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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
Full 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.
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Inclusion and exclusion criteria
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
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:
Respiratory Rate:
WBC:
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:
Platelet count <100000/mL
Bilirubin >2 mg/dL
Mean arterial pressure (MAP)
SBP less than two SD below normal for age
Prolonged capillary refill: > 5 sec
Inclusion Criteria of Control group :
Exclusion Criteria:
Primary purpose
Allocation
Interventional model
Masking
160 participants in 2 patient groups
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Central trial contact
Alexandros Popotas, MD; Nicolas Lefevre, MD, PhD
Data sourced from clinicaltrials.gov
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