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

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.
Competing Interests: 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.
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