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

Bradley S. Podd; Russell K. Banks; Ron Reeder; Russell Telford; Richard Holubkov; Joseph Carcillo; Robert A. Berg; David Wessel; Murray M. Pollack; Kathleen Meert; Mark Hall; Christopher Newth; John C. Lin; Allan Doctor; Tom Shanley; Tim Cornell; Rick E. Harrison; Athena F. Zuppa; Katherine Sward; J. Michael Dean; Adrienne G. Randolph

doi:10.1097/CCM.0000000000005993

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

Bradley S. Podd, Russell K. Banks, Ron Reeder, Russell Telford, Richard Holubkov, Joseph Carcillo^*, Robert A. Berg, David Wessel, Murray M. Pollack, Kathleen Meert, Mark Hall, Christopher Newth, John C. Lin, Allan Doctor, Tom Shanley, Tim Cornell, Rick E. Harrison, Athena F. Zuppa, Katherine Sward, J. Michael DeanAdrienne G. Randolph

^*Corresponding author for this work

Pediatrics

Research output: Contribution to journal › Article › peer-review

7 Scopus citations

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.

Original language	English (US)
Pages (from-to)	1766-1776
Number of pages	11
Journal	Critical care medicine
Volume	51
Issue number	12
DOIs	https://doi.org/10.1097/CCM.0000000000005993
State	Published - Dec 1 2023

Funding

Supported, in part, by grant R01GM108618 (to Dr. Carcillo) from the National Institute of General Medical Sciences, and by 5U01HD049934-10S1 (to Dr. Carcillo), and R21HD095228 (to Dr. Randolph), from the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Department of Health and Human Services and the following cooperative agreements: U10HD049983, U10HD050096, U10HD049981, U10HD063108, U10HD63106, U10HD063114, U10HD050012, and U01HD049934.

Keywords

lymphopenia
mortality
multiple organ dysfunction syndrome
pediatric
sepsis

ASJC Scopus subject areas

Critical Care and Intensive Care Medicine

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10.1097/CCM.0000000000005993

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Podd, B. S., Banks, R. K., Reeder, R., Telford, R., Holubkov, R., Carcillo, J., Berg, R. A., Wessel, D., Pollack, M. M., Meert, K., Hall, M., Newth, C., Lin, J. C., Doctor, A., Shanley, T., Cornell, T., Harrison, R. E., Zuppa, A. F., Sward, K., ... Randolph, A. G. (2023). Early, Persistent Lymphopenia Is Associated With Prolonged Multiple Organ Failure and Mortality in Septic Children. Critical care medicine, 51(12), 1766-1776. https://doi.org/10.1097/CCM.0000000000005993

@article{82189993316b461a91f4efeea540a380,

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

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.",

keywords = "lymphopenia, mortality, multiple organ dysfunction syndrome, pediatric, sepsis",

author = "Podd, {Bradley S.} and Banks, {Russell K.} and Ron Reeder and Russell Telford and Richard Holubkov and Joseph Carcillo and Berg, {Robert A.} and David Wessel and Pollack, {Murray M.} and Kathleen Meert and Mark Hall and Christopher Newth and Lin, {John C.} and Allan Doctor and Tom Shanley and Tim Cornell and Harrison, {Rick E.} and Zuppa, {Athena F.} and Katherine Sward and Dean, {J. Michael} and Randolph, {Adrienne G.}",

year = "2023",

month = dec,

day = "1",

doi = "10.1097/CCM.0000000000005993",

language = "English (US)",

volume = "51",

pages = "1766--1776",

journal = "Critical care medicine",

issn = "0090-3493",

publisher = "Lippincott Williams and Wilkins",

number = "12",

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Podd, BS, Banks, RK, Reeder, R, Telford, R, Holubkov, R, Carcillo, J, Berg, RA, Wessel, D, Pollack, MM, Meert, K, Hall, M, Newth, C, Lin, JC, Doctor, A, Shanley, T, Cornell, T, Harrison, RE, Zuppa, AF, Sward, K, Dean, JM & Randolph, AG 2023, 'Early, Persistent Lymphopenia Is Associated With Prolonged Multiple Organ Failure and Mortality in Septic Children', Critical care medicine, vol. 51, no. 12, pp. 1766-1776. https://doi.org/10.1097/CCM.0000000000005993

TY - JOUR

T1 - Early, Persistent Lymphopenia Is Associated With Prolonged Multiple Organ Failure and Mortality in Septic Children

AU - Podd, Bradley S.

AU - Banks, Russell K.

AU - Reeder, Ron

AU - Telford, Russell

AU - Holubkov, Richard

AU - Carcillo, Joseph

AU - Berg, Robert A.

AU - Wessel, David

AU - Pollack, Murray M.

AU - Meert, Kathleen

AU - Hall, Mark

AU - Newth, Christopher

AU - Lin, John C.

AU - Doctor, Allan

AU - Shanley, Tom

AU - Cornell, Tim

AU - Harrison, Rick E.

AU - Zuppa, Athena F.

AU - Sward, Katherine

AU - Dean, J. Michael

AU - Randolph, Adrienne G.

PY - 2023/12/1

Y1 - 2023/12/1

N2 - 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.

AB - 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.

KW - lymphopenia

KW - mortality

KW - multiple organ dysfunction syndrome

KW - pediatric

KW - sepsis

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UR - http://www.scopus.com/inward/citedby.url?scp=85178120208&partnerID=8YFLogxK

U2 - 10.1097/CCM.0000000000005993

DO - 10.1097/CCM.0000000000005993

M3 - Article

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AN - SCOPUS:85178120208

SN - 0090-3493

VL - 51

SP - 1766

EP - 1776

JO - Critical care medicine

JF - Critical care medicine

IS - 12

ER -

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

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