Cytokine 65 (2014) 184–191
Contents lists available at ScienceDirect
Cytokine journal homepage: www.journals.elsevier.com/cytokine
Circulating soluble triggering receptor expressed on myeloid cells-1 (sTREM-1) as diagnostic and prognostic marker in neonatal sepsis Amira A.M. Adly a, Eman A. Ismail b,⇑, Nevine G. Andrawes a, Marwa A. El-Saadany a a b
Pediatric Department, Faculty of Medicine, Ain Shams University, Egypt Clinical Pathology Department, Faculty of Medicine, Ain Shams University, Egypt
a r t i c l e
i n f o
Article history: Received 3 April 2013 Received in revised form 2 October 2013 Accepted 5 November 2013 Available online 2 December 2013 Keywords: sTREM-1 Neonatal sepsis Outcome Therapy hs-CRP
a b s t r a c t Objective: Triggering receptor expressed on myeloid cells-1 (TREM-1) is an important receptor involved in the innate inflammatory response and sepsis. We assessed soluble TREM-1 (sTREM-1) in 112 septic neonates (63 culture-positive and 49 culture-negative) and 40 healthy controls as a potential early diagnostic and prognostic marker for neonatal sepsis (NS). Methods: Studied neonates were evaluated for early- or late-onset sepsis using clinical and laboratory indicators upon admission. sTREM-1 was measured on initial sepsis evaluation and at 48 h after antibiotic therapy. For ethical reasons, cord blood samples were collected from control neonates and only samples from neonates that proved to be healthy by clinical examination and laboratory analysis were further analyzed for sTREM-1. Results: Baseline sTREM-1 levels were significantly elevated in culture-proven (1461.1 ± 523 pg/mL) and culture-negative sepsis (1194 ± 485 pg/mL) compared to controls (162.2 ± 61 pg/mL) with no significant difference between both septic groups. Culture-positive or negative septic preterm neonates had significantly higher sTREM-1 compared to full term neonates. sTREM-1 was significantly higher in neonates with early sepsis than late sepsis and was associated with high mortality. sTREM-1 was significantly decreased 48 h after antibiotic therapy compared to baseline or levels in neonates with persistently positive cultures. sTREM-1 was positively correlated to white blood cells (WBCs), absolute neutrophil count, immature/total neutrophil (I/T) ratio, C-reactive protein (hs-CRP) and sepsis score while negatively correlated to gestational age and weight. hs-CRP and sepsis score were independently related to sTREM-1 in multiregression analysis. sTREM-1 cutoff value of 310 pg/mL could be diagnostic for NS with 100% sensitivity and specificity (AUC, 1.0 and 95% confidence interval [CI], 0.696–1.015) while the cutoff value 1100 pg/mL was predictive of survival with 100% sensitivity and 97% specificity (AUC, 0.978 and 95% CI, 0.853–1.13). However, hs-CRP cutoff 13.5 mg/L could be diagnostic for NS with a sensitivity of 76% and specificity of 72% (AUC, 0.762 and 95% CI, 0.612–0.925) and levels were not related to survival as no significant difference was found between dead and alive septic neonates. Conclusions: Elevated sTREM-1 could be considered an early marker for NS that reflects sepsis severity and poor prognosis. Ó 2013 Elsevier Ltd. All rights reserved.
1. Introduction Sepsis is a complex clinical condition caused by dysregulated immune response to an infection resulting in multiorgan failure with a fatal outcome. The initial line of defense is the immediate innate host immune response which involves coordinated action of effector cells that express numerous membrane-bound receptors. Of these, the Toll-like receptors (TLRs) detect microbial structures such as lipopolysaccharide, lipoteichoic acid, flagellin and bacterial DNA [1,2]. Neonatal infections annually claim lives of 1.4 million neonates worldwide [3]. More than 90% of these deaths occur in the poorest ⇑ Corresponding author. Tel.: +20 2 0105118652; fax: +20 2 33375435. E-mail address: [email protected] (E.A. Ismail). 1043-4666/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.cyto.2013.11.004
countries of Asia and Africa [4]. Identification and treatment of newborns with infection are weak in many developing countries [5]. Detailed studies on the etiology and antibiotic resistance profile of neonatal sepsis (NS) are uncommon [5]. Neonatal susceptibility is related to the immature immunologic defense [6]. Mortality rate in NS differs according to the type of organism being the highest with Gram-negative bacteria [7] and diagnosis remains challenging [8]. There is no gold standard for diagnosing sepsis as clinical and laboratory signs are neither sensitive enough nor specific enough [3] and the main limitations of microbiological studies are the unavailability of the results until 72 h and low sensitivity as 57% of septic infants may have negative results [9]. Thus, management of possible sepsis cases often depends on clinical algorithm leading to empirical treatment. This often results in unnecessary
A.A.M. Adly et al. / Cytokine 65 (2014) 184–191
