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Role of serum (1,3)-β-d-glucan assay in early diagnosis of invasive fungal infections in a neonatal intensive care unit
O papel do (1.3)-β-D-glucano no soro no diagnóstico precoce de infecções fúngicas invasivas em uma unidade de terapia intensiva neonatal
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El-Emshaty, Basma Shouman" "autores" => array:4 [ 0 => array:4 [ "nombre" => "Abd Elazeez" "apellidos" => "Shabaan" "email" => array:1 [ 0 => "ashabaan1973@gmail.com" ] "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">*</span>" "identificador" => "cor0005" ] ] ] 1 => array:3 [ "nombre" => "Lobna Mahmoud" "apellidos" => "Elbaz" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">b</span>" "identificador" => "aff0010" ] ] ] 2 => array:3 [ "nombre" => "Wafaa M." "apellidos" => "El-Emshaty" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">c</span>" "identificador" => "aff0015" ] ] ] 3 => array:3 [ "nombre" => "Basma" "apellidos" => "Shouman" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] ] ] ] "afiliaciones" => array:3 [ 0 => array:3 [ "entidad" => "Mansoura University, Department of Pediatrics, Mansoura, Egypt" "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Mansoura General Hospital, Department of Pediatrics, Mansoura, Egypt" "etiqueta" => "b" "identificador" => "aff0010" ] 2 => array:3 [ "entidad" => "Mansoura University, Department of Clinical Pathology, Mansoura, Egypt" "etiqueta" => "c" "identificador" => "aff0015" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "pt" => array:1 [ "titulo" => "O papel do (1.3)-β-D-glucano no soro no diagnóstico precoce de infecções fúngicas invasivas em uma unidade de terapia intensiva neonatal" ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0015" "etiqueta" => "Figure 3" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr3.jpeg" "Alto" => 1414 "Ancho" => 1460 "Tamanyo" => 56761 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0055" class="elsevierStyleSimplePara elsevierViewall">ROC curve of 1,3-β-<span class="elsevierStyleSmallCaps">d</span>-glucan for discrimination between no fungemia and definite fungemia groups.</p>" ] ] ] "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Neonatal sepsis (NS), together with pneumonia and meningitis, account for 1.4 million annual neonatal deaths worldwide.<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">1</span></a> Newborn infants are at high risk for infection due to underdevelopment of their immune barriers, including fragile skin and relative immune tolerance.<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">2</span></a> Fungal sepsis is a type of late onset sepsis (LOS) and should be considered in neonates with prolonged hospitalization and in those on prolonged antibiotic treatment.<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">3</span></a> The incidence of fungal sepsis ranges from 0.4 to 2 cases per 1000 live births, and from 3.8% to 12.9% among very low birth weight infants.<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">4</span></a> The most commonly reported risk factors for invasive fungal infection (IFIs) are prematurity, low birth weight, major congenital malformations, exposure to broad spectrum antibiotics, central venous catheters, delayed enteral feeds, prolonged parenteral nutrition, endotracheal intubation, surgery, postnatal steroids, and longer neonatal intensive care unit (NICU) stay.<a class="elsevierStyleCrossRefs" href="#bib0175"><span class="elsevierStyleSup">5,6</span></a> IFI manifestations are nonspecific, and blood culture is considered the gold standard for its diagnosis.<a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">7</span></a> Unfortunately, preliminary results of blood cultures are usually obtained after 48<span class="elsevierStyleHsp" style=""></span>h or more. Moreover, diagnosis of IFI in neonatal infants is difficult, due to the high rate of false negative in cultures<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">8</span></a>; blood cultures are negative in approximately 50% of cases of autopsy-proven disseminated candidiasis.<a class="elsevierStyleCrossRef" href="#bib0195"><span class="elsevierStyleSup">9</span></a> Therefore, new tools are required for early diagnosis of IFIs in neonates. 1,3-β-<span class="elsevierStyleSmallCaps">d</span>-Glucan (BG) is a component of the outer cell wall of fungi, including <span class="elsevierStyleItalic">Candida</span> spp., <span class="elsevierStyleItalic">Aspergillus</span> spp., and <span class="elsevierStyleItalic">Pneumocystis jiroveci</span>, and it is released into the blood stream during IFI.<a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">10</span></a> To date, only three small trials were conducted in neonates; they concluded that BG is a useful adjunctive diagnostic method of IFI.<a class="elsevierStyleCrossRefs" href="#bib0205"><span class="elsevierStyleSup">11–13</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">The authors hypothesized that early assessment of serum BG in neonates with suspected fungal sepsis is a good substitute to fungal blood culture. Accordingly, this study aimed to assess the microbiological pattern of neonatal LOS and the diagnostic performance of BG for early diagnosis of IFI in high-risk infants admitted to NICUs.</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Subjects and methods</span><p id="par0015" class="elsevierStylePara elsevierViewall">This was a prospective multi-center cohort study conducted in NICUs of the Mansoura University Children's Hospital and of the Mansoura General Hospital from March 2014 to February 2016.</p><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Ethics</span><p id="par0020" class="elsevierStylePara elsevierViewall">The Research Ethics Committee of Mansoura Faculty of Medicine approved the study, and written informed consents were obtained from the parents of all neonates included in the study.</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Included subjects</span><p id="par0025" class="elsevierStylePara elsevierViewall">Neonates with clinically suspected LOS (sepsis after 72<span class="elsevierStyleHsp" style=""></span>h from birth) who were at high risk of IFI were included. Clinical manifestations suggestive of neonatal sepsis were defined in accordance with the Brazilian National Health Surveillance Agency (ANVISA) criteria, in which neonatal sepsis was defined as a systemic response, without any other recognized cause than infection, associated with at least two or more of the following signs and symptoms: thermal instability, apnea, worsening of respiratory discomfort, hemodynamic instability, bradycardia, feeding intolerance, glucose intolerance, hypoactivity, and lethargy.