Hypofibrinogenemia Is Associated With Poor Outcome and Secondary Hemophagocytic Lymphohistiocytosis/Macrophage Activation Syndrome in Pediatric Severe Sepsis

Pediatr Crit Care Med. 2018 May;19(5):397-405. doi: 10.1097/PCC.0000000000001507.

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.

Publication types

  • Observational Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Afibrinogenemia / complications*
  • Afibrinogenemia / diagnosis
  • Afibrinogenemia / mortality
  • Case-Control Studies
  • Child
  • Child, Preschool
  • Female
  • Humans
  • Infant
  • Infant, Newborn
  • Lymphohistiocytosis, Hemophagocytic / diagnosis
  • Lymphohistiocytosis, Hemophagocytic / etiology*
  • Lymphohistiocytosis, Hemophagocytic / mortality
  • Macrophage Activation Syndrome / diagnosis
  • Macrophage Activation Syndrome / etiology*
  • Macrophage Activation Syndrome / mortality
  • Male
  • Multiple Organ Failure / diagnosis
  • Multiple Organ Failure / etiology
  • Prognosis
  • Retrospective Studies
  • Sepsis / complications*
  • Sepsis / diagnosis
  • Sepsis / mortality
  • Young Adult