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.

Global Epidemiology of Pediatric Severe Sepsis: The Sepsis Prevalence, Outcomes, and Therapies Study

“…The hospital mortality rate of 25% confirms that severe sepsis remains a critical public 23 (12-28) 20 (5-26) 21 25 (19-28) 26 (20-28) 25 (16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28) 22 (12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28) ,0.001…”

“…Hospital mortality was 25% and did not differ by age or between developed and resourcelimited countries. Median ventilator-free days were 16 (IQR, 0-25), and vasoactive-free days were 23 (IQR,(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28). Sixty-seven percent of patients had multiorgan dysfunction at sepsis recognition, with 30% subsequently developing new or progressive multiorgan dysfunction.…”

“…Consequently, debate remains about the optimal approach to both basic and adjuvant therapies. For example, vasoactive strategies, immune stimulation, and plasma exchange would all benefit from further evaluation in rigorous pediatric trials (21,24,25). The low frequency of pediatric sepsis at any one institution necessitates broad-ideally international-collaboration across many sites to achieve adequate enrollment and generalizability (26).…”

Why a second look might be worth it: immuno-modulatory therapies in the critically ill patient

“…Regeneration of the monocyte function reduced in-hospital and ICU stay (24,25). In addition, several trials showed a lower susceptibility for nosocomial infections under GM-CSF therapy in paediatric patients (24,26). Beside IFN-γ and GM-CSF, IL-7 seems to be of potential value in (re)activation of the immune system.…”

What’s New in the Recognition and Management of Septic Shock in Children: Dos and Don'ts

“…Children with septic shock may have immunoparalysis [111], and particular attention must be paid to ensuring that risks of nosocomial infection are decreased as far as possible [111]. It is particularly important in environments where many children have infections, and the number of available staff is limited to focus on the needs for reduction of patient-to-patient transmission of infection.…”