<a class="elsevierStyleCrossRef" href="#bib0220"><span class="elsevierStyleSup">14</span></a></p><p id="par0030" class="elsevierStylePara elsevierViewall">Patients were considered at high risk for IFI if they had three or more of the following criteria: Low birth weight (<2500<span class="elsevierStyleHsp" style=""></span>g), hospitalization for >3 weeks, prolonged mechanical ventilation (>1 week), systemic antibiotic exposure >72<span class="elsevierStyleHsp" style=""></span>h, postoperative patients, abdominal wall defects, central venous catheter, arterial catheter >72<span class="elsevierStyleHsp" style=""></span>h, total parenteral nutrition administration, and persistent severe thrombocytopenia despite second line antibiotics administration.<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">13</span></a></p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Excluded subjects</span><p id="par0035" class="elsevierStylePara elsevierViewall">Neonates who received systemic antifungal drugs (prophylactic or therapeutic), intravenous immunoglobulin, albumin, plasma protein, and amoxicillin-clavulanic acid antibiotic were excluded from the study.</p><p id="par0040" class="elsevierStylePara elsevierViewall">All recruited infants underwent LOS investigations: complete blood count, total and differential; quantitative C-reactive protein (CRP); and full septic workup, including blood, urine, CSF cultures, as well as serum BG level. Other laboratory and radiological investigations were performed according to the decision of the attending physician.</p><p id="par0045" class="elsevierStylePara elsevierViewall">Neonates included were categorized according to their blood culture results into three groups. The no fungemia group included 41 neonates with blood culture-proven bacterial sepsis. The definite fungemia group included 11 neonates with blood culture-proven fungemia. Finally, the suspected fungemia group included 25 neonates with negative blood culture for bacteria and fungi, but at high risk of IFI with abnormal white blood cells (WBCs), low platelets, or elevated CRP.</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Laboratory workup</span><p id="par0050" class="elsevierStylePara elsevierViewall">All infants included in the study underwent full septic workup, as well as BG assay, within 24<span class="elsevierStyleHsp" style=""></span>h of recruitment. A total of 3<span class="elsevierStyleHsp" style=""></span>mL of blood were collected; 2<span class="elsevierStyleHsp" style=""></span>mL were used for blood culture using blood culture vials (BD BactecPedsPlus™/F culture vials; Becton Dickinson, Maryland, USA) and the other 2<span class="elsevierStyleHsp" style=""></span>mL were used for complete blood count (CBC), CRP, and BG analysis.</p></span></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Methods</span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Blood culture</span><p id="par0055" class="elsevierStylePara elsevierViewall">An automated continuous-monitoring blood culture system, BD BACTEC™ FX 40 (Becton Dickinson Maryland, USA) was used. Bottles were incubated for five days before being discarded as negative; however, they were sub-cultured according to the laboratory operating procedure if they were flagged as positive before this time. Bacterial isolates were identified through colonies morphology, haemolysis on blood agar, Gram-stained smears, catalase test, coagulase test, and biochemical reactions.</p><p id="par0060" class="elsevierStylePara elsevierViewall">CRP was quantified using latex-enhanced turbid metric assay. The turbidity is measured at 630<span class="elsevierStyleHsp" style=""></span>nm using HEALES analyzer (Shenzhen Huisong Technology Department Co., Ltd. – China).</p><p id="par0065" class="elsevierStylePara elsevierViewall">BG was detected with the Dynamiker Fungus (Dynamiker Biotechnology, Tianjin, China) in clinical pathology laboratory of Mansoura faculty of medicine. This colorimetric assay based upon a modification of the limulus amebocyte lysate pathway. The absorbance is measured at 405<span class="elsevierStyleHsp" style=""></span>nm kinetically every 60<span class="elsevierStyleHsp" style=""></span>s for 40<span class="elsevierStyleHsp" style=""></span>min at 37<span class="elsevierStyleHsp" style=""></span>°C with TECAN reader (TECAN, IInfinite F 50, Life Sciences, Mannedorf, Switzerland). The concentration of BG is interpreted according to standard curve: values >95, 70–95, and <70<span class="elsevierStyleHsp" style=""></span>pg/mL were considered positive, equivocal, and negative, respectively, and abnormal results were omitted.</p></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Data analysis</span><p id="par0070" class="elsevierStylePara elsevierViewall">Statistical analysis was done using SPSS software (IBM SPSS Statistics for Windows, version 20.0. NY, USA). The Kolmogorov-Smirnov test was used to check for normal data distribution. Categorical data were described using number and percentage. Continuous data were described using median, range, mean, and standard deviation. The Chi-squared test was used for categorical variables, one-way ANOVA for Gaussian data, and Kruskal–Walls test for non-Gaussian data to compare between three or more groups. The sensitivity and specificity of the BG assay were determined; the positive (PPV) and negative predictive values (NPV) of the test were calculated, and the ROC curve was constructed.</p></span></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0110">Results</span><p id="par0075" class="elsevierStylePara elsevierViewall">During the study period, a total of 77 neonates with LOS at a high risk of IFI were included; the stratification of patients into groups is demonstrated in the study flow chart (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>). Baseline characteristics of studied groups revealed that gestational age and birth weight were significantly lower in definite fungemia patients when compared with those in the no fungemia and suspected fungemia groups. Postnatal age, Cesarean section delivery, and male gender were significantly higher in definite fungemia patients when compared with no fungemia and suspected fungemia patients (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>). Low birth weight, hospitalization >3 weeks, central device, persistent thrombocytopenia, WBC, and CRP were significantly higher in the definite fungemia group when compared with the other two groups, while mechanical ventilation or continuous positive airway pressure (CPAP) >1 week was significantly higher in the definite fungemia group when compared with the no fungemia group only (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>). Gram-negative bacteria were more predominant than Gram-positive bacteria, with a frequency of 32/54 and 11/54, respectively. The growing organisms were <span class="elsevierStyleItalic">Klebsiella</span> spp. (14/54); <span class="elsevierStyleItalic">Escherichia coli</span> (12/54); <span class="elsevierStyleItalic">Staphylococcus</span> spp. (12/54; coagulase-negative <span class="elsevierStyleItalic">Staphylococcus</span> [9/54]; <span class="elsevierStyleItalic">Staphylococcus aureus</span> [3/54]); <span class="elsevierStyleItalic">Pseudomonas aerouginosa</span> (3/54); and <span class="elsevierStyleItalic">Proteus</span> spp. (2/54). Moreover, 11/54 presented <span class="elsevierStyleItalic">Candida</span>. Two neonatal blood cultures revealed mixed growth of <span class="elsevierStyleItalic">Candida</span> with bacteria.