Immunoparalysis and nosocomial infection in children with multiple organ dysfunction syndrome

Abstract

Purpose: Immunoparalysis defined by prolonged monocyte human leukocyte antigen DR depression is associated with adverse outcomes in adult severe sepsis and can be reversed with granulocyte macrophage colony-stimulating factor (GM-CSF). We hypothesized that immunoparalysis defined by whole-blood ex vivo lipopolysaccharide-induced tumor necrosis factor-alpha (TNFα) response <200 pg/mL beyond day 3 of multiple organ dysfunction syndrome (MODS) is similarly associated with nosocomial infection in children and can be reversed with GM-CSF.

Methods: In study period 1, we performed a multicenter cohort trial of transplant and nontransplant multiple organ dysfunction syndrome (MODS) patients (≥2 organ failure). In study period 2, we performed an open-label randomized trial of GM-CSF therapy for nonneutropenic, nontransplant, severe MODS patients (≥3 organ failure) with TNFα response <160 pg/mL.

Results: Immunoparalysis was observed in 34% of MODS patients (n = 70) and was associated with increased nosocomial infection (relative risk [RR] 3.3, 95% confidence interval [1.8-6.0] p < 0.05) and mortality (RR 5.8 [2.1-16] p < 0.05). TNFα response <200 pg/mL throughout 7 days after positive culture was associated with persistent nosocomial infection, whereas recovery above 200 pg/mL was associated with resolution of infection (p < 0.05). In study period 2, GM-CSF therapy facilitated rapid recovery of TNFα response to >200 pg/mL by 7 days (p < 0.05) and prevented nosocomial infection (no infections in seven patients versus eight infections in seven patients) (p < 0.05).

Conclusions: Similar to in adults, immunoparalysis is a potentially reversible risk factor for development of nosocomial infection in pediatric MODS. Whole-blood ex vivo TNFα response is a promising biomarker for monitoring this condition.

Fig. 1

Monocyte HLA-DR expression and ex vivo LPS-induced TNFα response in 27 children with MODS. These children underwent measurement of both biomarkers on day 7 of MODS. Top Children who went on to develop nosocomial infection (gray squares) had lower ex vivo LPS-induced TNFα production and monocyte HLA-DR expression compared with children who recovered without developing infection (open circles). Bottom Children who went on to die (gray squares) similarly demonstrated lower immune function compared with survivors (open circles). The dashed lines show the biomarker threshold levels which define immunoparalysis. Patients below these thresholds had greater risk of developing nosocomial infection and death (p < 0.01)

Fig. 2

GM-CSF therapy in nontransplant, nonneutropenic patients resulted in increased LPS sensitivity and prevention of development of nosocomial infection without increasing systemic inflammation. Children with ex vivo LPS-induced TNFα production <160 pg/mL on day 3 of MODS were randomized to receive GM-CSF or standard therapy. Top Children receiving GM-CSF (open circles, n = 7) demonstrated more rapid recovery of ex vivo LPS-induced TNFα production >200 pg/mL compared with children receiving standard therapy alone (filled squares, n = 7) (p = 0.001; two-way RM-ANOVA). Bottom The seven patients who received standard care all developed nosocomial infections, with one patient developing two, for a total of eight nosocomial infections (three Gram negative, five fungal). At day 7 and 14, six patients had active infections, and at day 2, three patients had active infections. No nosocomial infections were observed in the GM-CSF-treated group (p < 0.05)