Hypofibrinogenemia is associated with poor outcome and secondary hemophagocytic lymphohistiocytosis/macrophage activation syndrome in pediatric severe sepsis

Jessica Signoff, Julie C. Fitzgerald, David T. Teachey, Fran Balamuth, Scott L. Weiss

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

Objectives: Some children with sepsis exhibit a sustained hyperinflammatory response that can trigger secondary hemophagocytic lymphohistiocytosis/macrophage activation syndrome. Although hypofibrinogenemia is a shared feature of sepsis and hemophagocytic lymphohistiocytosis, there are no data about fibrinogen as a biomarker to identify children with sepsis/secondary hemophagocytic lymphohistiocytosis/macrophage activation syndrome overlap. We hypothesized that hypofibrinogenemia is associated with poor outcomes and secondary hemophagocytic lymphohistiocytosis/macrophage activation syndrome and has utility as a screening biomarker for this sepsis phenotype. Design: A retrospective cohort study of patients less than or equal to 21 years treated for severe sepsis from January 2012 to December 2014. Setting: Emergency department and PICU at a single academic children's hospital. Patients: Consecutive patients with greater than or equal to one episode of hypofibrinogenemia (serum fibrinogen < 150 mg/dL) within 7 days of sepsis were compared with a random sample of patients without hypofibrinogenemia using an a priori sample size target of 190. Thirty-eight patients with hypofibrinogenemia were compared with 154 without hypofibrinogenemia. Interventions: None. Measurements and Main Results: The primary outcome was "complicated course" (composite of 28-d mortality or ≥ two organ failures at 7 d). Secondary outcomes were 28-day mortality and fulfillment of diagnostic criteria for secondary hemophagocytic lymphohistiocytosis/macrophage activation syndrome. We used Wilcoxon rank-sum, Fisher exact test, and multivariable logistic regression to compare patients with versus without hypofibrinogenemia. Patients with hypofibrinogenemia were more likely to have a complicated course (73.7% vs 29.2%; p < 0.001), 28-day mortality (26.3% vs 7.1%, p = 0.002), and meet diagnostic criteria for secondary hemophagocytic lymphohistiocytosis/ macrophage activation syndrome (21.1% vs 1.3%; p < 0.001). After controlling for confounders, hypofibrinogenemia remained associated with complicated course (adjusted odds ratio, 8.8; 95% CI, 3.5.22.4), mortality (adjusted odds ratio, 6.0; 95% CI, 2.0.18.1), and secondary hemophagocytic lymphohistiocytosis/macrophage activation syndrome (adjusted odds ratio, 27.6; 95% CI, 4.4.173). Conclusions: Hypofibrinogenemia was independently associated with poor outcome and secondary hemophagocytic lymphohistiocytosis/ macrophage activation syndrome in pediatric sepsis. Measurement of fibrinogen may provide a pragmatic biomarker to identify children with possible sepsis/secondary hemophagocytic lymphohistiocytosis/macrophage activation syndrome overlap for whom further diagnostic testing and consideration of adjunctive immunomodulatory therapies should be considered.

Original languageEnglish (US)
Pages (from-to)397-405
Number of pages9
JournalPediatric Critical Care Medicine
Volume19
Issue number5
DOIs
StatePublished - May 1 2018

Fingerprint

Macrophage Activation Syndrome
Hemophagocytic Lymphohistiocytosis
Sepsis
Pediatrics
Fibrinogen
Mortality
Biomarkers
Odds Ratio
Immunomodulation
Sample Size
Hospital Emergency Service
Cohort Studies
Retrospective Studies
Logistic Models

Keywords

  • Hemophagocytic lymphohistiocytosis
  • Hemophagocytic syndrome
  • Pediatrics
  • Reactive
  • Sepsis

ASJC Scopus subject areas

  • Pediatrics, Perinatology, and Child Health
  • Critical Care and Intensive Care Medicine

Cite this

Hypofibrinogenemia is associated with poor outcome and secondary hemophagocytic lymphohistiocytosis/macrophage activation syndrome in pediatric severe sepsis. / Signoff, Jessica; Fitzgerald, Julie C.; Teachey, David T.; Balamuth, Fran; Weiss, Scott L.

In: Pediatric Critical Care Medicine, Vol. 19, No. 5, 01.05.2018, p. 397-405.

