Adaptive Immune Function and Immunoparalysis in Children With Septic Shock

Saturday, January 21, 2023

5:15 PM – 5:30 PM PT

Location: 201

First Author(s)

Diego A. Cruz Vidal, MD, (he/him/his)

Fellow, Pediatric Infectious Diseases
Nationwide Children's Hospital
Columbus, Ohio

Disclosure information not submitted.

Co-Author(s)

Jennifer Muszynski, MD, MPH, FCCM

Nationwide Children's Hospital At Ohio State University
Columbus, Ohio

Disclosure information not submitted.
IG

Ian Goldthwaite, BS

Research Associate
Nationwide Children's Hospital
Columbus, Ohio, United States

Disclosure information not submitted.
LA

Leahmaria Ayad, BS

Research Associate
Nationwide Children's Hospital
Columbus, Ohio, United States

Disclosure information not submitted.
JP

Jill Popelka, RN

Clinical Research Coordinator
Nationwide Children's Hospital, United States

Disclosure information not submitted.
JH

Josey Hensley, RN

Research Nurse
Nationwide Children's Hospital, United States

Disclosure information not submitted.
AS

Andrew Snyder, PhD

Senior Research Associate
Nationwide Children's Hospital
Columbus, Ohio, United States

Disclosure information not submitted.
AW

Amber Wolfe, RN

Clinical Research Coordinator
Nationwide Children's Hospital
Columbus, Ohio, United States

Disclosure information not submitted.
Mark W. Hall, MD, FCCM

Chief Division Pediatric Critical Care Medicine
Nationwide Children's Hospital At Ohio State University
Columbus, Ohio

Disclosure(s): Abbvie: Consulting fees or other remuneration (Ongoing); Partner Therapeutics: Other Research Support (includes receipt of drugs, supplies, equipment or other in-kind support) (Ongoing); Sobi: Other Research Support (includes receipt of drugs, supplies, equipment or other in-kind support) (Ongoing)

Disclosure(s):

Mark W. Hall, MD, FCCM: Abbvie: Consulting fees or other remuneration (Ongoing); Partner Therapeutics: Other Research Support (includes receipt of drugs, supplies, equipment or other in-kind support) (Ongoing); Sobi: Other Research Support (includes receipt of drugs, supplies, equipment or other in-kind support) (Ongoing)

INTRODUCTION: Immunoparalysis is defined in children by severe reduction in innate immune function (whole blood ex vivo LPS-induced TNFα production capacity < 200 pg/ml). Adaptive (lymphocyte) immune function is poorly understood in this setting. We hypothesize that septic children with immunoparalysis will have concurrent suppression of lymphocyte cytokine production capacity.

METHODS : This single-center, prospective, observational study is open to children < 18 years old, excluding those with leukopenia due to myeloablative therapy. Subjects are enrolled and sampled within 48 hours of septic shock onset. Whole blood is stimulated with 500 pg/ml LPS for 4 hrs at 37°C and TNFα is measured in the supernatant. Additional whole blood aliquots are stimulated with 10 µg/ml phytohemagglutinin (PHA, a lymphocyte stimulant) for 24 hrs at 37°C and interleukin (IL)-2, IL4, IL5, IL10, IL12, IL13, IL17, IFNγ, and TNFα are measured in the supernatants. Identical sampling and processing were done in a cohort of healthy control children. Data represent median (IQR).

RESULTS: 16 children with septic shock (age: 15 [8-16] yrs, 58% male, PRISM III score: 9 [6-12]) and 6 healthy controls (age: 7 [5-9] yrs, 67% male) have been enrolled to date. Among septic subjects, 12% had baseline immunocompromise, 56% received hydrocortisone, and 6 (38%) had immunoparalysis. Ex vivo PHA-induced cytokine production was lower in subjects with immunoparalysis vs healthy controls for IL2 (6.1 vs 65 pg/ml, p=0.03), IL4 (0.24 vs 1.7 pg/ml, p=0.02), IL5 (6.9 vs 12 pg/ml, p=0.009), IL12 (1.7 vs 5.0 pg/ml, p=0.008), and TNFα (90.4 vs 4146 pg/ml, p=0.003). Subjects without immunoparalysis had lower ex vivo PHA-induced production capacities for IL5 (6.9 vs 12 pg/ml, p=0.006), IL12 (1.7 vs 5.0 pg/ml, p=0.0005), and TNFα (502 vs 4146 pg/ml, p=0.03) vs healthy controls.

CONCLUSIONS: Immunoparalysis in septic children is associated with suppression of both innate and adaptive immune responses. Suppression of PHA-induced IL5, IL12, and TNFα production was seen in all septic children. Suppression of PHA-induced IL2 and IL4 production was only seen in children with immunoparalysis. This approach could be used to drive enrollment into future clinical trials of immunomodulatory therapies aimed at restoring adaptive immune function in septic children.