauther MD, Hussmann B, Keitel J, Schmitz D, Lendemans S. Gender-specific differences in severely injured patients between 2002 and 2011: data analysis with matched-pair analysis. Crit Care. 2013 Nov 29;17(6):R277. doi: 10.1186/cc13132.
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• Kuczynski J, Stombaugh J, Walters WA, Gonzalez A, Caporaso JG, Knight R. Using QIIME to analyze 16S rRNA gene sequences from microbial communities. Curr Protoc Bioinformatics. 2011 Dec;Chapter 10:10.7.1-10.7.20. doi: 10.1002/0471250953.bi1007s36.

Study record dates

Study Major Dates

• Study Start (ACTUAL): August 17, 2019
• Primary Completion (ANTICIPATED): December 31, 2023
• Study Completion (ANTICIPATED): December 31, 2023

Study Registration Dates

• First Submitted: October 21, 2020
• First Submitted That Met QC Criteria: March 22, 2021
• First Posted (ACTUAL): March 25, 2021

Study Record Updates

• Last Update Posted (ACTUAL): March 25, 2021
• Last Update Submitted That Met QC Criteria: March 22, 2021
• Last Verified: October 1, 2020

More Information

Terms related to this study

• Keywords: Sex, immunology, inflammation, child, sepsis, UTI, pneumonia
• Other Study ID Numbers: P2019/LABO/SepsiX

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No