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Plasma Levels of Interleukin-6 and Interleukin-10 in Preterm Neonates Evaluated for Sepsis

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Plasma Levels of Interleukin-6 and Interleukin-10 in Preterm Neonates Evaluated for Sepsis Eur J Pediatr &2001) 160: 345±350 Ó Springer-Verlag 2001 ORIGINAL PAPER Costantino Romagnoli á Simonetta Frezza á Antonella Cingolani Andrea De Luca á Maria Puopolo á Maria Pia De Carolis Giovanni Vento á Andrea Antinori á Giuseppe Tortorolo Plasma levels of interleukin-6 and interleukin-10 in preterm neonates evaluated for sepsis Received: 21 November 2000 / Accepted: 23 January 2001 Abstract In a prospective study, plasma interleukin-6 &IL-6) and interleukin-10 &IL-10) levels were measured by enzyme-linked immunosorbent assay in 45 premature neonates &25±34 weeks gestational age) with signs and symptoms of suspected sepsis at 0, 12 and 24 h; C-reactive protein &CRP) was measured at 0±24 h after enrolment. Six subjects were excluded due to insucient blood sampling. The remaining 39 neonates were assigned to one of three groups: 25 newborns with sepsis &blood culture positive), seven with pneu- monia &positive results on broncho-alveolar lavage ¯uid culture and characteristic chest radiography) and seven with necrotising enterocolitis &NEC) &characteristic intestinal and radiological signs according to the criteria of Bell et al.). A group of 20 healthy preterm neonates represented control subjects. On admission, higher levels of IL-6, IL-10 and CRP were observed in neonates with sepsis: IL-6 &median 1500 pg/ml, range 487± 10000 pg/ml), IL-10 &median 113 pg/ml, range 70±196 pg/ml), CRP &median 22 mg/l, range 4±80 mg/l); pneumonia: IL-6 &median 1500 pg/ml, range 747±8000 pg/ml, IL-10 &median 84 pg/ml, range 76±92 pg/ml), CRP &median 10 mg/l, range 8±33 mg/l) and NEC: IL-6 &median 6650 pg/ml, range 1595±7950 pg/ml), IL-10 &median 80 pg/ml, range 61±147 pg/ml), CRP &median 3 mg/l, range 2.8±8 mg/l) ascompared to controls&IL-6 median 208 pg/ml, range 198±349 pg/ml; IL-10 median 36 pg/ml, range 19±50 pg/ml; CRP median <2 mg/l) &P<0.05). In neonates with sepsis, IL-6 levels were signi®cantly correlated with IL-10 levels& r 0.65; P 0.04) at the time of the second sample. The highest IL-6 levels were observed at onset, while IL-10 was predominant 12 h later. On admission, IL-10 and CRP levels were signi®cantly higher in non-survivors &IL-10 median 507 pg/ml, range 422±753 pg/ml; CRP median 123 mg/l, range 20±219 mg/l) than in survivors &IL-10 median 76 pg/ml, range 61±143 pg/ml; CRP median 8 mg/l range 3± 46 mg/l), while IL-10 levelswere signi®cantly higher & P<0.05) also 12 h after admission &non-survivors: IL-10 median 600 pg/ml, range 538±800 pg/ml; survivors: IL-10 median 74 pg/ml, range 53±161 pg/ml). IL-6 and IL-10 levelswere signi®cantly correlated with CRP levels on admission &r 0.45; P 0.05). Conclusion Preterm neonates with sepsis, pneumonia or necrotising enterocolitis showed increased interleukin-6, interleukin-10 and C-reactive protein levels. High interleukin-10 concentration was associated with mortality and could be an early indicator of prognosis. C. Romagnoli &&) á S. Frezza á M. P. De Carolis Catholic University ``Sacred Heart'', G. Vento á G. Tortorolo Rome, Italy Department of Neonatology, Catholic University ``Sacred Heart'', M. Puopolo Largo A. Gemelli 8, 00168 Rome, Italy Laboratory of Organ and System Pathophysiology, Tel.: +39-6-30154357; Fax: +39-6-3055301 Istituto Superiore di SanitaÁ , Rome, Italy e-mail: [email protected] A. Antinori A. Cingolani á A. De Luca National Institute for Infectious Diseases, Department of Infectious Diseases, ``L Spallanzani'', IRCCS, Rome, Italy 346 Keywords Interleukin-6 á Interleukin-10 á Necrotising enterocolitis á Preterm neonates á Sepsis Abbreviations BALF broncho-alveolar lavage ¯uid á CRP C-reactive protein á INFcc-interferon á IL-1 interleukin-1 á IL-6 interleukin-6 á IL-8 interleukin-8 á IL-10 interleukin-10 á NEC necrotising enterocolitis á NICU neonatal intensive care unit á TNF-a tumour necrosis factor-a levels has not previously been investigated in premature Introduction neonates. The principal aim of thisstudywasto evaluate The under-developed immune system predisposes pre- plasma IL-6 and IL-10 concentrations and to analyse the term neonatesto infection, which isa major causeof interaction between IL-6 and IL-10 and CRP in pre- neonatal morbidity and mortality [3, 11]. Sepsis and mature neonates investigated for sepsis. endotoxin activate monocytes, macrophages, lympho- cytes, ®broblasts and endothelial cells that produce and secrete interleukin-1 &IL-1), tumour necrosis factor-a Patients and methods &TNF-a), c-interferon&INFc), interleukin-6 &IL-6), in- terleukin-8 &IL-8) and other pro-in¯ammatory cytokin- Study population es. IL-6, stimulated by TNF-a, IL-1, endotoxin, viral and bacterial infections, acts as a T-cell