Evaluation of microbiologic and hematologic parameters and E-selectin as early predictors for outcome of neonatal sepsis.
* Context.--Early diagnosis of neonatal sepsis is mandatory.
Various markers are used to diagnose the condition.
Objective.--To evaluate the diagnostic value of various clinical data and hematologic parameters, such as total leukocyte count, absolute neutrophil count, immature to total neutrophil ratio, and soluble E-selectin (sE-selectin) in identification and outcome of neonatal sepsis.
Design.--Newborn infants with a clinical diagnosis of sepsis in the neonatal intensive care unit at Mansoura University Children's Hospital during the period between July 2007 and December 2007 were eligible for study. In addition, 30 healthy neonates were included in the study. Complete hematologic and microbiologic laboratory investigations were performed, and serum E-selectin was measured.
Results.--Plasma sE-selectin levels were significantly higher (P < .001) in infected infants (mean [SD], 156.9 [77.0] ng/mL) than in noninfected (mean [SD], 88.8 [47.1] ng/mL) and healthy infants (mean [SD], 8.67 [3.74] ng/ mL). Infants with gram-negative sepsis had higher sE-selectin levels than did those with gram-positive sepsis (P = .04). C-reactive protein was the best laboratory test for diagnosis of neonatal sepsis, with an overall sensitivity and specificity of 86% and 97%, respectively. Performing sE-selectin with C-reactive protein or immature to total ratio tests increased the specificity, but reduced the sensitivity, of the tests for the determination of neonatal sepsis. Plasma sE-selectin levels were higher in nonsurvivors than in survivors (P = .01) and were higher in those with hemodynamic dysfunction than in those without hemodynamic dysfunction (P < .001).
Conclusions.--We conclude that plasma sE-selectin levels are elevated in neonatal sepsis. Significant elevation was associated with gram-negative sepsis. Plasma sE-selectin had low diagnostic value when used alone or in combination with other tests; however, it can be used as a prognostic indicator for the outcome of neonatal sepsis.
(Arch Pathol Lab Med. 2009;133:1291-1296)
(Development and progression)
Infection (Care and treatment)
Parameter estimation (Methods)
Biological markers (Identification and classification)
Outcome and process assessment (Health Care) (Methods)
Clinical pathology (Research)
Infants (Newborn) (Diseases)
Infants (Newborn) (Development and progression)
Infants (Newborn) (Care and treatment)
Zaki, Maysaa El Sayed
Sayed, Hesham El
|Publication:||Name: Archives of Pathology & Laboratory Medicine Publisher: College of American Pathologists Audience: Academic; Professional Format: Magazine/Journal Subject: Health Copyright: COPYRIGHT 2009 College of American Pathologists ISSN: 1543-2165|
|Issue:||Date: August, 2009 Source Volume: 133 Source Issue: 8|
|Topic:||Event Code: 310 Science & research|
|Geographic:||Geographic Scope: United States Geographic Code: 1USA United States|
Morbidity and mortality from neonatal sepsis are major health
problems. Early warning signs and symptoms are often nonspecific and can
easily be confused with those from noninfective causes. Timely diagnosis
of neonatal sepsis is critical because, in this age group, the illness
can progress more rapidly and have a higher mortality rate than in other
age groups. (1)
Microbiologic culture results are usually unavailable until a minimum of 48 to 72 hours after the specimen reaches the laboratory; therefore, early identification of infected cases is a major diagnostic problem in newborn infants. Thus, a reliable infection marker or a set of markers are needed to promptly and accurately identify the infected cases so that treatment can be started without delay. Equally difficult is the exclusion of infection in infants with suspected sepsis. Continuation of broad-spectrum antibiotics for presumptive bacterial infection frequently
leads to unnecessary treatment and also to emergence of multiresistant organisms. (2,3)
Hematologic and biochemical markers, such as immature to total neutrophil ratio (I/T), (4) platelet count, (5,6) C-reactive protein (CRP), various cytokines, procalcitonin, (7) and neutrophil CD64 (8) have all been suggested as useful indicators for early identification of infants with sepsis. Studies evaluating these parameters as indicators of sepsis have yielded conflicting results, and satisfactory solutions remain to be found.