Research output: Contribution to journalArticle

@article{c1023c1714de458b93a23d2c34a754d1,
title = "Hypofibrinogenemia is associated with poor outcome and secondary hemophagocytic lymphohistiocytosis/macrophage activation syndrome in pediatric severe sepsis",
abstract = "Objectives: Some children with sepsis exhibit a sustained hyperinflammatory response that can trigger secondary hemophagocytic lymphohistiocytosis/macrophage activation syndrome. Although hypofibrinogenemia is a shared feature of sepsis and hemophagocytic lymphohistiocytosis, there are no data about fibrinogen as a biomarker to identify children with sepsis/secondary hemophagocytic lymphohistiocytosis/macrophage activation syndrome overlap. We hypothesized that hypofibrinogenemia is associated with poor outcomes and secondary hemophagocytic lymphohistiocytosis/macrophage activation syndrome and has utility as a screening biomarker for this sepsis phenotype. Design: A retrospective cohort study of patients less than or equal to 21 years treated for severe sepsis from January 2012 to December 2014. Setting: Emergency department and PICU at a single academic children's hospital. Patients: Consecutive patients with greater than or equal to one episode of hypofibrinogenemia (serum fibrinogen < 150 mg/dL) within 7 days of sepsis were compared with a random sample of patients without hypofibrinogenemia using an a priori sample size target of 190. Thirty-eight patients with hypofibrinogenemia were compared with 154 without hypofibrinogenemia. Interventions: None. Measurements and Main Results: The primary outcome was {"}complicated course{"} (composite of 28-d mortality or ≥ two organ failures at 7 d). Secondary outcomes were 28-day mortality and fulfillment of diagnostic criteria for secondary hemophagocytic lymphohistiocytosis/macrophage activation syndrome. We used Wilcoxon rank-sum, Fisher exact test, and multivariable logistic regression to compare patients with versus without hypofibrinogenemia. Patients with hypofibrinogenemia were more likely to have a complicated course (73.7{\%} vs 29.2{\%}; p < 0.001), 28-day mortality (26.3{\%} vs 7.1{\%}, p = 0.002), and meet diagnostic criteria for secondary hemophagocytic lymphohistiocytosis/ macrophage activation syndrome (21.1{\%} vs 1.3{\%}; p < 0.001). After controlling for confounders, hypofibrinogenemia remained associated with complicated course (adjusted odds ratio, 8.8; 95{\%} CI, 3.5.22.4), mortality (adjusted odds ratio, 6.0; 95{\%} CI, 2.0.18.1), and secondary hemophagocytic lymphohistiocytosis/macrophage activation syndrome (adjusted odds ratio, 27.6; 95{\%} CI, 4.4.173). Conclusions: Hypofibrinogenemia was independently associated with poor outcome and secondary hemophagocytic lymphohistiocytosis/ macrophage activation syndrome in pediatric sepsis. Measurement of fibrinogen may provide a pragmatic biomarker to identify children with possible sepsis/secondary hemophagocytic lymphohistiocytosis/macrophage activation syndrome overlap for whom further diagnostic testing and consideration of adjunctive immunomodulatory therapies should be considered.",
keywords = "Hemophagocytic lymphohistiocytosis, Hemophagocytic syndrome, Pediatrics, Reactive, Sepsis",
author = "Jessica Signoff and Fitzgerald, {Julie C.} and Teachey, {David T.} and Fran Balamuth and Weiss, {Scott L.}",
year = "2018",
month = "5",
day = "1",
doi = "10.1097/PCC.0000000000001507",
language = "English (US)",
volume = "19",
pages = "397--405",
journal = "Pediatric Critical Care Medicine",
issn = "1529-7535",
publisher = "Lippincott Williams and Wilkins",
number = "5",

}

TY - JOUR

T1 - Hypofibrinogenemia is associated with poor outcome and secondary hemophagocytic lymphohistiocytosis/macrophage activation syndrome in pediatric severe sepsis

AU - Signoff, Jessica

AU - Fitzgerald, Julie C.

AU - Teachey, David T.

AU - Balamuth, Fran

AU - Weiss, Scott L.

