Pediatric Immune Response to Infectious Shock (PedIRIS)

Infectious shocks are associated with high mortality rates (20-40%). Anti-inflammatory strategies based on the postulate that mortality related to sepsis is mainly due to an overwhelming pro-inflammatory immune response have failed. Some patients surviving this initial phase can develop immune dysfunctions because the compensatory mechanisms become deleterious when they persist over time. The persistence of immunosuppression at day 3 or 5 is independently associated with more nosocomial infections and higher mortality rate. The clinical and laboratory evidence for sepsis induced immunosuppression have been recently reviewed by Hotchkiss et al. Apoptosis-induced depletion of immune effector and blood studies from septic patients showed decreased production of pro-inflammatory cytokines, decreased HLA-DR expression, increased percentage of regulatory T cells, and increased production of programmed cell death (PD)-1. Some small positive phase 2 trials of biomarker guided immune enhancing agents granulocyte-macrophage colony stimulating factor (GM-CSF) and interferon γ (IFN γ) have been reported.

There are insufficient data showing that such an immunosuppression exists in children. Only one study performed in children with organ dysfunctions admitted to pediatric intensive care unit (PICU), showed that 34% of them developed immunosuppression. This study was performed on a heterogeneous population and immunological analyses were limited. Therefore, there is a crucial need of studies on septic patients with matched controls to provide more evidence that the same paradigm exists in children. The collaboration of laboratories with a high level of experience in this domain, and a clinical unit with a high potential of recruitment of children with severe infectious shock should allow us to perform the first prospective study specifically done in children with infectious shock.

The main hypothesis is that children with severe infectious shock developed sepsis-induced immunosuppression as shown in adults. This will be assessed by the expression of HLA-DR on monocytes' surface. We make the hypothesis that children who become immunosuppressed are more prone to develop secondary nosocomial infectious and stayed longer in PICU and in hospital.

Children aged from 1 month to 17 years, admitted to PICU at HFME Lyon-Bron are eligible if they have the criteria for severe sepsis or septic shock, defined by the "Surviving Sepsis Campaign 2012" or those of Toxic Shock Syndrome (TSS) (definitions of CDC - Center for Disease Control). An information leaflet will be issued to parents and children / adolescents and they will be informed of their right to object to the search. Are provided as part of this research:

• Immunological measures (mHLA -DR) in three stages: in the first 48 hours, between D3/5 and D7/9. The volume of collected blood will not exceed 2.4 ml / kg.
• The collection of nosocomial infections and status at D30 A control group of patients hospitalized for surgery without sepsis or toxic shock criteria will be recruited in the same hospital by ICU investigators and matched for age. Similarly controls will be given oral and written information and they will have the opportunity to deny inclusion. They will have the same exams as the first group of patients.

Study Overview

• Status: Completed
• Conditions: Severe Pediatric Infectious Shock
• Intervention / Treatment: Other: blood samples; Other: Collection of nosocomial infections

• Study Type: Interventional
• Enrollment (Actual): 105
• Phase: Not Applicable

Contacts and Locations

Study Locations

• France
  • Lyon, France
    • Hospices Civils de Lyon

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 month to 17 years (Child)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

Inclusion Criteria Infectious shock group:

• Children aged from 1 month to <18 years
• Diagnosis of severe infectious shock at PICU or within the first 24 hours following PICU admission: severe sepsis or septic shock, defined by Surviving Sepsis Campaign 2012, or Toxic Shock Syndrome, defined by CDC criteria.

Inclusion Criteria Control group:

• Healthy children aged matched to cases
• Hospitalized for an elective surgery (dental, ENT, maxillofacial, urologic, hernia surgery, neurosurgery without massive hemorrhage)
• Without any criteria of infection.