E-selectin is expressed by the endothelium after activation at sites of acute inflammation and is significant in migration of neutrophils and some T-cell to the site of injury. It takes part in the first step of the adhesion cascade, the rolling of leukocytes, leading to the extravasation of white cells to the sites of inflammation, infection, or damage. The molecule is uniquely displayed only on endothelium and is almost exclusively inducible. (9)
In human diseases in which unchecked inflammation contributes to the pathogenesis of disease process, soluble forms of E-selectin (sE-selectin) are elevated. These elevations have been interpreted as indicating a role for the molecules in the pathogenesis of inflammation, as well as indicating the size of the inflammatory response. (10) For this reason, sE-selectin is considered an early and reliable marker of immune activation and response. Moreover, sE-selectin has been reported to be a reliable marker of infection and sepsis in adults. In infants, soluble E-selectin responses in neonatal sepsis have been studied to a lesser extent. (11)
The aims of this study were (1) to assess microbiologic and hematologic findings in neonatal sepsis; (2) to determine whether changes in sE-selectin levels are dependent on gestational age, onset of sepsis, or the bacterium causing the sepsis; (3) to establish the diagnostic utility (sensitivity, specificity, predictive values, and likelihood ratio) of sE-selectin in comparison to commonly used laboratory markers for sepsis (CRP, I/T ratio, total leukocyte count, absolute neutrophil count), both individually and in combination, for early diagnosis of neonatal sepsis; and (4) to test whether sE-selectin levels have any prognostic value in neonatal sepsis.
MATERIALS AND METHODS
Newborn infants with suspected clinical sepsis in the neonatal intensive care unit at Mansoura University Children's Hospital (Mansoura, Egypt) during the period between July 2007 and December 2007 were eligible for study. Both preterm and full-term infants were included in the study. Preterm is defined in obstetrics (American College of Obstetricians and Gynecologists, Washington, DC) as infants born at 37 weeks of gestation or less. Full-term is greater than 37 weeks and up to 42 weeks of gestation. Clinical sepsis was defined as the presence of 3 or more of the following categories of clinical signs derived from a validated sepsis score: (1) temperature instability (hypothermia, hyperthermia); (2) respiratory (grunting, intercostal retractions, apnea, tachypnea, cyanosis); (3) cardiovascular (bradycardia, tachycardia, poor perfusion, hypotension); (4) neurologic (hypotonia, lethargy, seizures); and (5) gastrointestinal (feeding intolerance, abdominal distension). (12) Infants with neonatal asphyxia, metabolic disease, or congenital malformations were excluded. The infants were recruited into the study at the time of evaluation for suspected clinical sepsis before the start of antibiotic therapy. Informed written consent was obtained from the parents of each infant.
A full laboratory sepsis screen, which included cerebrospinal fluid analysis and cultures from blood, urine, endotracheal aspirate (infants on mechanical ventilation), and indwelling central lines, was performed. Aerobic bacteria were identified using the BBL Crystal system (BD, Franklin Lakes, New Jersey). Hematologic and biochemical laboratory parameters, including a complete blood cell, differential white cell, and platelet counts; CRP; and plasma sE-selectin, were measured at the time of sepsis evaluation. Parenteral antibiotics were started immediately after the samples for the infection screen had been obtained.
Classification of Infants Included in the Study
Three groups were prospectively defined:
* Group 1: The infected group consisted of 58 infants (preterm, n = 24 [41%]; full-term, n = 34 [59%], full-term gestation range, 35-37 weeks) with positive blood culture results.
* Group 2: The noninfected group consisted of 32 infants (preterm, n = 14 [44%]; full-term, n = 18 [56%]) who were initially thought to be septic but who had negative blood, cerebrospinal, and urine culture results; negative radiologic evidence of pneumonia or necrotizing enterocolitis; and continued improvement after antibiotic treatment was stopped.
* Group 3: The control group consisted of 30 healthy, newborn infants (preterm, n = 12 [40%]; full-term, n = 18 [60%]).
Blood samples for CRP, sE-selectin, and creatinine were collected from each child and separated within 30 minutes of collection and were stored at -20[degrees]C until analysis was done, with the exception of the samples for CRP, which were analyzed immediately.
