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Pilot studies of monocyte intracellular interleukin-1b for detection of neonatal sepsis

Presented at the Neonatal Society 2003 Summer Meeting (programme).

Abraham J1, Roberts IAG2, Murray NA1

1 Department of Neonatal Medicine, Imperial College, Hammersmith Hospital, London.
2 Department of Haematology, Imperial College, Hammersmith Hospital, London.

Background: Sepsis remains a major problem in neonates. The early stages of neonatal sepsis are characterised by increased pro-inflammatory cytokines produced mainly by circulating monocytes. However, measuring plasma levels of single or combinations of pro-inflammatory cytokines has not proved reliable in the diagnosis of neonatal sepsis1 probably due to their transient nature in the systemic circulation and their differing time course of production2. However, monocytes produce intracellular interleukin-1b (IL-1b) within 1 hour of activation and cytoplasmic levels remain high for at least 6 hours3 providing a potential early onset marker of monocyte activation/neonatal sepsis.

Hypothesis: Assessing monocyte intracellular IL-1b (MI-IL-1b) will be useful in the early detection of neonatal sepsis.

Setting, methods and study subjects: Level III neonatal unit. Mononuclear cells were purified from 50ul peripheral blood by density centrifugation and MI-IL-1b was assessed using an anti-IL-1b monoclonal antibody by alkaline phosphatase anti-alkaline phosphatase (APAAP) immunochemical staining. Two pilot studies were undertaken: a) cross-section study of MI-IL-1b in 12 neonates (GA range 26 - 34 wks) and; b) longitudinal study of 6 neonates at high risk of sepsis (GA range 24 - 41 wks).

Results: a) Two of the 12 neonates showed positive MI-IL-1b. Both had culture-negative sepsis (clinical features, neutrophil toxic granulation and raised CRP). The remaining 10 neonates were clinically well. b) Three of the 6 neonates showed positive MI-IL-1b. One term neonate (ventilation-dependent neuromuscular disease) was negative at study entry (day 7), became positive on day 11, 6 hours prior to developing clinical and radiographic pneumonia and 12 hours before CRP became elevated. MI-IL-1b remained positive until (day 15). The second subject (preterm twin with PROM) was positive at birth until day 2, in contrast to the twin sibling who did not suffer PROM and had negative MI-IL-1b. The final subject had suspected early-onset sepsis (term neonate with ventilation-dependent respiratory distress from birth and raised CRP) was positive on the day of referral (day 2). MI-IL-1b became negative on day 4, in conjunction with clinical improvement. CRP returned to normal 2 days later. The remaining 3 neonates (negative MI-IL-1b) remained clinically well with normal CRP (range 1 -10 days).

Conclusion: These pilot data suggest that MI-IL-1b provides an easily detectable marker of monocyte activation. They also suggest that MI-IL-1b may be useful in the early diagnosis of neonatal sepsis and that further work to refine methods of demonstrating monocyte activation may be useful in the assessment of sick neonates at risk of sepsis.

1. Dollner H, et. al. Early diagnostic markers for neonatal sepsis: comparing C-reactive protein, interleukin-6, soluble tumour necrosis factor receptors and soluble adhesion molecules. J Clin Epidemiol 2001; 54: 1251-7.
2. Anderson MR, Blumer JL. Advances in the therapy for sepsis in children. Pediatr Clin North Am. 1997; 44: 179-205.
3. de Bont ES, et. al. Lipopolysaccharide-induced cytokine production in peripheral blood mononuclear cells: intracellular localization of tumor necrosis factor alpha and interleukin 1 beta detected with a three-color immunofluorescence technique. Histochem Cell Biol. 1996; 106: 593-8.

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