Interleukin-11 levels in healthy and thrombocytopenic neonates

Thrombocytopenia is common in sick neonates, and affected neonates have adverse outcomes compared with those without thrombocytopenia. As impaired platelet production underlies many neonatal thrombocytopenias, affected neonates are potential candidates for hemopoietic growth factor therapy. Although recombinant human (rh) thrombopoietin remains under therapeutic development, rhIL-11, which stimulates megakaryocytopoiesis and increases platelet counts after chemotherapy, is already licensed for clinical use. However, nothing is known about IL-11 in neonates. We therefore measured plasma IL-11 by ELISA in healthy term neonates, stable preterm neonates with or without thrombocytopenia, and preterm neonates with sepsis or necrotizing enterocolitis (NEC) with or without thrombocytopenia. At birth IL-11 was undetectable (<10 pg/mL) in healthy term neonates (n = 20) and 27 of 31 (87%) stable preterm neonates. Three stable preterm neonates with detectable IL-11 (mean+/-SD, 11.3 +/- 0.4 pg/mL; median, 11.6 pg/mL) suffered chorioamnionitis, the remaining neonate (IL-11, 14 pg/mL) being one of nine with early onset thrombocytopenia (present by <72 h of age). IL-11 was also measured in 58 preterm neonates with suspected sepsis or NEC. In 25 of 58, sepsis or NEC was unconfirmed and IL-11 was undetectable. By contrast, 14 of 33 with proven sepsis or NEC had elevated IL-11 (median, 14.9 pg/mL; range, 11.2-92.2 pg/mL). Of these 33 neonates, 19 developed thrombocytopenia: nine of 19 (47%) had detectable IL-11 and 10 of 19 (53%) did not (p > 0.05). Although its role in platelet production in neonates remains unclear, these data suggest that IL-11 is involved in the endogenous cytokine response to sepsis or NEC in preterm neonates. Further studies of IL-11 in neonates are warranted to assess its role both in platelet production and in mediation of the endogenous inflammatory response.     

Effects of sepsis on neonatal thrombopoiesis

We serially evaluated the effects of sepsis and/or necrotizing enterocolitis (NEC) on neonatal thrombopoiesis, using a panel of tests that included platelet counts, thrombopoietin concentrations (Tpo), circulating megakaryocyte progenitor concentrations (CMPs), and reticulated platelets (RPs). Variables analyzed included sepsis type, time after onset of sepsis, platelet counts, and gestational (GA) and postconceptional ages (PCA). Twenty neonates were enrolled. Ten had Gram-negative, six had Gram-positive, and four had presumed sepsis. Four neonates had NEC stage II or higher, and six developed thrombocytopenia. Overall, septic neonates had significantly elevated Tpo concentrations and circulating megakaryocyte progenitors. The highest Tpo levels were associated with Gram-negative or presumed sepsis. RP percentages were increased only in neonates with low platelet counts, while RP counts (RP% x platelet count) were elevated in neonates with high platelet counts. Our findings suggest that septic neonates up-regulate Tpo production, leading to increased megakaryocytopoiesis and platelet release, although the degree of upregulation is moderate. The changes in RP% and RP count most likely reflect increased thrombopoiesis with variable degrees of platelet consumption. In addition, our findings suggest that different factors, likely including level of illness and/or specific platelet or bacterial products, can down-regulate the magnitude of the thrombopoietic response.     