Other blood samples were obtained for complete blood cell counts in an automatic cell counter (Abbott Cell-Dyn 1700 hematology analyzer, Abbott Laboratories, North Chicago, Illinois), and differential counts were performed manually on Wright-stained blood slides.
Plasma CRP concentrations were measured using an immunoturbidimetric method (Human Diagnostics, Wiesbaden, Germany) and were quantified with a spectrophotometer. According to the manufacturer, the detection limits of the assays for CRP was 0.1 mg/L. Reference values for healthy neonates, using quantitative techniques, are less than 1.6 mg/dL during the first 2 days of life and less than 1 mg/dL for the reminder of the neonatal period. (13)
Plasma concentrations of sE-selectin were determined using a CD62E enzyme-linked immunosorbent assay kit (Diaclone Research, Besancon, France). This technique uses a monoclonal antibody that is specific for E-selectin, which is precoated onto the wells of microtiter strips. Standards, samples, and a human control were placed into the wells, followed by a polyclonal antibody, conjugated to horseradish peroxidase, which is specific for E-selectin. After removal of the unbound conjugated antibody, substrates for horseradish peroxidase were added, and the product was quantified at 450 nm, with a correction by subtraction of background absorbance at 650 nm. A standard curve was plotted and sE-selectin concentrations were determined by interpolation from the curve. The sensitivity, intra-assay coefficient of variance, and interassay coefficient of variance of the assay were <0.5 ng/ mL, 6.4%, and 4.1%, respectively.
Values are presented as means (standard deviation), median (range), or the number of subjects and proportions. A 1-way analysis of variance test and an independent-samples Student t test were used for group comparisons of normally distributed variables, and the Kruskal-Wallis test and Mann-Whitney U test were used for comparisons of variables with skewed distribution. The [chi square] test was used to compare proportions.
The receiver-operator characteristic method was used to determine the best possible cutoff values for the selection of the best combination of tests for the diagnosis of neonatal sepsis. The curves were obtained by plotting sensitivity on the y-axis against the false-positive rate (1-specificity) on the x-axis for all possible cutoff values of the tests. From this curve, the best or optimal cutoff value was determined. Significance was considered when P < .05. All statistical tests were performed by SPSS for Windows
Release 10.0.1 (SPSS Inc, Chicago, Illinois).
The clinical characteristics of the study groups are summarized in Table 1. There were no significant differences in gestational age, birth weight, gender, or postnatal age at blood sampling among the 3 groups. Early sepsis was associated with ascending infections during delivery, and late-onset sepsis was developed in the nursery.
Plasma sE-selectin, CRP, and the I/T ratio in the infected group were significantly increased compared with the corresponding values in the noninfected and control groups of infants (P < .001 for all; Table 2). In contrast, no significant differences were detected between the noninfected group and controls for sE-selectin, total leukocyte count, absolute neutrophil count, or platelet counts (P = .06).
Suspected sepsis was confirmed in 58 neonates. Of these, 42 cases (72%) were due to gram-negative organisms, and 16 cases (28%) were due to gram-positive organisms; 18 infants (31%) had early onset sepsis, and 40 infants (69%) had late-onset sepsis.
Detailed accounts of the organisms are summarized in Table 3. Klebsiella pneumoniae was the most common organism (41%) isolated from blood cultures followed by Pseudomonas aeruginosa (14%), methicillin-sensitive Staphylococcus aureus (10%), Escherichia coli (10%), methicillin-resistant S. aureus (7%), coagulase-negative staphylococci (7%), Serratia marscens (3%), Enterobacter spp. (3%), and Enterococcus faecalis (3%). In 32 neonates (noninfected group), infection was excluded by negative bacterial and fungal culture findings.
The early onset sepsis was associated with Klebsiella pneumoniae and Escherichia coli, whereas gram-positive cocci, such as Staphylococcus aureus, was isolated more frequently from late-onset sepsis (Table 4).
In subgroups analyses, neonates with gram-negative sepsis (n = 42; 72%) had higher levels of sE-selectin than did infants with gram-positive sepsis (n = 16; 28%; P = .04). Infected preterm infants (n = 24; 41%) had similar sE-selectin levels as those of infected full-term infants (n = 34;59%;P = .10). We did not find any significant differences for sE-selectin levels when comparing early and late-onset sepsis subgroups (P = .07; Table 5).