</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0080" class="elsevierStylePara elsevierViewall">The results of the BG assay were negative in 34, equivocal in 23, and positive in 20 cases. The no fungemia group was significantly associated with negative BG results when compared with the definite fungemia group (<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.005); in turn, the definite fungemia group was significantly associated with positive BG results when compared with the no fungemia group (<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.001).</p><p id="par0085" class="elsevierStylePara elsevierViewall">In all studied neonates, the median and ranges of BG concentrations are demonstrated in <a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>. BG concentration was significantly higher in the definite fungemia group when compared with the no fungemia and suspected fungemia groups (<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.001 and <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.011, respectively; <a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>). The sensitivity and specificity of BG assay at the 99<span class="elsevierStyleHsp" style=""></span>pg/mL level were 63.6% and 95.1%, respectively. The PPV and NPV were 77.8% and 90.7%, respectively with accuracy 88.5%. The area under the receiver operating curve (ROC) was 0.837 (95% CI [0.689–0.985]; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.001; <a class="elsevierStyleCrossRef" href="#fig0015">Fig. 3</a>).</p><elsevierMultimedia ident="fig0010"></elsevierMultimedia><elsevierMultimedia ident="fig0015"></elsevierMultimedia></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0115">Discussion</span><p id="par0090" class="elsevierStylePara elsevierViewall">In spite of the development of new antifungal drugs, mortality and life-threatening complications of IFIs are still frequently reported in critically ill patients.<a class="elsevierStyleCrossRef" href="#bib0225"><span class="elsevierStyleSup">15</span></a> The diagnosis of nosocomial IFI is negatively affected by suboptimal culture results. Therefore, new tools are required for early diagnosis of IFIs in neonates.</p><p id="par0095" class="elsevierStylePara elsevierViewall">In the present study, the microbiological pattern of blood stream neonatal LOS was prospectively tested, and the diagnostic performance of serum BG assay in early diagnosis of IFI in high-risk infants admitted to a NICU was assessed.</p><p id="par0100" class="elsevierStylePara elsevierViewall">In the present study, the most prevalent isolates were Gram-negative bacteria (57.2%), particularly <span class="elsevierStyleItalic">Klebsiella</span> spp. accounting for 25.9% of culture positive cases. Similarly, multiple studies reported Gram-negative pathogens as the predominant bacterial isolate in neonatal sepsis, with <span class="elsevierStyleItalic">Klebsiella pneumoniae</span> as the most frequently detected organism.<a class="elsevierStyleCrossRefs" href="#bib0230"><span class="elsevierStyleSup">16,17</span></a> Moreover, Al-Shamahy et al. conducted a study in Sanaa (Yemen), and reported a very high rate of Gram-negative bacteria, comprising 97.8% of the total isolates; <span class="elsevierStyleItalic">Klebsiella</span> spp. was the most predominant (36.7%) pathogen.<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">18</span></a> In contrast, Hornik et al. found that Gram-positive organisms accounted for 45–75% of causes of LOS in neonates.<a class="elsevierStyleCrossRef" href="#bib0245"><span class="elsevierStyleSup">19</span></a></p><p id="par0105" class="elsevierStylePara elsevierViewall">Fungi represented 20.3% of culture positive cases in the present study. Similarly, a multicenter study conducted by Cotton et al. demonstrated that the rate of IFIs was 2.4–20.4% in extremely low birth weight infants.<a class="elsevierStyleCrossRef" href="#bib0250"><span class="elsevierStyleSup">20</span></a> However, a large retrospective study demonstrated a very low incidence of IFIs (0.06%) in neonates >1500<span class="elsevierStyleHsp" style=""></span>g birth weight.<a class="elsevierStyleCrossRef" href="#bib0255"><span class="elsevierStyleSup">21</span></a> The high incidence of IFIs in the present study can be explained by the fact that infants who had three or more risk factors for fungal infection were included, as well as by the lack of compliance to strict hygiene in developing countries. In the present study, <span class="elsevierStyleItalic">Candida albicans</span> was the only isolated fungal growth, which is in agreement with the results of Hope et al., who stated that <span class="elsevierStyleItalic">C. albicans</span> is the most frequent <span class="elsevierStyleItalic">Candida</span> species causing invasive candidiasis in neonates.<a class="elsevierStyleCrossRef" href="#bib0260"><span class="elsevierStyleSup">22</span></a></p><p id="par0110" class="elsevierStylePara elsevierViewall">Regarding the BG assay in the present study, in the no fungemia group, 23 were found negative, 14 were equivocal, and four were positive. In turn, in the definite fungemia group, seven were found positive, three were equivocal, and one was negative. False-positive BG reactions are suspected to occur in patients treated with intravenous immunoglobulins, albumin, coagulation factors, and plasma protein fraction manufactured by certain fungal vendors, or antibiotics derived from fungal sources as amoxicillin-clavulanic acid, which were all excluded in our study. Patients’ exposure to gauze or materials containing glucans during surgery, mucosal damage from chemotherapy or radiotherapy, cross-experimental contamination with BG due to excess manipulation of a sample, certain streptococci, and <span class="elsevierStyleItalic">P. aeruginosa</span> may also cause false positive reactivity.