Genotypes and Phenotypes in Pediatric SIRS and Sepsis

Study Overview
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Brief Summary
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The aim of this investigation is to longitudinally quantify host gene expression and serum proteins in children with infectious and non-infectious SIRS. The investigators hypothesize that children with non-infectious SIRS, with bacterial infection associated SIRS, or with viral infection associated SIRS will exhibit distinct patterns of host gene expression and serum proteins. The investigators further hypothesize that it should be possible to discover sets of mRNA or protein biomarkers that will permit unambiguous diagnosis of non-infectious SIRS, SIRS associated with bacterial infection, and SIRS associated with viral infection.

Detailed Description
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The investigators will undertake a proof-of-concept, pilot, prospective, observational trial that aims to recruit  90 children from the Seattle Children's Hospital Pediatric Intensive Care Unit (PICU) and Cardiac Intensive Care Unit (CICU). The study will plan to recruit 30 children who are scheduled for surgery to repair congenital cardiac malformations, 15 - 25 immunocompetent children with culture positive sepsis, and 15 - 25 immunocompromised children with culture positive sepsis, and 30-40 children who are polymerase chain reaction (PCR) positive for viral respiratory pathogens (RSV, influenza, parainfluenza, rhinovirus, etc), and who meet the eligibility criteria. In total, accounting for culture negative bacterial sepsis (estimated 40%), the investigators plan to enroll 50 children with sepsis, 30-40 with viral sepsis, and 20 children undergoing surgery for congenital heart disease. Demographic data will be collected at the time of ICU admission. Illness severity will be quantified by PRISM III and day 1 PELOD scores. Additional measures of sepsis severity will include oxygenation index, saturation index and duration of mechanical ventilation, vasoactive inotropic score and duration of vasoactive-inotropic support and highest serum creatinine on day 1. Resource utilization will be measured as PICU and hospital duration of stay. For all children enrolled in the study, blood samples will be obtained on study days 1, 2 and 3. For children with sepsis, if cultures remain sterile or PCR negative, no additional research blood samples will be obtained. For children with sepsis and a positive culture or positive PCR by study day 3, additional blood samples will be obtained on the day of PICU discharge.

Official Title
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Genotypes and Phenotypes in Pediatric SIRS and Sepsis (GAPPSS)

Conditions
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Systemic Inflammatory Response Syndrome (SIRS), Sepsis

Participation Criteria
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Eligibility Criteria
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A. INSI group: systemic inflammation, in the absence of culture positive infection. Cardiac surgery patients, n=30. Inclusion Criteria: Admission to the CICU AND Age  1-18 years AND Weight exceeding 10 kg Vascular catheter capable of providing the blood draw or anticipated orders for venipuncture for clinical labs AND Status post open heart surgery requiring cardiopulmonary bypass AND Parents speak English AND Not previously enrolled in the GAPPSS investigation Exclusion Criteria: Pre- or post-operative culture positive infection OR Not expected to survive the CICU stay OR Ward of the state OR Concurrent malignancy or autoimmune disorder B. CSSS (Clinical Severe Sepsis Syndrome) group: systemic inflammation, in the presence of highly suspected or documented bacterial infection. Children with clinical severe sepsis, n = 40. In this group, the investigators will enroll children who are immunocompetent as well as children who are immunocompromised. Inclusion Criteria: Admitted to the PICU AND Age newborn (>38 weeks EGA)-18 years AND Weight equal to or greater than 4 kg AND Vascular catheter capable of providing the blood draw or anticipated orders for venipuncture for clinical labs AND At least one organ dysfunction (severe sepsis) AND Parents speak English AND SIRS (systemic inflammatory response syndrome) AND Strongly suspected or documented source of infection Not previously enrolled in the GAPPSS investigation Exclusion Criteria: PICU nosocomial primary infection accounting for the sepsis event Not expected to survive the PICU stay Ward of the state C. Viral Infection group. Severe respiratory dysfunction in the presence of PCR -documented viral infection. Children with clinical severe viral sepsis, n=6. In this group, the investigators will enroll children who are immunocompetent as well as children who are immunocompromised. Inclusion Criteria: Admitted to the PICU AND Age newborn (>38 weeks EGA)-18 years AND Weight equal to or greater than 4 kg AND Vascular catheter capable of providing the blood draw or anticipated orders for venipuncture for clinical labs AND Parents speak English AND Severe respiratory dysfunction requiring invasive or non-invasive positive pressure mechanical ventilation support AND Positive PCR verifying a viral infection Not previously enrolled in the GAPPSS investigation Exclusion Criteria: PICU nosocomial primary infection accounting for the sepsis event Not expected to survive the PICU stay Ward of the state

Ages Eligible for Study
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Minimum Age: 38 Weeks
Maximum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| INSI<br>Infection-negative systemic inflammation (INSI). The INSI group consists of children who have undergone congenital cardiac defect corrective surgery requiring cardiopulmonary bypass, known to induce an INSI response for  24 hours thereafter; all children in this cohort are culture negative. This group is demarcated further by inclusion & exclusion criteria (see Eligibility section below). | |
| CSSS<br>Clinical severe sepsis syndrome (CSSS). Children assigned to the CSSS group had confirmed or highly suspected infection (microbial culture orders, antimicrobial prescription), exhibited 2 or more systemic inflammatory response syndrome criteria (including temperature and leukocyte criteria), and demonstrated at least cardiovascular ± pulmonary organ dysfunction. This group is demarcated further by inclusion & exclusion criteria (see Eligibility section below). | |
| Viral<br>The Viral Infection group consists of children who displayed signs and symptoms of severe viral infection, and who tested positive for respiratory viral infection(s) by a molecular virus panel test. These children were clinically evaluated to not have bacterial sepsis. This group is demarcated further by inclusion & exclusion criteria (see Eligibility section below). | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Gene Expression Levels | Gene expression levels (quantitative) will be compared between CSSS, INSI and viral infection groups, in a search for signatures that can discriminate these groups | Day 1 of admission to the pediatric intensive care unit (PICU) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Serum Protein Expression Profiles | Serum protein expression profiles (semi-quantitative) will be compared between CSSS and INSI groups, in a search for signatures that can discriminate the two groups | Day 1 of admission to the pediatric intensive care unit (PICU) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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sepsis, inflammation, pediatric, transcripts, serum proteins, cardiopulmonary bypass