Clinical trial NCT02848144: Pediatric Immune Response to Infectious Shock
Official title: Pediatric Immune Response to Infectious Shock
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Severe Pediatric Infectious Shock
Keywords: Immunoparalysis
immune response
sepsis
toxic shock syndrome
Lead sponsor: Hospices Civils de Lyon
Sponsor class: OTHER
First posted: 2016-07-28
Enrollment: 105
Sex: ALL
Minimum age (years): 1
Maximum age (years): 17
Standard ages: CHILD
Accepts healthy volunteers: yes
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: BASIC_SCIENCE

Brief summary: 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.


Eligibility criteria: 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.

Primary outcomes:
measure: proportion of patients with a mHLA-DR level <30%
timeFrame: up to Day 9
measure: proportion of patients with a mHLA-DR level significantly lower than healthy children.
timeFrame: in the pre-operative period
Secondary outcomes:
measure: total lymphocytes
timeFrame: Day 1
measure: total lymphocytes
timeFrame: between Day 3 and day 5
measure: total lymphocytes
timeFrame: between Day 7 and day 9
measure: levels of CD4+
timeFrame: Day 1
measure: levels of CD4+
timeFrame: between Day 3 and day 5
measure: levels of CD4+
timeFrame: between Day 7 and day 9
measure: levels of CD25+
timeFrame: day 1
measure: levels of CD25+
timeFrame: between Day 3 and day 5
measure: levels of CD25+
timeFrame: between Day 7 and day 9
measure: levels of T lymphocytes (Treg)
timeFrame: Day 1
measure: levels of T lymphocytes (Treg)
timeFrame: between Day 3 and day 5
measure: levels of T lymphocytes (Treg)
timeFrame: between Day 7 and day 9
measure: dosage of cytokines
timeFrame: Day 1
measure: dosage of cytokines
timeFrame: between Day 3 and day 5
measure: dosage of cytokines
timeFrame: between Day 7 and day 9
measure: Number of nosocomial infections
timeFrame: up to Day 30
measure: Type of nosocomial infections
timeFrame: up to Day 30
measure: Mortality
timeFrame: up to Day 30
measure: Length of vasoactive treatments
timeFrame: up to Day 30
Other outcomes:
Locations:
city: Lyon
country: France
facility: Hospices Civils de Lyon
Study officials:
affiliation: Hospices Civils de Lyon
name: Etienne JAVOUHEY
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.