Higher plasma levels of sE-selectin were found in nonsurvivors than in survivors (P < .001) and in those with homodynamic dysfunction (defined as a requirement for inotropic and vasopressors support) compared with those without homodynamic dysfunction (P = .01; Table 5).
Table 6 summarizes the sensitivity, specificity, predictive values, and likelihood ratios of the 5 laboratory markers and combination of these markers using the different cutoff values. The receiver operating characteristic curves of sE-selectin, CRP, and I/T ratio are shown in the Figure.
Comparison of each individual test using the optimal cutoff values showed that CRP has a higher sensitivity (86%) and specificity (97%) for detecting neonatal sepsis than all other laboratory markers.
In contrast, sE-selectin had rather low sensitivity (59%) and moderate specificity (87%) for detecting infection. The combination of sE-selectin with either CRP or I/T ratio and the combination of I/T ratio and CRP slightly improved the specificity and positive predictive value but significantly lowered the sensitivity and negative predictive value. The areas under the curve were CRP, .89/L (range, .79-.99/L);I/T ratio, .80 (range, .68-.92);and sE-selectin, .80 (range, .69-.91).
Early diagnosis of neonatal sepsis is difficult because the clinical signs are neither uniform nor specific. However, empirical treatment should not be delayed because of the high mortality. The inability to adequately exclude the diagnosis of neonatal sepsis can result in unnecessary and prolonged exposure to antibiotics. Laboratory tests used to support diagnosis have shown varied predictive values.
The data presented here demonstrated several important findings relating to the altered functional status following neonatal sepsis. Infected newborn infants had higher plasma sE-selectin levels compared with noninfected and control infants. This confirms previous reports indicating elevated sE-selectin in infected adults14 and neonates. (11)
Unlike Austgulen et al, (15) we have found that levels of sE-selectin in infected preterm infants were not statistically different from those in infected term infants. The divergent results may be due to differences in the criteria that were used to classify newborn infants as infected and the postnatal age of neonates at sampling. Other investigators reported increased levels of sE-selectin in premature infants with sepsis (16) and with persistent inflammation of chronic lung disease. (17) These findings indicate that the shedding of sE-selectin molecules is a component of the immune system and infection-induced immune response that develops early in gestation.
In the patients in our study, sE-selectin levels were higher in patients with gram-negative sepsis than in those with gram-positive sepsis, suggesting that the endothelium was more intensely activated in gram-negative than in gram-positive infections. Moreover, gram-negative bacilli was isolated mainly from early onset sepsis. The mechanisms by which the concentrations of soluble adhesion molecules increase in the plasma during infection with gram-negative bacilli includes interaction of endotoxin through membrane-specific endotoxin receptors, such as L-selectin and CD13/CD14, which cause increased production of adhesions molecules like E-selectin. Increased amounts of sE-selectin in blood may be due to endothelial injury rather than to mere activation. However, numerous studies have demonstrated that-E-selectin is shed from cultured endothelial cells that are activated but have no evidence of injury or detachment. (18)
There is evidence that sE-selectin, as well as other adhesion molecules, remains active once it is shed and can influence subsequent adhesion in several ways. E-selectin upregulates neutrophil CD1 1b and the ligand for ICAM1, the intracellular adhesion molecule 1 gene, enhancing firm leukocyte attachment and transendothelial migration. Because recombinant E-selectin can inhibit leukocyte adhesion to endothelium in vitro, it is likely that circulating E-selectin limits E-selectin-mediated rolling of activated leukocytes via competitive binding of cell bound ligands, thus down-regulating the inflammatory response. (11)
In our study, the cutoff value for sE-selectin in diagnosis of neonatal sepsis was found to be 130 ng/mL, which is lower than that reported in previous studies. A 150-ng/ mL cutoff value for sE-selectin in detection of sepsis in full-term neonates had a sensitivity of 79% and a specificity of 61%. (11) On the other hand, a cutoff value for sE-selectin of 174 ng/mL for detection of late-onset sepsis in very low birth weight infants gave a sensitivity of 64% and a specificity of 89% when samples were taken from infants during the first 24 hours of suspected clinical sepsis.