Effects of oxygen-induced lung damage on megakaryocytopoiesis and platelet homeostasis in a rat model

The association between lung injury and thrombocytopenia was investigated by comparing the megakaryocyte and platelet counts, and platelet activation using P-selectin as a marker, between the prepulmonary (right atrial) and postpulmonary (left atrial) blood in adult and neonatal (preterm and term) rats with and without hyperoxic lung injury. In the healthy controls, the postpulmonary blood had lower megakaryocyte count (prepulmonary versus postpulmonary: Preterm: 8.7[0.6] versus 3.9[0.3] per ml, p < 0.001; Term: 8.7[1.1] versus 2.6[0.4] per ml, p < 0.001; Adult: median [interquartile ranges]: 2.5[1.0, 5.0] versus 1.0[0, 3.0] per ml, p < 0.001), higher platelet count (prepulmonary versus postpulmonary: Preterm: 491.2[11.1] x 10(9)/L versus 595.1[10.2] x 10(9)/L, p < 0.001; Term: 472.5[19.9] x 10(9)/L versus 579.3[26.2] x 10(9)/L, p < 0.001; Adult: 513.9[31.5] x 10(9)/L versus 664.7[28.8] x 10(9)/L, p < 0.001), but similar P-selectin expression. In contrast, the lung-damaged animals did not show any such differences in either megakaryocyte or platelet count, but P-selectin expression was greater in the postpulmonary blood (prepulmonary versus postpulmonary: Preterm: 38.7[3.9] versus 56.4[4.9]% platelets, p = 0.02; Term: 40.9[2.0] versus 54.0[4.2]% platelets, p = 0.002; Adults: 30.0[3.6] versus 49.1[4.7]% platelets, p = 0.003). Peripheral platelet and intra-pulmonary megakaryocyte counts in the lung-damaged rats were significantly lower than those in their respective controls. Intra-pulmonary thrombi or platelet aggregation were detected in the lung-damaged rats but not in the controls. These findings showed that hyperoxic lung damage reduced circulating platelets through (1) failure of the lungs to retain and fragment megakaryocytes to release platelets, and (2) platelet activation leading to platelet aggregation, thrombi formation and platelet consumption. The magnitude of platelet reduction was physiologically significant, as demonstrated by higher counts of megakaryocyte colony forming units in the bone marrow culture of the animals in the hyperoxia group when compared with the controls.     

Juvenile cyclic amegakaryocytic thrombocytopenia: a novel entity

Cyclic thrombocytopenia is a rare disorder described in adults, characterized by periodic platelet count fluctuations of unknown etiology. The authors describe a boy with cyclic changes in platelet counts ranging from 2 x 10(9)/L to 224 x 10(9)/L with a periodicity of 25 days. Since birth, the patient had periods of bruising. Platelet counts were periodically low during these periods. Thrombopoietin plasma levels oscillated inversely with the platelet count, whereas glycocalicin levels oscillated in phase with the platelets. No oscillation was seen in neutrophil and reticulocyte numbers. The bone marrow showed periodic reduction in megakaryocyte counts. In an in vitro megakaryocytopoiesis assay, the patient's CD34+ cells showed megakaryocyte formation, although to a lower level than controls. Addition of patient plasma, collected during the rise in platelet numbers, to cultures with normal bone marrow-derived CD34+ cells caused an increase in the development of CD41+ megakaryoblasts. Because the periods with bruising had existed since birth, apparently this is a form of congenital cyclic thrombocytopenia. The underlying mechanism of the cyclic thrombocytopenia in this patient is not yet clear, and until now, no therapy has been found for this patient. However, platelet transfusions have resulted in cessation of bleeding during thrombocytopenic periods.     

Neonatal thrombocytopenia: new insights into pathogenesis and implications for clinical management

The healthy fetus has a platelet count of greater than 150 x 10(9)/L by the second trimester of pregnancy and only 2% of term infants are thrombocytopenic at birth. Severe thrombocytopenia (platelets < 50 x 10(9)/L) occurs in fewer than three per 1000 term infants, the most important cause being alloimmune thrombocytopenia. In contrast, in infants admitted to neonatal intensive care units, thrombocytopenia develops in 25% and in up to half of sick preterm infants. Recent evidence shows that these infants mostly have evidence of underlying impaired fetal megakaryocytopoiesis and platelet production following pregnancy complications characterized by placental insufficiency or fetal hypoxia. The mechanism of this is unknown. However, many neonatal complications exacerbate this thrombocytopenic potential and 20% of thrombocytopenias in neonatal intensive care unit patients are severe. Evidence-based guidelines for platelet transfusion therapy in these patients are yet to be defined, but as platelet underproduction underlies most neonatal thrombocytopenias, recombinant hemopoietic growth factors, including thrombopoietin and interkeukin-11, may be useful future therapies.     