<a class="elsevierStyleCrossRefs" href="#bib0265"><span class="elsevierStyleSup">23,24</span></a> Moreover, Zheng et al. reported that postnatal corticosteroids therapy can cause false positive BG result.<a class="elsevierStyleCrossRef" href="#bib0275"><span class="elsevierStyleSup">25</span></a> In the present study, two neonates from the no fungemia group had history of recent surgery, with possible exposure to materials that contained glucans. In addition, <span class="elsevierStyleItalic">P. aeruginosa</span> was isolated from three neonates within the no fungemia group, which may explain their false positive reactivity. In the suspected fungemia group, nine of the neonates presented positive BG reaction, which might be explained by the low sensitivity of blood culture in the diagnosis of invasive candidiasis, as only 50% of invasive candidiasis are blood-culture positive.<a class="elsevierStyleCrossRef" href="#bib0195"><span class="elsevierStyleSup">9</span></a> Furthermore, fungi other than <span class="elsevierStyleItalic">Candida</span>, such as <span class="elsevierStyleItalic">Aspergillus</span>, may be the cause of positive BG in these patients, since blood cultures are almost always negative in disseminated aspergillosis.<a class="elsevierStyleCrossRef" href="#bib0280"><span class="elsevierStyleSup">26</span></a> Finally, the false negative result of BG in one patient from the definite fungemia group may be explained by IFI at an early stage.</p><p id="par0115" class="elsevierStylePara elsevierViewall">The sensitivity, specificity, PPV, NPP, and accuracy of the BG assay in the present study at the cut-off value of 95<span class="elsevierStyleHsp" style=""></span>pg/mL recommended by the manufacturer (after considering the equivocal results to be negative) were 63.6%, 90.2%, 63.6%, 90.2%, and 84.6%, respectively, in comparison to 90%, 56.1%, 35.15, 95.8%, and 63.5%, respectively, at a cut-off value ≥70<span class="elsevierStyleHsp" style=""></span>pg/mL (after considering equivocal results to be positive). At the best obtained cut-off value (99<span class="elsevierStyleHsp" style=""></span>pg/mL), these levels were 63.6%, 95.1%, 77.8%, 90.7%, and 88.5%, respectively. In the present study, the specificity of BG assay used for early diagnosis of IFIs was excellent (95.1%), while its sensitivity (63.6%) is limited at an optimal cut-off value of 99<span class="elsevierStyleHsp" style=""></span>pg/mL. The excellent specificity and NPV suggest the good ability of BG assay to exclude IFI in suspected neonates, while its ability to diagnose the disease is limited. Thus, BG assay is better when combined with other clinical, radiological, and microbiological findings to improve its sensitivity. The primary value of the BG assay is to exclude the presence of IFIs based on a negative result, which would eliminate the need for toxic and expensive antifungal therapy.</p><p id="par0120" class="elsevierStylePara elsevierViewall">In a previous study in a similar population of neonates with clinically suspected LOS who were at high risk of fungemia, the BG assay at the 60<span class="elsevierStyleHsp" style=""></span>pg/mL level showed sensitivity, specificity, PPV, NPV values of 73.2%, 71.0%, 76.9%, and 66.7%, respectively while at the level of 80<span class="elsevierStyleHsp" style=""></span>pg/mL, these values were 70.7%, 77.4%, 80.6%, and 66.7%, respectively.<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">13</span></a> In turn, in a retrospective study carried out by Goudjil et al., it was reported that BG levels increased in neonatal IFI with an optimal cut-off value for BG positivity >125<span class="elsevierStyleHsp" style=""></span>pg/mL; at this cut-off value, Sensitivity and specificity were 84% and 75%, respectively.<a class="elsevierStyleCrossRef" href="#bib0205"><span class="elsevierStyleSup">11</span></a> Moreover, a study conducted by Zhao et al. found that BG sensitivity in diagnosing IFD at cut-off levels ≥10<span class="elsevierStyleHsp" style=""></span>pg/mL, ≥200<span class="elsevierStyleHsp" style=""></span>pg/mL, and ≥400<span class="elsevierStyleHsp" style=""></span>pg/mL was 68.3%, 49.2%, and 33.3%, respectively while its specificity was 75.6%, 91.3%, and 96.3%, respectively. However, serum BG was measured in their study by a different technique than that of the present study, with BG values <10<span class="elsevierStyleHsp" style=""></span>pg/mL interpreted as negative and values >20<span class="elsevierStyleHsp" style=""></span>pg/mL as positive.<a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">12</span></a> Furthermore, Liu et al. evaluated the BG assay for diagnosis of candidemia in pediatric patients; they reported results similar to those of the present study, with sensitivity, specificity, PPV, NPV values of 68%, 91%, 66%, and 91%, respectively. They concluded that plasma BG assay has a moderate efficacy to aid the diagnosis of candidemia in pediatric patients, while it is useful to rule out candidemia due to its high NPV.<a class="elsevierStyleCrossRef" href="#bib0285"><span class="elsevierStyleSup">27</span></a></p><p id="par0125" class="elsevierStylePara elsevierViewall">In a meta-analysis including 31 studies, it was concluded that BG has a sensitivity of 80% and a specificity of 82% in the diagnosis of IFI. However, most of the studies included in that meta-analysis were conducted in adults.<a class="elsevierStyleCrossRef" href="#bib0290"><span class="elsevierStyleSup">28</span></a> In a more recent meta-analysis by Hou et al.,<a class="elsevierStyleCrossRef" href="#bib0295"><span class="elsevierStyleSup">29</span></a> in which a total of 1068 patients of different age groups from 11 studies were analyzed, the pooled sensitivity, specificity, positive likelihood ratio, negative likelihood ratio, diagnostic odds ratio, and area under the summary ROC curve, with 95% confidence intervals, were 0.75 (0.63,0.84), 0.87 (0.81,0.92), 5.85 (3.96,8.63), 0.30 (0.20,0.45), 19.53 (11.16,34.18), and 0.89 (0.86,0.91), respectively.<a class="elsevierStyleCrossRef" href="#bib0295"><span class="elsevierStyleSup">29</span></a></p><p id="par0130" class="elsevierStylePara elsevierViewall">It is evident that the cut-off value of serum BG can vary according to the kits and techniques used in the assay; in the present study, the best obtained cut-off value for diagnosing IFI was 99<span class="elsevierStyleHsp" style=""></span>pg/mL with the Dynamiker Fungus technique. Meanwhile, according to a systematic review and meta-analysis conducted by He et al. to evaluate the diagnostic accuracy of serum BG for IFI, the best diagnostic accuracy in the Fungitell assay was observed using a cut-off of 60<span class="elsevierStyleHsp" style=""></span>pg/mL; in the Fungitec <span class="elsevierStyleItalic">G</span>-Test assay (Seikagaku Corporation, Tokyo, Japan), 20<span class="elsevierStyleHsp" style=""></span>pg/mL; and in the Wako assay (Wako Chemicals, VA, USA), 11<span class="elsevierStyleHsp" style=""></span>pg/mL.