PY - 2018/5/1

Y1 - 2018/5/1

N2 - Objectives: Some children with sepsis exhibit a sustained hyperinflammatory response that can trigger secondary hemophagocytic lymphohistiocytosis/macrophage activation syndrome. Although hypofibrinogenemia is a shared feature of sepsis and hemophagocytic lymphohistiocytosis, there are no data about fibrinogen as a biomarker to identify children with sepsis/secondary hemophagocytic lymphohistiocytosis/macrophage activation syndrome overlap. We hypothesized that hypofibrinogenemia is associated with poor outcomes and secondary hemophagocytic lymphohistiocytosis/macrophage activation syndrome and has utility as a screening biomarker for this sepsis phenotype. Design: A retrospective cohort study of patients less than or equal to 21 years treated for severe sepsis from January 2012 to December 2014. Setting: Emergency department and PICU at a single academic children's hospital. Patients: Consecutive patients with greater than or equal to one episode of hypofibrinogenemia (serum fibrinogen < 150 mg/dL) within 7 days of sepsis were compared with a random sample of patients without hypofibrinogenemia using an a priori sample size target of 190. Thirty-eight patients with hypofibrinogenemia were compared with 154 without hypofibrinogenemia. Interventions: None. Measurements and Main Results: The primary outcome was "complicated course" (composite of 28-d mortality or ≥ two organ failures at 7 d). Secondary outcomes were 28-day mortality and fulfillment of diagnostic criteria for secondary hemophagocytic lymphohistiocytosis/macrophage activation syndrome. We used Wilcoxon rank-sum, Fisher exact test, and multivariable logistic regression to compare patients with versus without hypofibrinogenemia. Patients with hypofibrinogenemia were more likely to have a complicated course (73.7% vs 29.2%; p < 0.001), 28-day mortality (26.3% vs 7.1%, p = 0.002), and meet diagnostic criteria for secondary hemophagocytic lymphohistiocytosis/ macrophage activation syndrome (21.1% vs 1.3%; p < 0.001). After controlling for confounders, hypofibrinogenemia remained associated with complicated course (adjusted odds ratio, 8.8; 95% CI, 3.5.22.4), mortality (adjusted odds ratio, 6.0; 95% CI, 2.0.18.1), and secondary hemophagocytic lymphohistiocytosis/macrophage activation syndrome (adjusted odds ratio, 27.6; 95% CI, 4.4.173). Conclusions: Hypofibrinogenemia was independently associated with poor outcome and secondary hemophagocytic lymphohistiocytosis/ macrophage activation syndrome in pediatric sepsis. Measurement of fibrinogen may provide a pragmatic biomarker to identify children with possible sepsis/secondary hemophagocytic lymphohistiocytosis/macrophage activation syndrome overlap for whom further diagnostic testing and consideration of adjunctive immunomodulatory therapies should be considered.

AB - Objectives: Some children with sepsis exhibit a sustained hyperinflammatory response that can trigger secondary hemophagocytic lymphohistiocytosis/macrophage activation syndrome. Although hypofibrinogenemia is a shared feature of sepsis and hemophagocytic lymphohistiocytosis, there are no data about fibrinogen as a biomarker to identify children with sepsis/secondary hemophagocytic lymphohistiocytosis/macrophage activation syndrome overlap. We hypothesized that hypofibrinogenemia is associated with poor outcomes and secondary hemophagocytic lymphohistiocytosis/macrophage activation syndrome and has utility as a screening biomarker for this sepsis phenotype. Design: A retrospective cohort study of patients less than or equal to 21 years treated for severe sepsis from January 2012 to December 2014. Setting: Emergency department and PICU at a single academic children's hospital. Patients: Consecutive patients with greater than or equal to one episode of hypofibrinogenemia (serum fibrinogen < 150 mg/dL) within 7 days of sepsis were compared with a random sample of patients without hypofibrinogenemia using an a priori sample size target of 190. Thirty-eight patients with hypofibrinogenemia were compared with 154 without hypofibrinogenemia. Interventions: None. Measurements and Main Results: The primary outcome was "complicated course" (composite of 28-d mortality or ≥ two organ failures at 7 d). Secondary outcomes were 28-day mortality and fulfillment of diagnostic criteria for secondary hemophagocytic lymphohistiocytosis/macrophage activation syndrome. We used Wilcoxon rank-sum, Fisher exact test, and multivariable logistic regression to compare patients with versus without hypofibrinogenemia. Patients with hypofibrinogenemia were more likely to have a complicated course (73.7% vs 29.2%; p < 0.001), 28-day mortality (26.3% vs 7.1%, p = 0.002), and meet diagnostic criteria for secondary hemophagocytic lymphohistiocytosis/ macrophage activation syndrome (21.1% vs 1.3%; p < 0.001). After controlling for confounders, hypofibrinogenemia remained associated with complicated course (adjusted odds ratio, 8.8; 95% CI, 3.5.22.4), mortality (adjusted odds ratio, 6.0; 95% CI, 2.0.18.1), and secondary hemophagocytic lymphohistiocytosis/macrophage activation syndrome (adjusted odds ratio, 27.6; 95% CI, 4.4.173). Conclusions: Hypofibrinogenemia was independently associated with poor outcome and secondary hemophagocytic lymphohistiocytosis/ macrophage activation syndrome in pediatric sepsis. Measurement of fibrinogen may provide a pragmatic biomarker to identify children with possible sepsis/secondary hemophagocytic lymphohistiocytosis/macrophage activation syndrome overlap for whom further diagnostic testing and consideration of adjunctive immunomodulatory therapies should be considered.

KW - Hemophagocytic lymphohistiocytosis

KW - Hemophagocytic syndrome

KW - Pediatrics

KW - Reactive

KW - Sepsis

UR - http://www.scopus.com/inward/record.url?scp=85051802641&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85051802641&partnerID=8YFLogxK

U2 - 10.1097/PCC.0000000000001507

DO - 10.1097/PCC.0000000000001507

M3 - Article

C2 - 29470247

AN - SCOPUS:85051802641

VL - 19

SP - 397

EP - 405

JO - Pediatric Critical Care Medicine

JF - Pediatric Critical Care Medicine

SN - 1529-7535

IS - 5

ER -