Plasma immunoreactive endothelin-1 concentration in human fetal blood: its relation to asphyxia

To elucidate the effects of birth stress on immunoreactive endothelin-1 (irET-1) concentrations in fetal blood, we determined irET-1 levels in cord plasma in different modes of delivery associated with or without complications such as asphyxia. The irET-1 concentrations in both the umbilical artery and vein were significantly higher than those found in maternal venous blood at delivery, although there was no significant difference between preterm and full-term infants. When plasma irET-1 concentrations of healthy infants born by vaginal delivery and by cesarean section without labor were compared, the former had significantly (p less than 0.05) higher levels than the latter (15.4 +/- 4.9 pg/mL versus 11.1 +/- 3.1 pg/mL). Furthermore, umbilical venous plasma obtained from vaginally delivered infants complicated by asphyxia showed significantly (p less than 0.001) higher irET-1 levels (28.2 +/- 9.4 pg/mL) than those of nonasphyxiated infants (14.2 +/- 4.5 pg/m). These data suggest that birth stress, especially asphyxia, may contribute to the increase in fetal circulating irET-1 levels.     

Fetal and neonatal thrombopoietin levels in alloimmune thrombocytopenia

Thrombopoietin (Tpo) is the main hematopoietic growth factor for platelet production. Plasma Tpo levels in autoimmune thrombocytopenic patients are normal or slightly elevated. Although thrombocytopenia exists, Tpo levels are not increased because the produced megakaryocytes and platelets can bind circulating Tpo, thereby normalizing Tpo levels. In this study, plasma samples from fetuses and neonates with neonatal alloimmune thrombocytopenia (NAIT), a different form of immune thrombocytopenia, were measured. Umbilical cord samples from 50 fetuses before treatment because of severe thrombocytopenia and 51 fetuses after treatment, and peripheral blood samples of 21 untreated newborns with NAIT were analyzed. As controls, plasma Tpo levels were determined in 21 umbilical cord samples of 14 nonthrombocytopenic fetuses with hemolytic disease resulting from red blood cell alloimmunization and in umbilical cord samples of 51 healthy newborns. The values were also compared with the plasma Tpo levels in 193 healthy adults. Mean Tpo levels from the groups of fetuses and neonates, including both NAIT and control plasma, were slightly but significantly elevated compared with levels in healthy adults. Tpo levels in NAIT samples were not significantly different from the levels in hemolytic disease samples or in samples from healthy newborns. Thus, as in autoimmune thrombocytopenic patients, normal Tpo levels are present in NAIT patients.     

The concentration of circulating megakaryocyte progenitors in preterm neonates is a function of post-conceptional age

Circulating megakaryocyte (Mk) progenitors have been used as a measure of megakaryocytopoiesis in neonates. Prior studies have shown a gestational age-dependent decrease in their concentration, but it is unclear how this process continues after birth in preterm neonates. To answer this question, we quantified the Mk progenitors in the blood of 42 neonates of varying post-conceptional ages (gestational age+days of life). We found an inverse relationship between concentration of circulating Mk progenitors and post-conceptional age (r=-0.54, p=0.0002).     