Exclusion Criteria (both groups):

• Chronic inflammatory disease;
• Immunodeficiency;
• Long-term corticosteroids;
• Ongoing immunosuppressive treatment;
• Transplanted patients;
• Tumors, hematological diseases;
• No health insurance coverage;
• Refusal to participate (from parents and/or patient) or inability to understand information.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Other: Children with infectious shock; Children aged from 1 month to <18 years. In 3 stratified groups : <2 years, 2-8 years, and >8 years. About one third of the patients are expected in each age-group.	Other: blood samples; Other: Collection of nosocomial infections
Other: Control group: healthy children; Healthy children aged-matched to cases (same stratification group, about 20 per age group); They will be hospitalized for an elective surgery (dental, ENT, maxillofacial, urologic, hernia surgery, neurosurgery without massive hemorrhage) and without any infection.	Other: blood samples; Other: Collection of nosocomial infections

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
proportion of patients with a mHLA-DR level <30%	mHLA-DR is measured by flow cytometry	up to Day 9
proportion of patients with a mHLA-DR level significantly lower than healthy children.	mHLA-DR is measured by flow cytometry	in the pre-operative period

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
total lymphocytes	From the whole blood samples, each lymphocytes sub-populations are determined by flow-cytometry with addition of specific monoclonal antibodies	Day 1
total lymphocytes	From the whole blood samples, each lymphocytes sub-populations are determined by flow-cytometry with addition of specific monoclonal antibodies	between Day 3 and day 5
total lymphocytes	From the whole blood samples, each lymphocytes sub-populations are determined by flow-cytometry with addition of specific monoclonal antibodies	between Day 7 and day 9
levels of CD4+	From the whole blood samples, each lymphocytes sub-populations are determined by flow-cytometry with addition of specific monoclonal antibodies	Day 1
levels of CD4+	From the whole blood samples, each lymphocytes sub-populations are determined by flow-cytometry with addition of specific monoclonal antibodies	between Day 3 and day 5
levels of CD4+	From the whole blood samples, each lymphocytes sub-populations are determined by flow-cytometry with addition of specific monoclonal antibodies	between Day 7 and day 9
levels of CD25+	From the whole blood samples, each lymphocytes sub-populations are determined by flow-cytometry with addition of specific monoclonal antibodies	day 1
levels of CD25+	From the whole blood samples, each lymphocytes sub-populations are determined by flow-cytometry with addition of specific monoclonal antibodies	between Day 3 and day 5
levels of CD25+	From the whole blood samples, each lymphocytes sub-populations are determined by flow-cytometry with addition of specific monoclonal antibodies	between Day 7 and day 9
levels of T lymphocytes (Treg)	From the whole blood samples, each lymphocytes sub-populations are determined by flow-cytometry with addition of specific monoclonal antibodies	Day 1
levels of T lymphocytes (Treg)	From the whole blood samples, each lymphocytes sub-populations are determined by flow-cytometry with addition of specific monoclonal antibodies	between Day 3 and day 5
levels of T lymphocytes (Treg)	From the whole blood samples, each lymphocytes sub-populations are determined by flow-cytometry with addition of specific monoclonal antibodies	between Day 7 and day 9
dosage of cytokines		Day 1
dosage of cytokines		between Day 3 and day 5
dosage of cytokines		between Day 7 and day 9
Number of nosocomial infections		up to Day 30
Type of nosocomial infections	bacteremia, ventilator-associated pneumonia, urinary tract infection, other sites.	up to Day 30
Mortality		up to Day 30
Length of vasoactive treatments		up to Day 30

Collaborators and Investigators

• Sponsor: Hospices Civils de Lyon
• Investigators: Principal Investigator: Etienne JAVOUHEY, Hospices Civils de Lyon

Publications and helpful links

General Publications

• Remy S, Kolev-Descamps K, Gossez M, Venet F, Demaret J, Javouhey E, Monneret G. Occurrence of marked sepsis-induced immunosuppression in pediatric septic shock: a pilot study. Ann Intensive Care. 2018 Mar 13;8(1):36. doi: 10.1186/s13613-018-0382-x.

Study record dates

Study Major Dates

• Study Start (Actual): September 26, 2014
• Primary Completion (Actual): August 4, 2018
• Study Completion (Actual): August 4, 2018

Study Registration Dates

• First Submitted: July 21, 2016
• First Submitted That Met QC Criteria: July 25, 2016
• First Posted (Estimate): July 28, 2016

Study Record Updates

• Last Update Posted (Actual): November 14, 2018
• Last Update Submitted That Met QC Criteria: November 9, 2018
• Last Verified: November 1, 2018

More Information

Terms related to this study

• Keywords: sepsis; immune response; Immunoparalysis; toxic shock syndrome
• Additional Relevant MeSH Terms: Pathologic Processes; Disease Attributes; Infections; Communicable Diseases; Shock
• Other Study ID Numbers: 69HCL16_0478

Plan for Individual participant data (IPD)

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