INTERLEUKIN 12 LEVELS DURING THE INITIAL PHASE OF SEPTIC SHOCK WITH PURPURA IN CHILDREN: RELATION TO SEVERITY OF DISEASE Jan A. Hazelzet, 1 Rene´ F. Kornelisse, 2 Tineke C.T.M. van der Pouw Kraan, 4 Koen F.M. Joosten, 1 Edwin van der Voort, 1 Gerard van Mierlo, 4 Marja H. Suur, 2 Wim C.J. Hop, 3 Ronald de Groot, 2 C. Erik Hack 4 Plasma levels of interleukin 12 (IL-12), a cytokine consisting of two different polypeptide subunits (p40 and p35), were measured together with interferon  (IFN-) and other cytokines in 46 children with septic shock and purpura. The median (range) plasma IL-12 p40 level on admission was 457 (244–2677) pg/ml in non-survivors vs 189 (40–521) pg/ml in survivors (P = 0.001). IL-12 p70 levels were elevated in only nine patients. IL-12 p40 plasma levels were positively correlated with tumour necrosis factor  (TNF-), IL-6, IL-8, IL-10 and PRISM- score, whereas they were negatively correlated with C-reactive protein (CRP), whole blood cell (WBC) and serum glucose levels. Twelve (29%) of the patients had detectable levels of IFN-. Thus, circulating levels of IL-12 p40 and to a lesser extent those of IL-12 p70, are elevated in children with septic shock and purpura, and correlate with severity of disease and outcome.  1997 Academic Press Limited Septic shock with purpura is a clinical syndrome predominantly caused by Neisseria meningitidis and characterized by a sudden onset and rapid progression of disease. Children younger than 10 years are most frequently affected. Lipopolysaccharide (LPS) released from Gram-negative bacteria such as meningococci initiate the production of pro-inflammatory cytokines by cells of the mononuclear-macrophage lineage and endothelial cells. Circulating levels of these cytokines, including tumor necrosis factor (TNF)-, interleukin (IL)-1, 1 IL-6, 1,2 IL-8, 3 and IL-10, 4,5 are increased in children with septic shock and purpura. Severity of disease is related to the initial plasma levels of LPS 6 and of these cytokines. Interleukin 12 (IL-12), 7,8 initially called natural killer cell stimulatory factor or cytotoxic lymphocyte maturation factor, is unique in that it is a heterodimeric protein composed of two different polypeptide subunits, p40 and p35 (for a review see Refs 8–14). The precise role of IL-12 in vivo is not known, although it seems to play a key role in the differentiation of Th1 cells, 10,15 and in the host defense against bacterial, parasitic and viral infections. 8 IL-12 also induces the production of interferon (IFN)- by T cells and natural killer (NK)-cells. 16,17 The plasma levels of IFN- are increased in experimental models for sepsis 18–20 as well as in human sepsis, 21,22 although not consistently. 1 Recently, IL-12 was characterized as a major cytokine in the pathogenesis of gram-negative endotoxaemia in mice 16 and in primates. 23 We therefore questioned whether IL-12 and IFN- play a role in the pathogenesis of septic shock and purpura in humans. To this purpose initial plasma levels of IL-12 and IFN- were measured in children with this disease and their relation with outcome and severity of disease were studied. In addition, plasma levels of TNF-, IL-6, IL-8, and IL-10 were determined and the possible correlation between these cytokines and IL-12 and IFN-, respectively, was studied. From the Department of Pediatrics, 1 Divisions of Pediatric Intensive Care, and 2 Pediatric Infectious Diseases and Immunology, Sophia Children’s Hospital/University Hospital Rotterdam, 3 Department of Biostatistics and Epidemiology, Erasmus University, Rotterdam. 4 Central Laboratory of the Netherlands Red Cross Blood Transfusion Services and Laboratory for Experimental and Clinical Immunology, University of Amsterdam, Amsterdam, The Netherlands. Correspondence to: Jan A. Hazelzet, Department of Pediatrics, Division of Pediatric Intensive Care, Sophia Children’s Hospital/University Hospital Rotterdam, P.O. Box 2060, 3000-CB Rotterdam, The Netherlands; E-mail: hazelzetalkg.azr.nl Received 17 October 1996; accepted for publication 28 February 1997  1997 Academic Press Limited 1043–4666/97/090711 + 6 $25.00/0/ck970215 KEY WORDS: interleukin 12/meningococcal infections/purpura/ septic shock/T lymphocytes CYTOKINE, Vol. 9, No. 9 (September), 1997: pp 711–716 711