<a class="elsevierStyleCrossRef" href="#bib0300"><span class="elsevierStyleSup">30</span></a></p><p id="par0135" class="elsevierStylePara elsevierViewall">The limitations of the present study include a small sample size, heterogeneous cohort of newborn infants, the fact that two different centers manipulated the samples, and use of blood culture as a gold standard for diagnosis of IFI, which is only positive in 50% of cases. Furthermore, there is the limitation of BG itself as an expensive test, especially for developing countries, and it does not identify species.</p><p id="par0140" class="elsevierStylePara elsevierViewall">It is difficult to measure the actual performance of BG test, due to the poor sensitivity of blood culture. The available data indicates that the BG test has a limited sensitivity and excellent specificity that allow its use as an aid in diagnosis or exclusion of fungal neonatal sepsis. The adjustment of BG cut-off value to 99<span class="elsevierStyleHsp" style=""></span>pg/mL appears suitable when there are no other causes of false reactivity. The NPV at this level could exclude the presence of fungemia by 90.7% based on a negative result. The authors recommend that accurate diagnosis and therapeutic decisions should be based on combining BG assay with other clinical, radiological, and microbiological findings, due to its limited sensitivity.</p></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0120">Conflicts of interest</span><p id="par0145" class="elsevierStylePara elsevierViewall">The authors declare no conflicts of interest.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:11 [ 0 => array:3 [ "identificador" => "xres1092914" "titulo" => "Abstract" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0005" "titulo" => "Objectives" ] 1 => array:2 [ "identificador" => "abst0010" "titulo" => "Methods" ] 2 => array:2 [ "identificador" => "abst0015" "titulo" => "Results" ] 3 => array:2 [ "identificador" => "abst0020" "titulo" => "Conclusion" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec1035775" "titulo" => "Keywords" ] 2 => array:3 [ "identificador" => "xres1092913" "titulo" => "Resumo" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0025" "titulo" => "Objetivos" ] 1 => array:2 [ "identificador" => "abst0030" "titulo" => "Métodos" ] 2 => array:2 [ "identificador" => "abst0035" "titulo" => "Resultados" ] 3 => array:2 [ "identificador" => "abst0040" "titulo" => "Conclusão" ] ] ] 3 => array:2 [ "identificador" => "xpalclavsec1035774" "titulo" => "Palavras-chave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 5 => array:3 [ "identificador" => "sec0010" "titulo" => "Subjects and methods" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "sec0015" "titulo" => "Ethics" ] 1 => array:2 [ "identificador" => "sec0020" "titulo" => "Included subjects" ] 2 => array:2 [ "identificador" => "sec0025" "titulo" => "Excluded subjects" ] 3 => array:2 [ "identificador" => "sec0030" "titulo" => "Laboratory workup" ] ] ] 6 => array:3 [ "identificador" => "sec0035" "titulo" => "Methods" "secciones" => array:2 [ 0 => array:2 [ "identificador" => "sec0040" "titulo" => "Blood culture" ] 1 => array:2 [ "identificador" => "sec0045" "titulo" => "Data analysis" ] ] ] 7 => array:2 [ "identificador" => "sec0050" "titulo" => "Results" ] 8 => array:2 [ "identificador" => "sec0055" "titulo" => "Discussion" ] 9 => array:2 [ "identificador" => "sec0060" "titulo" => "Conflicts of interest" ] 10 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2017-04-18" "fechaAceptado" => "2017-07-18" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec1035775" "palabras" => array:3 [ 0 => "(1,3)-β-<span class="elsevierStyleSmallCaps">d</span>-glucan" 1 => "Invasive candidiasis" 2 => "Neonatal sepsis" ] ] ] "pt" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palavras-chave" "identificador" => "xpalclavsec1035774" "palabras" => array:3 [ 0 => "(1,3)-β-D-glucano" 1 => "Candidíase invasiva" 2 => "Sepse neonatal" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:3 [ "titulo" => "Abstract" "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Objectives</span><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">To study the microbiological pattern of late onset neonatal sepsis cultures and to assess the diagnostic performance of serum (1,3)-β-<span class="elsevierStyleSmallCaps">d</span>-glucan level for early diagnosis of invasive fungemia in high-risk infants admitted to a neonatal intensive care unit.</p></span> <span id="abst0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Methods</span><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">A prospective multicenter clinical trial conducted on infants at high risk for invasive fungal infections, with suspected late onset sepsis, admitted to a neonatal intensive care unit at Mansoura University Children's Hospital and Mansoura General Hospital between March 2014 and February 2016.</p></span> <span id="abst0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Results</span><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">A total of 77 newborn infants with high risk of invasive fungal infection were classified based on blood culture into three groups: no fungemia (41 neonates with proven bacterial sepsis), suspected fungemia (25 neonates with negative blood culture), and definite fungemia group (11 neonates with culture-proven <span class="elsevierStyleItalic">Candida</span>). The growing organisms were <span class="elsevierStyleItalic">Klebsiella</span> spp. (14/54); <span class="elsevierStyleItalic">Escherichia coli</span> (12/54); <span class="elsevierStyleItalic">Staphylococcus</span> spp. (12/54; coagulase-negative <span class="elsevierStyleItalic">Staphylococcus</span> [9/54]; <span class="elsevierStyleItalic">Staphylococcus aureus</span> [3/54]); <span class="elsevierStyleItalic">Pseudomonas aerouginosa</span> (3/54); and <span class="elsevierStyleItalic">Proteus</span> spp. (2/54). Moreover, 11/54 presented <span class="elsevierStyleItalic">Candida</span>. Serum (1,3)-β-<span class="elsevierStyleSmallCaps">d</span>-glucan concentration was significantly lower in the no fungemia group when compared with the definite fungemia group. The best cut-off value of (1,3)-β-<span class="elsevierStyleSmallCaps">d</span>-glucan was 99<span class="elsevierStyleHsp" style=""></span>pg/mL with sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of 63.6%, 95.1%, 77.8%, 90.7%, and 88.5%, respectively.