Thrombopoietin in preterm infants: gestational age-dependent response

PURPOSE: To investigate the factors affecting thrombopoietin (TPO) levels in preterm infants and to determine if TPO levels differ in infants born to mothers with preeclampsia and those infants with culture-proven sepsis. METHODS: Serial serum samples (N = 95) were obtained from 27 infants less than 33 weeks' gestation. Samples were analyzed for TPO using enzyme-linked immunosorbent assay. All samples had an accompanying complete blood count. Analysis of variance with post hoc analysis by least significant difference test, Mann-Whitney test, or chi2 was used to compare groups, as appropriate. Forward, stepwise linear regression was used to account for potential confounding variables. Data are expressed as mean +/- SD. RESULTS: TPO levels were not significantly correlated with the absolute platelet counts (R = -0.04, P = 0.69). TPO levels were significantly correlated with gestational age (R= 0.50, P < 0.001) when the platelet count was less than 150,000/mm3. TPO levels were significantly elevated in infants with platelets less than 150,000/mm3 born to mothers with preeclampsia compared with infants with sepsis (1184 +/- 98 vs. 579 +/- 363 pg/mL, P < 0.01). After adjusting for confounding variables using multivariate analysis (model: r2 = 0.43, P < 0.01), gestational age (r2 = 0.26) and preeclampsia (r2 = 0.03) remained significantly associated with TPO levels, whereas sepsis did not contribute to the variability of TPO. CONCLUSIONS: TPO response of infants with platelets less than 150,000/mm3 is dependent on gestational age. Infants with thrombocytopenia associated with preeclampsia have increased circulating levels of TPO. Infants with thrombocytopenia secondary to sepsis do not show an increase in TPO, but this appears to be an effect of low gestational age.     

Megakaryocyte size and concentration in the bone marrow of thrombocytopenic and nonthrombocytopenic neonates

Thrombocytopenia is frequent among sick neonates, but little is known about its underlying mechanisms. It is known, however, that neonatal megakaryocytes are smaller and of lower ploidy than their adult counterparts and that smaller megakaryocytes produce fewer platelets than larger, more polyploid, megakaryocytes. We hypothesized that neonatal megakaryocytes would not increase their size in response to thrombocytopenia, thus limiting the ability of neonates to mount a response. To test this, we obtained marrow specimens from thrombocytopenic and nonthrombocytopenic neonates and adults. Megakaryocytes were immunohistochemically stained, quantified using an eyepiece reticle, and measured using an image analysis system with incorporated electronic micrometer. We found that, after adjusting for differences in cellularity, neonates and adults had similar megakaryocyte concentrations. When samples from the same sources were compared (tibial clot and vertebral body sections in neonates, iliac crest biopsies in adults), there were also no differences in megakaryocyte concentration between thrombocytopenic and nonthrombocytopenic subjects. The megakaryocyte diameter, however, was greater in adults than in neonates (19.4 +/- 3.0 versus 15.3 +/- 1.7 microm, p<0.0001). Thrombocytopenic adults also had a higher proportion of large megakaryocytes than nonthrombocytopenic adults (p<0.001). This was not observed among thrombocytopenic neonates, suggesting a developmental limitation in their ability to increase megakaryocyte size.     

Sequential administration of interleukin-6 and granulocyte-colony stimulating factor in newborn rats: modulation of newborn granulopoiesis and thrombopoiesis.