activation in- This study was carried out at the Neonatal Intensive Care Unit dicator, induces antibody secretion by human B-cells, &NICU) of the Catholic University of Rome over a 1-year period causes dierentiation of cytotoxic T-cells, and also has ending in October 1999. During thisperiod, 130 preterm neonates the ability to inhibit TNF-a production. Moreover, IL-6 were admitted to the NICU. Neonatespresentingwith malforma- tions, chromosomal abnormalities, severe brain damage, or who is the major stimulant in hepatic protein synthesis, i.e., had undergone major surgery, were excluded from the study. A C-reactive protein &CRP) and ®brinogen during acute group of 45 infants were prospectively and consecutively evaluated phase responses [15]. Previous studies have shown that when they showed the following signs and symptoms of suspected determinationsof IL-6 in neonatal blood are of diag- sepsis: &1) respiratory dysfunction, as demonstrated by a progres- sive increase in ventilation settings or oxygen intake in a previously nostic value in sepsis and necrotising enterocolitis stable baby and/or apnoea spells and/or tachypnoea, &2) brady- &NEC) [2, 6, 14, 21]. cardia, tachycardia, poor peripheral circulation, arterial hypoten- Interleukin-10 &IL-10) isproduced by monocytes, sion, &3) temperature instability, hypotonia, seizures, irritability, B-cellsand TH-cellsand isinduced by endotoxin and lethargy, &4) feeding intolerance, vomiting, abdominal distension, its subsequent pro-in¯ammatory cytokine cascade. IL-10 bloody stools, &5) persistent metabolic acidosis, hyperglycaemia. In these neonates blood, CSF, stool and urine cultures were has anti-in¯ammatory properties such as suppression of immediately carried out; broncho-alveolar lavage wasalsoper- in vitro synthesis of multiple pro-in¯ammatory cyto- formed in ventilated neonates. Chest and abdominal X-rays were kines, i.e. TNF-a, IL-1, IL-6, INFc, and IL-8 [8, 20] and taken when clinically indicated. All these babies were then treated in vivo suppression of cell-mediated immunity. More- with antibiotics. A group of 20 healthy preterm neonates, who had no respiratory or infectious problems and were born consecutively over, IL-10 could play an important role asa regulatory on the NICU, were included in the study. In all study neonates, factor in the intestinal immune response. Kuhn et al. CRP was measured at the start of the study and at 24 h. IL-6 and [16] showed that IL-10 de®cient ``knockout'' mice were IL-10 were determined upon enrolment and then 12 h and 24 h predisposed to in¯ammatory enterocolitis indicating later. Only two blood samples at 12 hourly intervals were taken in control subjects. The study was approved by the Ethics Committee that IL-10 counteractsthe intestinal in¯ammatory re- of the Department of Paediatrics. Informed consent was obtained sponse stimulated by enteric antigens and food. Edelson from the parents of all studied babies before the start of the study. et al. [10] report that systemic concentration of IL-10 is The enrolled neonateswere grouped asfollows:Group 1. elevated in preterm neonateswith NEC, especially in Con®rmed sepsis: neonates with positive results on blood culture; those with stage 3. Animal studies have shown that Group 2. Pneumonia: neonates with characteristic chest radiogra- phy and positive broncho-alveolar lavage ¯uid &BALF) results; IL-10 administered as a bolus reduces the antigen-pre- Group 3. NEC: neonates with characteristic intestinal and radio- senting capacity of monocytes and pro-in¯ammatory logical signs according to criteria of Bell et al. [1]; Group 4. Con- cytokine response and protects against endotoxin- trols: healthy preterm neonates. For the purposes of our study, induced mortality in mice [12]. Marchant et al. [19] neonates were considered non-survivors if death was infection- related. reported that IL-10 concentrationsincreasedin adults with sepsis, particularly in cases of septic shock. A pos- itive correlation between pro-in¯ammatory &TNF-a, IL- Methods 6) and anti-in¯ammatory cytokines&IL-10) in meningo- coccal disease was observed by Riordan et al. [22] who CRP wasdetermined by the nephelometric method using500 llof found higher IL-10 concentrationsin non-surviving in- heparinised blood. A value >10 mg/l was de®ned as increased. For cytokine determinations, aliquots &200 ll) of blood were collected fants. The role of IL-10 in neonatal sepsis is still not clear in EDTA-coated plastic tubes and immediately centrifuged. Plasma [4] and the relationship between plasma IL-6 and IL-10 wasstoredat )70 °C prior to cytokine assay. Plasma IL-6 and 347 IL-10 levelswere measuredby meansof enzyme-linked immuno- Group 3 neonates with NEC were classi®ed in ac- sorbent assays &Quantikine, R&D Systems, Minneapolis, USA), cordance with the criteria of Bell et al. [1] and treatment according to the manufacturer'sprocedure.
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