</p></span> <span id="abst0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Conclusion</span><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">(1,3)-β-<span class="elsevierStyleSmallCaps">d</span>-glucan assay has a limited sensitivity with excellent specificity and negative predictive value, which allow its use as an aid in exclusion of invasive neonatal fungal infection. Accurate diagnosis and therapeutic decisions should be based on combining (1,3)-β-<span class="elsevierStyleSmallCaps">d</span>-glucan assay with other clinical, radiological, and microbiological findings.</p></span>" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0005" "titulo" => "Objectives" ] 1 => array:2 [ "identificador" => "abst0010" "titulo" => "Methods" ] 2 => array:2 [ "identificador" => "abst0015" "titulo" => "Results" ] 3 => array:2 [ "identificador" => "abst0020" "titulo" => "Conclusion" ] ] ] "pt" => array:3 [ "titulo" => "Resumo" "resumen" => "<span id="abst0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Objetivos</span><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Estudar o padrão microbiológico das culturas de sepse neonatal de início tardio e avaliar o desempenho diagnóstico do nível de (1,3)-β-D-glucano no soro para diagnóstico precoce de fungemia invasiva em neonatos de alto risco internados em uma unidade de terapia intensiva neonatal.</p></span> <span id="abst0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Métodos</span><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Ensaio clínico multicêntrico prospectivo conduzido em neonatos internados em uma unidade de terapia intensiva neonatal com suspeita de sepse de início tardio que estavam em risco de infecções fúngicas invasivas no hospital universitário infantil de Almançora e no hospital geral de Almançora entre março de 2014 e fevereiro de 2016.</p></span> <span id="abst0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Resultados</span><p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Foram classificados 77 neonatos recém-nascidos com risco de infecção fúngica invasiva, com base na hemocultura, em: grupo sem fungemia, incluindo 41 neonatos com sepse bacteriana comprovada, grupo com suspeita de fungemia, incluindo 25 neonatos com hemocultura negativa; e grupo com fungemia definida, incluindo 11 neonatos com Candida comprovada por cultura. Os organismos em crescimento foram: {<span class="elsevierStyleItalic">Klebsiella</span> spp 14/54; <span class="elsevierStyleItalic">E. coli</span> 12/54; <span class="elsevierStyleItalic">Staphylococcus</span> spp 12/54 (<span class="elsevierStyleItalic">Staph</span> coagulase negativa 9/54; <span class="elsevierStyleItalic">Staph aureus</span> 3/54); <span class="elsevierStyleItalic">pseudomonous aerouginosa</span> 3/54 e <span class="elsevierStyleItalic">Proteus</span> spp 2/54}, além de 11/54 Candida. A concentração de (1,3)-β-D-glucano no soro foi significativamente inferior no grupo sem fungemia em comparação ao grupo com fungemia definida. O melhor valor de corte da (1,3)-β-D-glucano foi 99 pg/mL com sensibilidade, especificidade, valor preditivo positivo, valor preditivo negativo e precisão de 63,6%, 95,1%, 77,8%, 90,7% e 88,5%, respectivamente.</p></span> <span id="abst0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Conclusão</span><p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">O ensaio de (1,3)-β-D-glucano possui sensibilidade limitada com especificidade e valor preditivo negativo excelentes que possibilitam seu uso e ajudam na exclusão de infecção fúngica invasiva neonatal. O diagnóstico preciso e as decisões oterapêuticas devem ter como base a combinação di ensaio de (1,3)-β-D-glucano com outros achados clínicos, radiológicos e microbiológicos.</p></span>" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0025" "titulo" => "Objetivos" ] 1 => array:2 [ "identificador" => "abst0030" "titulo" => "Métodos" ] 2 => array:2 [ "identificador" => "abst0035" "titulo" => "Resultados" ] 3 => array:2 [ "identificador" => "abst0040" "titulo" => "Conclusão" ] ] ] ] "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "<p class="elsevierStyleNotepara" id="npar0030">Please cite this article as: Shabaan AE, Elbaz LM, El-Emshaty WM, Shouman B. Role of serum (1,3)-β-<span class="elsevierStyleSmallCaps">d</span>-glucan assay in early diagnosis of invasive fungal infections in a neonatal intensive care unit. J Pediatr (Rio J). 2018;94:559–65.</p>" ] ] "multimedia" => array:4 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1272 "Ancho" => 2167 "Tamanyo" => 157204 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">Study flowchart.</p>" ] ] 1 => array:7 [ "identificador" => "fig0010" "etiqueta" => "Figure 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 1175 "Ancho" => 1476 "Tamanyo" => 70332 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">1,3-β-<span class="elsevierStyleSmallCaps">d</span>-glucan levels in studied neonates.</p>" ] ] 2 => array:7 [ "identificador" => "fig0015" "etiqueta" => "Figure 3" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr3.jpeg" "Alto" => 1414 "Ancho" => 1460 "Tamanyo" => 56761 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0055" class="elsevierStyleSimplePara elsevierViewall">ROC curve of 1,3-β-<span class="elsevierStyleSmallCaps">d</span>-glucan for discrimination between no fungemia and definite fungemia groups.</p>" ] ] 3 => array:8 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at1" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:3 [ "leyenda" => "<p id="spar0065" class="elsevierStyleSimplePara elsevierViewall">Data are expressed as number (percentage), mean<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>SD or median (range).</p><p id="spar0070" class="elsevierStyleSimplePara elsevierViewall">CPAP, continuous positive airway pressure; WBCs, white blood cells; CRP, C-reactive protein.