During states of increased demand, neonatal host defense is characterized by dysregulation of granulopoiesis, resulting in a high incidence of neutropenia. This study investigated the modulation of neonatal rat hematopoiesis by 14-d administration of recombinant human (rh) IL-6, rh-granulocyte-colony stimulating factor (G-CSF), or sequential combination of rhIL-6 and rhG-CSF. Specifically, newborn Sprague-Dawley rats were treated with either rhIL-6 (5 micrograms/kg/d for 14 d), rhG-CSF (5 micrograms/kg/d for 14 d), rhIL-6 for 7 d followed by rhG-CSF for 7 d, PBS/BSA for 7 d followed by rhG-CSF for 7 d, or PBS/BSA for 14 d. RhIL-6 alone significantly increased the peripheral platelet count during the latter part of the 2nd wk of administration (d 13: 980 +/- 42 versus 716 +/- 23 x 10(3)/mm3) (p = less than 0.001) (mean +/- SEM). Treatment with rhIL-6 for 7 d followed by rhG-CSF significantly increased the peripheral neutrophil count compared with 7 d of PBS/BSA and 7 d of G-CSF (d 14 absolute neutrophil count 4888 +/- 12 versus 2720 +/- 317/mm3) (p = less than 0.05). Similarly, sequential rhIL-6/rhG-CSF significantly increased the d-14 bone marrow neutrophil storage pool (9873 +/- 882 versus 3564 +/- 159/mm3) (p = less than 0.005). Lastly, sequential rhIL-6/rhG-CSF induced the highest increase in bone marrow (p less than 0.01) and liver/spleen CFU-GM pool (p less than 0.001) compared with any other treatment group. These studies suggest that rhIL-6 alone is associated with a significant increase in the neonatal platelet count.(ABSTRACT TRUNCATED AT 250 WORDS)     

Neonatal thrombocytopenia

Thrombocytopenia occurs in up to a third of preterm neonates admitted to intensive care units. In these babies, thrombocytopenia typically presents in one of two patterns: early-onset thrombocytopenia occurring within 72 h of birth and late-onset thrombocytopenia which develops after 72 h. Early-onset thrombocytopenia is most commonly caused by disorders associated with placental insufficiency (e.g. maternal hypertension), is mild-moderate, self-limiting and requires no treatment; it is caused by reduced platelet production. Late-onset thrombocytopenia is usually due to bacterial sepsis or necrotising enterocolitis; it is often severe (platelets <50 x 10(9)/l), prolonged and requires treatment with platelet transfusions. In term babies, neonatal thrombocytopenia is usually severe and most commonly caused by bacterial sepsis, perinatal asphyxia or neonatal alloimmune thrombocytopenia. There is a lack of evidence-based guidelines for treatment of neonatal thrombocytopenia. The most important future developments will depend upon studies aimed at determining optimal platelet transfusion schedules for term and preterm neonates.     

Inflammatory and growth mediators in growing preterm infants

Little is understood about the optimal balance between IGF-I and antagonistic inflammatory mediators, such as IL-6, in growing preterm infants. Using a prospective cohort study, we investigated the relationship between postnatal growth of preterm infants and key growth and inflammatory mediators. We studied 51 stable, growing preterm infants (mean gestational age: 27.8 +/- 0.4 weeks, mean birth weight: 1,032.8 +/- 50.6 g). IL-6 and IL-1ra (reflecting stress/ inflammation) and IGF-I and GHBP (reflecting anabolic activity and GH sensitivity) were measured at enrollment and discharge using ELISA. During the observation period (mean 6.1 +/- 0.34 weeks) there was a significant increase in weight (1,396 +/- 81 g, p < 0.0001). IGF-I increased from 46.6 +/- 4.1 to 88.7 +/- 5.2 ng/ml (p < 0.001). In contrast, IL-6 decreased from 9.5 +/- 1.0 to 2.3 +/- 0.34 pg/ml (p <0.001) and IL-1ra from 6,042 +/- 362 to 4,851 +/- 365 ng/ml (p = 0.007). GHBP increased from 65.8 +/- 6.7 to 82.5 +/- 7.9 ng/ml (p = 0.003). IL-6 was inversely correlated with IGF-I (p < 0.001). In addition, a multiple regression model showed IGF-I levels correlated positively and IL-6 levels inversely with various parameters of growth. Growth in preterm infants is characterized by increases in IGF-I and GHBP with simultaneous decreases in IL-6 and IL-1ra. Efforts to optimally balance inflammatory and growth mediators may benefit somatic growth in infants very early in life.     