antibiotic use, which may lead to emergence of antibiotic resistance [3]. Biomarkers have shown great promise in diagnosis of sepsis and guiding appropriate treatment of neonates [3]. Acute phase reactants, pro and anti-inflammatory mediators including chemokines and cytokines, and cell-surface antigens are nonspecific biomarkers that have been extensively studied for the diagnosis and management of late onset NS [10]. The triggering receptor expressed on myeloid cells 1 (TREM-1) has been identified as an important receptor involved in the innate inflammatory response and in sepsis [11–13]. TREM-1 is a member of the immunoglobulin superfamily and is up-regulated on the surfaces of neutrophils, monocytes and macrophages after exposure to lipopolysaccharide, heat-inactivated Gram-positive bacteria, Gram-negative bacteria or fungi [11,14–16]. It is involved in monocytic activation and inflammatory response mediated by TLR-2 and -4 [16,17]. The expression of membrane-bound TREM-1 is greatly increased on monocytes during sepsis. Moreover, infection induces release of a soluble form of this receptor, which can be measured in biological fluid and may be useful as a diagnostic tool [16]. Conversely, TREM-1 is not up-regulated in patients with non-infectious inflammatory conditions, defining the specific involvement of this receptor only in cases of infection [9]. Recently, increased soluble TREM-1 (sTREM-1) levels have been reported in neonates with late onset sepsis (>day 3 of life) [18]. However, data on sTREM-1 as an early diagnostic biomarker and its relation to prognosis of septic neonates are still lacking. Therefore, we aimed to assess sTREM-1 levels as a potential early diagnostic and prognostic marker for NS. 2. Materials and methods This prospective study was carried out on 112 neonates admitted to the Neonatal Intensive Care Unit (NICU), Pediatric Hospital, Ain Shams University with clinical and laboratory signs of sepsis. Another 40 gestational age- and sex-matched healthy newborns were enrolled as a control group. An informed consent was obtained from the legal guardian of each patients or controls before enrollment. This study was approved by the ethical committee of Ain Shams University. 2.1. Definition of sepsis The diagnosis of sepsis was based on at least 2 clinical and 2 laboratory criteria [19,20]. Clinical criteria were: hyperthermia (core body temperature P38 °C) or hypothermia 160 beats/min) or bradycardia (heart rate 60 breaths/min) or recurrent apnea >20 s, increased oxygen requirements or requirement for ventilatory support, feeding intolerance suspected by the presence of gastric residuals, abdominal distension, gross or occult blood in the stool and the onset of crises of apnea/bradycardia [21], abdominal distension, lethargy and hypotonia, hypotension
Contents lists available at ScienceDirect
Cytokine journal homepage: www.journals.elsevier.com/cytokine
Circulating soluble triggering receptor expressed on myeloid cells-1 (sTREM-1) as diagnostic and prognostic marker in neonatal sepsis Amira A.M. Adly a, Eman A. Ismail b,⇑, Nevine G. Andrawes a, Marwa A. El-Saadany a a b
Pediatric Department, Faculty of Medicine, Ain Shams University, Egypt Clinical Pathology Department, Faculty of Medicine, Ain Shams University, Egypt
a r t i c l e
i n f o
Article history: Received 3 April 2013 Received in revised form 2 October 2013 Accepted 5 November 2013 Available online 2 December 2013 Keywords: sTREM-1 Neonatal sepsis Outcome Therapy hs-CRP
a b s t r a c t Objective: Triggering receptor expressed on myeloid cells-1 (TREM-1) is an important receptor involved in the innate inflammatory response and sepsis. We assessed soluble TREM-1 (sTREM-1) in 112 septic neonates (63 culture-positive and 49 culture-negative) and 40 healthy controls as a potential early diagnostic and prognostic marker for neonatal sepsis (NS). Methods: Studied neonates were evaluated for early- or late-onset sepsis using clinical and laboratory indicators upon admission. sTREM-1 was measured on initial sepsis evaluation and at 48 h after antibiotic therapy. For ethical reasons, cord blood samples were collected from control neonates and only samples from neonates that proved to be healthy by clinical examination and laboratory analysis were further analyzed for sTREM-1. Results: Baseline sTREM-1 levels were significantly elevated in culture-proven (1461.1 ± 523 pg/mL) and culture-negative sepsis (1194 ± 485 pg/mL) compared to controls (162.2 ± 61 pg/mL) with no significant difference between both septic groups. Culture-positive or negative septic preterm neonates had significantly higher sTREM-1 compared to full term neonates. sTREM-1 was significantly higher in neonates with early sepsis than late sepsis and was associated with high mortality. sTREM-1 was significantly decreased 48 h after antibiotic therapy compared to baseline or levels in neonates with persistently positive cultures. sTREM-1 was positively correlated to white blood cells (WBCs), absolute neutrophil count, immature/total neutrophil (I/T) ratio, C-reactive protein (hs-CRP) and sepsis score while negatively correlated to gestational age and weight. hs-CRP and sepsis score were independently related to sTREM-1 in multiregression analysis. sTREM-1 cutoff value of 310 pg/mL could be diagnostic for NS with 100% sensitivity and specificity (AUC, 1.0 and 95% confidence interval [CI], 0.696–1.015) while the cutoff value 1100 pg/mL was predictive of survival with 100% sensitivity and 97% specificity (AUC, 0.978 and 95% CI, 0.853–1.13). However, hs-CRP cutoff 13.5 mg/L could be diagnostic for NS with a sensitivity of 76% and specificity of 72% (AUC, 0.762 and 95% CI, 0.612–0.925) and levels were not related to survival as no significant difference was found between dead and alive septic neonates. Conclusions: Elevated sTREM-1 could be considered an early marker for NS that reflects sepsis severity and poor prognosis. Ó 2013 Elsevier Ltd. All rights reserved.
