Abstract
Infection is a leading cause of neonatal morbidity and mortality worldwide. Premature neonates are particularly susceptible to infection because of physiologic immaturity, comorbidity, and extraneous medical interventions. Additionally premature infants are at higher risk of progression to sepsis or severe sepsis, adverse outcomes, and antimicrobial toxicity. Currently initial diagnosis is based upon clinical suspicion accompanied by nonspecific clinical signs and is confirmed upon positive microbiologic culture results several days after institution of empiric therapy. There exists a significant need for rapid, objective, in vitro tests for diagnosis of infection in neonates who are experiencing clinical instability. We used immunoassays multiplexed on microarrays to identify differentially expressed serum proteins in clinically infected and non-infected neonates. Immunoassay arrays were effective for measurement of more than 100 cytokines in small volumes of serum available from neonates. Our analyses revealed significant alterations in levels of eight serum proteins in infected neonates that are associated with inflammation, coagulation, and fibrinolysis. Specifically P- and E-selectins, interleukin 2 soluble receptor alpha, interleukin 18, neutrophil elastase, urokinase plasminogen activator and its cognate receptor, and C-reactive protein were observed at statistically significant increased levels. Multivariate classifiers based on combinations of serum analytes exhibited better diagnostic specificity and sensitivity than single analytes. Multiplexed immunoassays of serum cytokines may have clinical utility as an adjunct for rapid diagnosis of infection and differentiation of etiologic agent in neonates with clinical decompensation.
Highlights
Infection is a leading cause of neonatal morbidity and mortality worldwide
The positive predictive value or negative predictive value (NPV) of individual analytes has not been adequate for routine use in the diagnosis and management of neonatal infection
Single Factor Analysis—Logarithm-transformed mean fluorescence intensities (MFIs) of analyte values in clinically infected and non-infected samples were compared by analysis of variance (ANOVA), Type III, sum of squares (SAS 8.2 general linear model procedure) with a significance level or p value Ͻ0.05 as described previously [26]
Summary
Multiplexed immunoassays of serum cytokines may have clinical utility as an adjunct for rapid diagnosis of infection and differentiation of etiologic agent in neonates with clinical decompensation. Neonatal Sepsis Biomarkers leukin 6 (IL-6)1 [11, 13], tumor necrosis factor ␣ (TNF␣) [11, 13], neutrophil elastase (NE) [14], C-reactive protein (CRP) [12, 15], soluble CD14 [16, 17], granulocyte colony-stimulating factor (G-CSF) [18], soluble intercellular adhesion molecule-1 (ICAM-1) [12], and soluble L-selectin [19] have shown association with infection in neonates. We used amplified, multiplexed, immunoassay arrays to measure 142 small serum proteins and assess their utility in differential diagnosis of neonatal infection.
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