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

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

Research output: Contribution to journalArticle

6 Scopus citations

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
Externally publishedYes

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Keywords

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

ASJC Scopus subject areas

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

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