</p>" "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head " align="" valign="top" scope="col" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">No fungemia<br><span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>41 \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Suspected fungemia<br><span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>25 \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Definite fungemia<br><span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>11 \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black"><span class="elsevierStyleItalic">p</span><a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a> \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black"><span class="elsevierStyleItalic">p</span><a class="elsevierStyleCrossRef" href="#tblfn0010"><span class="elsevierStyleSup">b</span></a> \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black"><span class="elsevierStyleItalic">p</span><a class="elsevierStyleCrossRef" href="#tblfn0015"><span class="elsevierStyleSup">c</span></a> \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black"><span class="elsevierStyleItalic">p</span><a class="elsevierStyleCrossRef" href="#tblfn0020"><span class="elsevierStyleSup">d</span></a> \t\t\t\t\t\t\n \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Gestational age (weeks) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">33.41<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>3.294 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">33.08<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>3.511 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">30<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>0.256 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.045 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.069 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.037 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.007 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Postnatal age (days) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">23.76<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>8.249 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">21.08<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>7.205 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">30.91<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>6.236 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.003 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.173 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.008 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.001 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Birth weight (g) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">2100 (850–3900) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1880 (830–4700) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">930 (830–3350) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.038 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.041 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.020 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.018 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Male gender \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">28 (68.3%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">13 (52%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">11 (100%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.007 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.187 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.031 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.005 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Cesarean section delivery \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">32 (78%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">19 (76%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">11 (100%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.041 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.847 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.047 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.035 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Prolonged rupture of membranes \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">28 (68.3%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">18 (72%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">7 (63.6%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.892 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.751 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.770 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.616 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Low birth weight (<2500<span class="elsevierStyleHsp" style=""></span>g) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">30 (73.2%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">16 (64%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">10 (90.9%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.026 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.432 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.015 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.027 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Hospitalization >3 weeks \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">30 (73.2%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">15 (60%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">11 (100%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.038 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.265 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.043 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.016 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Mechanical ventilation or CPAP >1 week \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">36 (87.8%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">22 (88%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">11 (100%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.049 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.041 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.538 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Systemic antibiotic exposure >72<span class="elsevierStyleHsp" style=""></span>h \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">33 (80.5%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">20 (80%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">9 (81.8%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Surgical intervention \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">4 (9.8%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">5 (20%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0 (0.0%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.367 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.282 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.567 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.295 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Central venous or arterial catheterization >72<span class="elsevierStyleHsp" style=""></span>h \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">23 (56.1%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">15 (60%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">10 (90.9%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.003 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.756 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.040 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.016 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Total parenteral nutrition administration \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">34 (82.9%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">20 (80%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">11 (100%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.355 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.754 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.322 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.295 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Persistent thrombocytopenia (<100<span class="elsevierStyleHsp" style=""></span>×<span class="elsevierStyleHsp" style=""></span>10<span class="elsevierStyleSup">9</span>/L) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">31(75.6%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">14 (56%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">10 (90.9%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.041 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.047 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.420 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.049 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Hemoglobin (g/dL) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">11.5 (7.5–18.5) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">12.8 (9.3–17.8) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">10.3 (9.3–13.5) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.113 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.947 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.858 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.797 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">WBCs (×10<span class="elsevierStyleSup">9</span>/L) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">6 (1.9–28.2) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">7 (1.9–28.1) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">11.5 (3.4–26.3) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.027 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.077 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.013 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.004 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">CRP (mg/L) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">48 (12–208) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">48 (12–112) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">96 (12–210) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.022 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.252 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.024 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.042 \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1869007.png" ] ] ] "notaPie" => array:4 [ 0 => array:3 [ "identificador" => "tblfn0005" "etiqueta" => "a" "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Comparison between all groups.</p>" ] 1 => array:3 [ "identificador" => "tblfn0010" "etiqueta" => "b" "nota" => "<p class="elsevierStyleNotepara" id="npar0010">Comparison between no fungemia and suspected fungemia.</p>" ] 2 => array:3 [ "identificador" => "tblfn0015" "etiqueta" => "c" "nota" => "<p class="elsevierStyleNotepara" id="npar0015">Comparison between no fungemia and definite fungemia.</p>" ] 3 => array:3 [ "identificador" => "tblfn0020" "etiqueta" => "d" "nota" => "<p class="elsevierStyleNotepara" id="npar0020">Comparison between suspected and definite fungemia.</p> <p class="elsevierStyleNotepara" id="npar0025">Chi-square, one-way ANOVA, and Kruskal–Wallis test were used.</p>" ] ] ] "descripcion" => array:1 [ "en" => "<p id="spar0060" class="elsevierStyleSimplePara elsevierViewall">Demographic, clinical, and laboratory characteristics of the studied groups.</p>" ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0015" "bibliografiaReferencia" => array:30 [ 0 => array:3 [ "identificador" => "bib0155" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Diagnostic accuracy and prognostic value of the CD64 index in very low birth weight neonates as a marker of early-onset sepsis" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "M. 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| Year/Month | Html | Total | |
|---|---|---|---|
| 2024 November | 9 | 4 | 13 |
| 2024 October | 57 | 19 | 76 |
| 2024 September | 56 | 38 | 94 |
| 2024 August | 60 | 26 | 86 |
| 2024 July | 57 | 40 | 97 |
| 2024 June | 51 | 20 | 71 |
| 2024 May | 49 | 12 | 61 |
| 2024 April | 67 | 23 | 90 |
| 2024 March | 51 | 18 | 69 |
| 2024 February | 65 | 43 | 108 |
| 2024 January | 54 | 35 | 89 |
| 2023 December | 20 | 27 | 47 |
| 2023 November | 31 | 27 | 58 |
| 2023 October | 39 | 40 | 79 |
| 2023 September | 49 | 34 | 83 |
| 2023 August | 29 | 18 | 47 |
| 2023 July | 32 | 15 | 47 |
| 2023 June | 44 | 140 | 184 |
| 2023 May | 51 | 19 | 70 |
| 2023 April | 34 | 9 | 43 |
| 2023 March | 59 | 24 | 83 |
| 2023 February | 50 | 18 | 68 |
| 2023 January | 45 | 12 | 57 |
| 2022 December | 70 | 23 | 93 |
| 2022 November | 38 | 28 | 66 |
| 2022 October | 67 | 28 | 95 |
| 2022 September | 38 | 36 | 74 |
| 2022 August | 40 | 42 | 82 |
| 2022 July | 46 | 30 | 76 |
| 2022 June | 33 | 27 | 60 |
| 2022 May | 41 | 33 | 74 |
| 2022 April | 86 | 35 | 121 |
| 2022 March | 59 | 36 | 95 |
| 2022 February | 34 | 29 | 63 |
| 2022 January | 47 | 22 | 69 |
| 2021 December | 33 | 23 | 56 |
| 2021 November | 14 | 15 | 29 |
| 2021 October | 23 | 14 | 37 |
| 2021 September | 10 | 10 | 20 |
| 2021 August | 16 | 15 | 31 |
| 2021 July | 11 | 6 | 17 |
| 2021 June | 9 | 8 | 17 |
| 2021 May | 20 | 15 | 35 |
| 2021 April | 42 | 31 | 73 |
| 2021 March | 27 | 9 | 36 |
| 2021 February | 18 | 15 | 33 |
| 2021 January | 28 | 6 | 34 |
| 2020 December | 38 | 12 | 50 |
| 2020 November | 24 | 12 | 36 |
| 2020 October | 28 | 13 | 41 |
| 2020 September | 33 | 13 | 46 |
| 2020 August | 6 | 4 | 10 |
| 2020 July | 18 | 10 | 28 |
| 2020 June | 18 | 4 | 22 |
| 2020 May | 22 | 7 | 29 |
| 2020 April | 16 | 7 | 23 |
| 2020 March | 13 | 8 | 21 |
| 2020 February | 25 | 30 | 55 |
| 2020 January | 19 | 23 | 42 |
| 2019 December | 12 | 7 | 19 |
| 2019 November | 7 | 3 | 10 |
| 2019 October | 20 | 11 | 31 |
| 2019 September | 16 | 18 | 34 |
| 2019 August | 25 | 12 | 37 |
| 2019 July | 22 | 12 | 34 |
| 2019 June | 21 | 16 | 37 |
| 2019 May | 19 | 9 | 28 |
| 2019 April | 20 | 7 | 27 |
| 2019 March | 19 | 13 | 32 |
| 2019 February | 7 | 7 | 14 |
| 2019 January | 18 | 8 | 26 |
| 2018 December | 10 | 6 | 16 |
| 2018 November | 64 | 3 | 67 |
| 2018 October | 313 | 27 | 340 |
| 2018 September | 115 | 5 | 120 |
| 2018 August | 12 | 10 | 22 |
| 2018 July | 11 | 4 | 15 |
| 2018 June | 11 | 2 | 13 |
| 2018 May | 1 | 17 | 18 |
| 2018 April | 2 | 5 | 7 |
| 2018 March | 3 | 11 | 14 |
| 2018 February | 1 | 6 | 7 |
| 2018 January | 0 | 2 | 2 |
| 2017 December | 0 | 6 | 6 |
| 2017 November | 0 | 3 | 3 |
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