In vitro megakaryocytopoiesis in children with acute idiopathic thrombocytopenic purpura

Idiopathic thrombocytopenic purpura (ITP) of childhood is a disorder characterized by a history of previous viral illness followed by acute onset of low circulating platelet count with present or increased megakaryocytes in the bone marrow. The majority of children recover a normal platelet count within 6 months to 1 year after onset of the disease. To better understand the regulation of megakaryocytopoiesis in this disorder, we studied nine patients with childhood ITP with the plasma clot colony assay in vitro for megakaryocyte colony forming units (CFU-Mk). Mononuclear bone marrow cells from some of the patients with ITP contained greater numbers of CFU-Mk and greater numbers of cells per colony than mononuclear bone marrow cells from healthy adult volunteers (p less than 0.026) when the cultures contained no added megakaryocyte colony-stimulating activity (Mk-CSA). The serum from patients with ITP did not stimulate in vitro megakaryocytopoiesis from healthy adult volunteers' bone marrow mononuclear cells above baseline values. These findings are consistent with the hypothesis that a decrease in bone marrow megakaryocytes is needed for Mk-CSA production. Alternatively, Mk-CSA is consumed by active megakaryocytopoiesis in the bone marrow.     

Peptide growth factors in tracheal aspirates of mechanically ventilated preterm neonates

Basic fibroblast growth factor (bFGF or FGF-2), vascular endothelial growth factor (VEGF), and endothelin-1 (ET-1) are peptide growth factors (PGF) mediating normal lung development, maturation, injury, and repair. These PGF may therefore be involved in the pathogenesis of bronchopulmonary dysplasia (BPD). We hypothesized that elevated levels of these PGF in tracheal aspirates would be associated with a) BPD and/or death; b) markers of cell injury and apoptosis; and c) chorioamnionitis, a risk factor for BPD. Tracheal aspirates collected in 29 preterm (<34 wk gestation, 500-2000 g birth weight), mechanically ventilated infants on d 1 of life were assayed for PGF and histone-associated DNA fragments by ELISA and for LDH by enzyme assay. Clinical and pathologic examination was performed for chorioamnionitis. BPD was defined as oxygen requirement/mechanical ventilation at 28 d postnatal age. The birth weight (mean +/- SE) was 1009 +/- 85 g and median gestational age was 26 wk (range, 22-33). Eighteen infants died or developed BPD. bFGF levels were elevated in infants who died or developed BPD [median (25%,75%) level of 36 (23, 44) pg/mL versus 14 (6, 30) in the survivors without BPD, p = 0.01]. bFGF levels correlated with apoptosis (r = 0.73, p < 0.001) and LDH levels (r = 0.59, p < 0.001). VEGF and ET-1 levels were not associated with apoptosis or with BPD/death. PGF levels were not associated with chorioamnionitis. We conclude that elevated bFGF levels in the preterm trachea correlate with BPD/death and markers of cell injury and apoptosis but not with chorioamnionitis. We speculate that bFGF may play a role in the development of BPD.     

Energy expenditure, inflammation, and oxidative stress in steady-state adolescents with sickle cell anemia

Sickle cell anemia (HbSS) is characterized by hypermetabolism, chronic inflammation, and increased oxidative stress, but the relationship between these factors is undefined. In this study, we examined indicators of inflammatory process and markers of oxidative damage and their impact on resting energy expenditure (REE) in stable HbSS adolescents (n = 35) and healthy controls carrying normal hemoglobin genotype (HbAA) (n = 39). C-reactive protein (CRP), white blood cell (WBC) count, and proinflammatory cytokines were measured as markers of inflammation and 2,3-dinor-5,6-dihydro-15-F2t-isoprostane (F2-IsoPM) as a marker of oxidative stress. REE was measured by indirect calorimetry. WBC counts (11.90 +/- 5.3 x10/muL versus 5.6 +/- 1.9 x10/muL; p < 0.001), serum CRP (9.1 +/- 11.0 mug/mL versus 0.4 +/- 0.7 mug/mL; p < 0.001) and serum IL-8 (7.5 +/- 4.4 pg/mL versus 5.5 +/- 4.8 pg/mL; p = 0.011) were higher in HbSS than HbAA, suggesting an anti-inflammatory response in HbSS. Higher urinary F2-IsoPM in HbSS (1.2 +/- 0.4 versus 0.7 +/- 0.3 ng/mg creatinine; p < 0.001) indicates increased oxidative stress. Fat free mass (FFM), hemoglobin (Hgb), interleukin (IL)-8, and F2-IsoPM were independent predictors of REE in HbSS (overall r = 0.778; p < 0.001). Low-grade inflammation and increased oxidative stress are present in adolescents with HbSS in the absence of acute crisis, and their markers are correlated with elevated REE.     

