Observational Study

. 2023 Dec 1;51(12):1766-1776.

doi: 10.1097/CCM.0000000000005993. Epub 2023 Jul 18.

Early, Persistent Lymphopenia Is Associated With Prolonged Multiple Organ Failure and Mortality in Septic Children

Bradley S Podd^{1

2}, Russell K Banks³, Ron Reeder³, Russell Telford⁴, Richard Holubkov³, Joseph Carcillo^{1

2}, Robert A Berg⁵, David Wessel⁶, Murray M Pollack⁶, Kathleen Meert^{7

8}, Mark Hall⁹, Christopher Newth¹⁰, John C Lin¹¹, Allan Doctor¹¹, Tom Shanley¹², Tim Cornell¹², Rick E Harrison¹³, Athena F Zuppa⁵, Katherine Sward³, J Michael Dean³, Adrienne G Randolph¹⁴; on behalf of the Eunice Kennedy Shriver National Institute of Child Health and Human Development Collaborative Pediatric Critical Care Research Network

Affiliations

¹ Division of Pediatric Critical Care Medicine, Department of Critical Care Medicine, Children's Hospital of Pittsburgh, Center for Critical Care Nephrology and Clinical Research Investigation and Systems Modeling of Acute Illness Center, University of Pittsburgh, Pittsburgh, PA.
² Department of Pediatrics, University of Pittsburgh, Pittsburgh, PA.
³ Department of Pediatrics, University of Utah, Salt Lake City, UT.
⁴ Department of Statistics, Carnegie Mellon University, Pittsburgh, PA.
⁵ Department of Anesthesiology, Children's Hospital of Philadelphia, Philadelphia, PA.
⁶ Division of Critical Care Medicine, Department of Pediatrics, Children's National Hospital, Washington, DC.
⁷ Division of Critical Care Medicine, Department of Pediatrics, Children's Hospital of Michigan, Detroit, MI.
⁸ Department of Pediatrics, Central Michigan University, Mt. Pleasant, MI.
⁹ Division of Critical Care Medicine, Department of Pediatrics, The Research Institute at Nationwide Children's Hospital Immune Surveillance Laboratory, and Nationwide Children's Hospital, Columbus, OH.
¹⁰ Division of Pediatric Critical Care Medicine, Department of Anesthesiology and Pediatrics, Children's Hospital Los Angeles, Los Angeles, CA.
¹¹ Division of Critical Care Medicine, Department of Pediatrics, St. Louis Children's Hospital, St. Louis, MO.
¹² Division of Critical Care Medicine, Department of Pediatrics, C. S. Mott Children's Hospital, Ann Arbor, MI.
¹³ Division of Critical Care Medicine, Department of Pediatrics, Mattel Children's Hospital at University of California Los Angeles, Los Angeles, CA.
¹⁴ Department of Anesthesiology, Critical Care and Pain Medicine, Boston Children's Hospital, Boston, MA.

PMID: 37462434
DOI: 10.1097/CCM.0000000000005993

Observational Study

Early, Persistent Lymphopenia Is Associated With Prolonged Multiple Organ Failure and Mortality in Septic Children

Bradley S Podd et al. Crit Care Med. 2023.

. 2023 Dec 1;51(12):1766-1776.

doi: 10.1097/CCM.0000000000005993. Epub 2023 Jul 18.

Authors

Affiliations

¹ Division of Pediatric Critical Care Medicine, Department of Critical Care Medicine, Children's Hospital of Pittsburgh, Center for Critical Care Nephrology and Clinical Research Investigation and Systems Modeling of Acute Illness Center, University of Pittsburgh, Pittsburgh, PA.
² Department of Pediatrics, University of Pittsburgh, Pittsburgh, PA.
³ Department of Pediatrics, University of Utah, Salt Lake City, UT.
⁴ Department of Statistics, Carnegie Mellon University, Pittsburgh, PA.
⁵ Department of Anesthesiology, Children's Hospital of Philadelphia, Philadelphia, PA.
⁶ Division of Critical Care Medicine, Department of Pediatrics, Children's National Hospital, Washington, DC.
⁷ Division of Critical Care Medicine, Department of Pediatrics, Children's Hospital of Michigan, Detroit, MI.
⁸ Department of Pediatrics, Central Michigan University, Mt. Pleasant, MI.
⁹ Division of Critical Care Medicine, Department of Pediatrics, The Research Institute at Nationwide Children's Hospital Immune Surveillance Laboratory, and Nationwide Children's Hospital, Columbus, OH.
¹⁰ Division of Pediatric Critical Care Medicine, Department of Anesthesiology and Pediatrics, Children's Hospital Los Angeles, Los Angeles, CA.
¹¹ Division of Critical Care Medicine, Department of Pediatrics, St. Louis Children's Hospital, St. Louis, MO.
¹² Division of Critical Care Medicine, Department of Pediatrics, C. S. Mott Children's Hospital, Ann Arbor, MI.
¹³ Division of Critical Care Medicine, Department of Pediatrics, Mattel Children's Hospital at University of California Los Angeles, Los Angeles, CA.
¹⁴ Department of Anesthesiology, Critical Care and Pain Medicine, Boston Children's Hospital, Boston, MA.

PMID: 37462434
DOI: 10.1097/CCM.0000000000005993

Abstract

Objectives: Sepsis-associated immune suppression correlates with poor outcomes. Adult trials are evaluating immune support therapies. Limited data exist to support consideration of immunomodulation in pediatric sepsis. We tested the hypothesis that early, persistent lymphopenia predicts worse outcomes in pediatric severe sepsis.