1. Introduction Sepsis is a complex clinical condition caused by dysregulated immune response to an infection resulting in multiorgan failure with a fatal outcome. The initial line of defense is the immediate innate host immune response which involves coordinated action of effector cells that express numerous membrane-bound receptors. Of these, the Toll-like receptors (TLRs) detect microbial structures such as lipopolysaccharide, lipoteichoic acid, flagellin and bacterial DNA [1,2]. Neonatal infections annually claim lives of 1.4 million neonates worldwide [3]. More than 90% of these deaths occur in the poorest ⇑ Corresponding author. Tel.: +20 2 0105118652; fax: +20 2 33375435. E-mail address: [email protected] (E.A. Ismail). 1043-4666/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.cyto.2013.11.004
countries of Asia and Africa [4]. Identification and treatment of newborns with infection are weak in many developing countries [5]. Detailed studies on the etiology and antibiotic resistance profile of neonatal sepsis (NS) are uncommon [5]. Neonatal susceptibility is related to the immature immunologic defense [6]. Mortality rate in NS differs according to the type of organism being the highest with Gram-negative bacteria [7] and diagnosis remains challenging [8]. There is no gold standard for diagnosing sepsis as clinical and laboratory signs are neither sensitive enough nor specific enough [3] and the main limitations of microbiological studies are the unavailability of the results until 72 h and low sensitivity as 57% of septic infants may have negative results [9]. Thus, management of possible sepsis cases often depends on clinical algorithm leading to empirical treatment. This often results in unnecessary
A.A.M. Adly et al. / Cytokine 65 (2014) 184–191
antibiotic use, which may lead to emergence of antibiotic resistance [3]. Biomarkers have shown great promise in diagnosis of sepsis and guiding appropriate treatment of neonates [3]. Acute phase reactants, pro and anti-inflammatory mediators including chemokines and cytokines, and cell-surface antigens are nonspecific biomarkers that have been extensively studied for the diagnosis and management of late onset NS [10]. The triggering receptor expressed on myeloid cells 1 (TREM-1) has been identified as an important receptor involved in the innate inflammatory response and in sepsis [11–13]. TREM-1 is a member of the immunoglobulin superfamily and is up-regulated on the surfaces of neutrophils, monocytes and macrophages after exposure to lipopolysaccharide, heat-inactivated Gram-positive bacteria, Gram-negative bacteria or fungi [11,14–16]. It is involved in monocytic activation and inflammatory response mediated by TLR-2 and -4 [16,17]. The expression of membrane-bound TREM-1 is greatly increased on monocytes during sepsis. Moreover, infection induces release of a soluble form of this receptor, which can be measured in biological fluid and may be useful as a diagnostic tool [16]. Conversely, TREM-1 is not up-regulated in patients with non-infectious inflammatory conditions, defining the specific involvement of this receptor only in cases of infection [9]. Recently, increased soluble TREM-1 (sTREM-1) levels have been reported in neonates with late onset sepsis (>day 3 of life) [18]. However, data on sTREM-1 as an early diagnostic biomarker and its relation to prognosis of septic neonates are still lacking. Therefore, we aimed to assess sTREM-1 levels as a potential early diagnostic and prognostic marker for NS. 2. Materials and methods This prospective study was carried out on 112 neonates admitted to the Neonatal Intensive Care Unit (NICU), Pediatric Hospital, Ain Shams University with clinical and laboratory signs of sepsis. Another 40 gestational age- and sex-matched healthy newborns were enrolled as a control group. An informed consent was obtained from the legal guardian of each patients or controls before enrollment. This study was approved by the ethical committee of Ain Shams University. 2.1. Definition of sepsis The diagnosis of sepsis was based on at least 2 clinical and 2 laboratory criteria [19,20]. Clinical criteria were: hyperthermia (core body temperature P38 °C) or hypothermia 160 beats/min) or bradycardia (heart rate 60 breaths/min) or recurrent apnea >20 s, increased oxygen requirements or requirement for ventilatory support, feeding intolerance suspected by the presence of gastric residuals, abdominal distension, gross or occult blood in the stool and the onset of crises of apnea/bradycardia [21], abdominal distension, lethargy and hypotonia, hypotension