Clinical impact of neonatal thrombocytopenia

In a 1-year prospective study, the outcome in infants with a platelet count less than 100 X 10(9)/L (n = 97) was compared with the outcome in an age-, weight-, and disease-matched nonthrombocytopenic control group (n = 80). The hemostatic impact of the thrombocytopenia was assessed by modified template bleeding time, hemorrhage score, and determination of the presence and extent of intraventricular hemorrhage (IVH) in thrombocytopenic infants weighing less than 1500 at birth (n = 39) compared with all nonthrombocytopenic infants less than 1500 g (n = 122) admitted during the study period. The development outcome in infants less than 1500 g was compared at 12 months after delivery. Neonatal thrombocytopenia had a major impact on hemostatic integrity: bleeding time was inversely related to platelet count (r = -0.56, P less than 0.001) and became prolonged when the platelet count fell to less than 100 X 10(9)/L. In addition, many infants (40%) had evidence of platelet dysfunction with prolonged bleeding times despite only moderately reduced platelet counts (75 to 150 X 10(9)/L). The hemorrhage score was greater in the thrombocytopenic infants compared with the sick control infants, and increased as the platelet count fell (r = -0.58, P less than 0.001). The incidence of IVH in thrombocytopenic infants less than 1500 g was 78%, compared with 48% in the nonthrombocytopenic infants (P less than 0.01). In addition, the more severe grades of IVH were more frequent in the thrombocytopenic infants. The serious neurologic morbidity for the surviving infants less than 1500 g was 41% in the thrombocytopenic infants and 7% in the nonthrombocytopenic infants. Thus, on the basis of three indices of abnormal bleeding, thrombocytopenic infants are at greater risk for bleeding than equally sick nonthrombocytopenic infants. The thrombocytopenia itself may have contributed to the high mortality and neurologic morbidity.     

Serum interleukin-18 levels are raised in diabetic ketoacidosis in Chinese children with type 1 diabetes mellitus

OBJECTIVE: To investigate the role of serum interleukin (IL-18) in children with type 1 diabetes mellitus (T1DM) and diabetic ketoacidosis (DKA). DESIGN: Case-control study. SUBJECTS: Sixty-one children with T1DM including 28 with DKA and 33 without DKA and 30 age - and sex-matched healthy controls were recruited. METHODS: Serum IL-18, IL-12, and IFN-gamma levels were measured in all subjects by enzyme linked immunosorbent assay. RESULTS: Serum IL-18 levels were significantly higher in patients with DKA than those in patients without DKA (759.2 +/- 353.8 pg/mL vs. 634.9 +/- 399.7 pg/mL, P = 0.001) and healthy controls (310.0 +/- 265.3 pg/mL). The serum IL-12 and IFN-gamma levels were not different between patients and controls (277.5 +/- 207 pg/mL vs. 351.4 +/- 223.4 pg/mL, P = 0.45 and 7.02 +/- 7.53 pg/mL vs. 5.59 +/- 5.34 pg/mL, P = 0.21, respectively). CONCLUSION: Serum IL-18 levels are increased in children with type 1 diabetes mellitus and could be a predictor of diabetic ketoacidosis.