Design: Observational cohort comparing children with severe sepsis and early, persistent lymphopenia (absolute lymphocyte count < 1,000 cells/µL on 2 d between study days 0-5) to children without. The composite outcome was prolonged multiple organ dysfunction syndrome (MODS, organ dysfunction beyond day 7) or PICU mortality.

Setting: Nine PICUs in the National Institutes of Health Collaborative Pediatric Critical Care Research Network between 2015 and 2017.

Patients: Children with severe sepsis and indwelling arterial and/or central venous catheters.

Interventions: Blood sampling and clinical data analysis.

Measurements and main results: Among 401 pediatric patients with severe sepsis, 152 (38%) had persistent lymphopenia. These patients were older, had higher illness severity, and were more likely to have underlying comorbidities including solid organ transplant or malignancy. Persistent lymphopenia was associated with the composite outcome prolonged MODS or PICU mortality (66/152, 43% vs 45/249, 18%; p < 0.01) and its components prolonged MODS (59/152 [39%] vs 43/249 [17%]), and PICU mortality (32/152, 21% vs 12/249, 5%; p < 0.01) versus children without. After adjusting for baseline factors at enrollment, the presence of persistent lymphopenia was associated with an odds ratio of 2.98 (95% CI [1.85-4.02]; p < 0.01) for the composite outcome. Lymphocyte count trajectories showed that patients with persistent lymphopenia generally did not recover lymphocyte counts during the study, had lower nadir whole blood tumor necrosis factor-α response to lipopolysaccharide stimulation, and higher maximal inflammatory markers (C-reactive protein and ferritin) during days 0-3 ( p < 0.01).

Conclusions: Children with severe sepsis and persistent lymphopenia are at risk of prolonged MODS or PICU mortality. This evidence supports testing therapies for pediatric severe sepsis patients risk-stratified by early, persistent lymphopenia.

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Conflict of interest statement

Drs. Banks’s, Carcillo’s, Pollack’s, and Sward’s institutions received funding from the National Institute of Child Health and Human Development. Drs. Banks, Reeder, Holubkov, Carcillo, Berg, Wessel, Pollack, Meert, Hall, Newth, Doctor, Shanley, Cornell, Harrison, Zuppa, Sward, Dean, and Randolph received support for article research from the National Institutes of Health (NIH). Dr. Banks disclosed government work. Drs. Reeder’s, Holubkov’s, Berg’s, Wessel’s, Meert’s, Hall’s, Newth’s, Doctor’s, Shanley’s, Harrison’s, Zuppa’s, and Dean’s institutions received funding from the NIH. Dr. Holubkov received funding from Pfizer (Data Safety Monitoring Board [DSMB] member), Medimmune (DSMB member), Physicians Committee for Responsible Medicine (biostatistical consulting), REVANCE, DURECT Corporation (biostatistical consulting), Armaron Bio (DSMB past member), and St Jude Medical (DSMB past member). Dr. Carcillo’s institution received funding from the National Institute of General Medical Sciences. Dr. Hall received funding from Abbvie, La Jolla Pharmaceuticals, and Kiadis. Dr. Doctor’s institution received funding from the Department of Defense and KaloCyte. Dr. Randolph disclosed that she is the Treasurer and Chair Elect for the International Sepsis Forum. Dr. Pollack disclosed that his research is supported by philanthropy from Mallinckrodt Pharmaceuticals. Drs. Hall and Randolph received funding from LaJolla Pharmaceuticals (service as a consultant), unrelated to the current submission. Dr. Randolph receives royalties from UpToDate. Dr. Newth received funding from Philips Research North America. Dr. Shanley received funding from Springer publishing, International Pediatric Research Foundation, and Pediatric Academic Societies. Dr. Cornell disclosed he is co-founder of Pre-Dixon Bio. The remaining authors have disclosed that they do not have any potential conflicts of interest.

References

1. Weiss SL, Fitzgerald JC, Pappachan J, et al.; Sepsis Prevalence, Outcomes, and Therapies (SPROUT) Study Investigators and Pediatric Acute Lung Injury and Sepsis Investigators (PALISI) Network: Global epidemiology of pediatric severe sepsis: The sepsis prevalence, outcomes, and therapies study. Am J Respir Crit Care Med. 2015; 191:1147–1157
1. Vulliamy PE, Perkins ZB, Brohi K, et al.: Persistent lymphopenia is an independent predictor of mortality in critically ill emergency general surgical patients. Eur J Trauma Emerg Surg. 2016; 42:755–760
1. Felmet KA, Hall MW, Clark RSB, et al.: Prolonged lymphopenia, lymphoid depletion, and hypoprolactinemia in children with nosocomial sepsis and multiple organ failure. J Immunol. 2005; 174:3765–3772
1. Hall MW, Knatz NL, Vetterly C, et al.: Immunoparalysis and nosocomial infection in children with multiple organ dysfunction syndrome. Intensive Care Med. 2011; 37:525–532
1. Hotchkiss RS, Swanson PE, Freeman BD, et al.: Apoptotic cell death in patients with sepsis, shock, and multiple organ dysfunction. Crit Care Med. 1999; 27:1230–1251

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Early, Persistent Lymphopenia Is Associated With Prolonged Multiple Organ Failure and Mortality in Septic Children

Affiliations

Early, Persistent Lymphopenia Is Associated With Prolonged Multiple Organ Failure and Mortality in Septic Children

Authors

Affiliations

Abstract

Conflict of interest statement

References

Publication types

MeSH terms

Grants and funding

LinkOut - more resources

Full Text Sources

Medical

Research Materials