Considering the high mortality and potential morbidity associated with neonatal sepsis, diagnostic tests with high sensitivity and negative predictive value are most desirable because all infants with sepsis have to be identified. The lack of reliable clinical signs and laboratory tests often results in anticipatory antimicrobial treatment. To minimize the unnecessary use of antibiotics in false-positive cases, tests need to have a reasonably high specificity and good positive predictive value.
We found that sE-selectin had a low diagnostic sensitivity and specificity. Measuring CRP had the best sensitivity (86%) and specificity (97%) for the diagnosis of infection. The combination of sE-selectin with either CRP or I/T ratio slightly improved the specificity but adversely affected the sensitivity of these tests, so it cannot be used as a diagnostic marker of neonatal sepsis. Furthermore, the likelihood ratio and receiver operating characteristic curve analysis demonstrated the higher diagnostic value of CRP and I/T ratio compared with sE-selectin as markers for sepsis.
C-reactive protein has been thoroughly studied as a diagnostic tool in neonatal sepsis and also as an indicator of response to therapy. (19,20) The sensitivity of CRP in initial determinations for the detection of early onset neonatal infection has been reported to vary from 35% to 65%, increasing to 94% to 97% by the time of the third determination. The specificity of CRP varied in initial determination from 92% to 96% and decreased to 76% to 86% for the third measurement. (21)
Our data support the view of some authors that the leukocyte count had little value in differentiating between infected and noninfected neonates. (22) Although the specificity of the I/T ratio has been questioned, in our study, we demonstrated low sensitivities and poor positive predictive values of the I/T ratio and total leukocyte count in identifying the small number of initially asymptomatic at-risk newborns who progressed to clinical sepsis. These results were similar to the results reported by Ottolini et al. (23)
We have found that plasma sE-selectin levels were higher in nonsurvivors and in those with homodynamic dysfunction. A striking positive relationship among sE-selectin level and concomitant homodynamic dysfunction and multiple organ failure was reported in adults with sep sis. (14)
Because the intensity of E-selectin expression and shedding appears to correlate with organ hypoperfusion and dysfunction, inactivation of cell-bound E-selectin might be expected to ameliorate these problems. In a preliminary study, administration of a murine monoclonal antibody to E-selectin to patients with septic shock was well tolerated and associated with dose-related improvement in oxygenation and trends for faster resolution of organ failure. (24)
We conclude that plasma sE-selectin levels were elevated in neonatal sepsis. Plasma sE-selectin had low diagnostic value when used alone or in combination with other tests. However, it can be used as a prognostic indicator in neonatal sepsis and can be used as clue in predicting that the causative bacteria in blood culture is gram-negative bacteria.
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Maysaa El Sayed Zaki, MD, PhD; Hesham El Sayed, PhD
Accepted for publication October 23, 2008.
From the Departments of Clinical Pathology (Dr Zaki) and Pediatric Medicine (Dr El Sayed), Mansoura University, Mansoura, 65, Egypt.
The authors have no relevant financial interest in the products or companies described in this article.
Reprints: Maysaa El Sayed Zaki, MD, Department of Clinical Pathology, Faculty of Medicine, Mansoura University, Mansoura, 65, Egypt (e-mail: firstname.lastname@example.org).
Table 1. Clinical Data of Study Population Infected (n = 58), Noninfected (n = 32), Characteristic Mean (SD) Mean (SD) Birth weight (g) 2367 (828) 2435 (846) Gestational age (wk) 36.3 (3) 36.6 (3) Male sex, No. (%) 16 (55) 8 (50) Postnatal age (d) 8.7 (4.5) 8.4 (3.6) Control (n = 30), Characteristic Mean (SD) P Value Birth weight (g) 2432 (839) .06 Gestational age (wk) 36.9 (2.6) .06 Male sex, No. (%) 8 (53) .06 Postnatal age (d) 8.8 (3.6) .06 Table 2. Laboratory Characteristics of Study Population Infected (n = 58), Noninfected (n = 32), Laboratory Test Mean (SD) Mean (SD) E-selectin (ng/mL) 156.9 (77.0) 88.8 (47.1) CRP (mg/L), mean (range) 48.0 (0-96) 0.5 (0-48) TLC (1000/mL) 13.8 (9.4) 10.5 (5.1) ANC 6.9 (4.2) 5.2 (2.0) I/T ratio 0.30 (0.17) 0.12 (0.11) Platelet count (1000/mL) 220 (80) 235 (80) Control (n = 30), Laboratory Test Mean (SD) P Value E-selectin (ng/mL) 86.7 (37.4) .001 CRP (mg/L), mean (range) 0 (0-8) .001 TLC (1000/mL) 9.9 (4.5) .07 ANC 4.9 (1.9) .10 I/T ratio 0.12 (0.12) .001 Platelet count (1000/mL) 242 (83) .10 Abbreviations: ANC, absolute neutrophil count; CRP, C-reactive protein; I/T, immature neutrophil to total leukocytes count; TLC, total leukocytes count. Table 3. Causative Organism in 58 Infants With Sepsis Gram-Positive Sepsis No. (%) Methicillin-sensitive Staphylococcus aureus 6 (10.3) Coagulase-negative staphylococci 4 (6.9) Methicillin-resistant Staphylococcus aureus 4 (6.9) Enterococcus faecalis 2 (3.5) Total associations 16 (27.6) Gram-Negative Sepsis No. (%) Klebsiella pneumoniae 24 (41.3) Pseudomonas aeruginosa 8 (13.8) Escherichia coli 6 (10.3) Serratia marscens 2 (3.5) Enterobacter spp 2 (3.5) Total associations 42 (72.4) Table 4. The Causative Organisms According to Onset of Sepsis Onset and Organism No. % Early onset sepsis (n = 18) Escherichia coli 6 33.3 Klebsiella pneumoniae 10 55.6 Coagulase-negative staphylococci 2 11.1 Late-onset sepsis (n = 40) Methicillin-sensitive Staphylococcus aureus 6 15 Coagulase-negative staphylococci 2 5 Enterococcus faecalis 2 5 Klebsiella pneumoniae 14 35 Pseudomonas aeruginosa 8 20 Serratia marscens 2 5 Enterobacter spp 2 5 Methicillin-resistant Staphylococcus aureus 4 10 Table 5. Soluble E-Selectin Levels in Relation to Gestational Age, Onset of Sepsis, Gram Stain of the Organism, and Prognosis Soluble E-Selectin Clinical and Laboratory Sorting ([micro]g/mL), of Patients (No.) Mean (SD) P Value Infected preterm infants (24) 125.0 (43.4) .10 Infected full-term infants (34) 179.4 (88.1) Early onset sepsis (18) 156.6 (74.4) .07 Late-onset sepsis (40) 170.0 (79.5) Gram-negative sepsis (42) 174.0 (81.4) .04 Gram-positive sepsis (16) 111.9 (39.5) .03 Homodynamic dysfunction (22) 176.0 (79.7) No homodynamic dysfunction (36) 96.4 (41.7) .01 Nonsurvivors (16) 188.0 (80.7) Survivors (42) 110.5 (61.7) .001 Table 6. Sensitivity, Specificity, Predictive Values, and Likelihood Ratios of Laboratory Markers in Early Diagnosis of Neonatal Sepsis Sensitivity, Marker Cutoff Value % CRP 8 mg/L 86 I/T ratio >0.20 76 sE-selectin 130 ng/mL 59 TLC <5 or >20/[cm.sup.3] 48 ANC <2 or >75/[cm.sup.3] 55 Platelet count <150/[cm.sup.3] 41 CRP + sE-selectin 45 I/T ratio + CRP 65 I/T ratio + sE-selectin 55 Positive Negative Specificity, Predictive Predictive Marker % Value, % Value, % CRP 97 96 88 I/T ratio 87 85 79 sE-selectin 87 81 69 TLC 77 67 62 ANC 74 67 64 Platelet count 87 50 52 CRP + sE-selectin 100 100 65 I/T ratio + CRP 100 100 74 I/T ratio + sE-selectin 94 89 69 Likelihood Likelihood Marker Positive Negative CRP 28.7 .11 I/T ratio 5.8 .28 sE-selectin 4.5 .32 TLC 2.1 .68 ANC 2.1 .61 Platelet count 1.1 .99 CRP + sE-selectin N/A .55 I/T ratio + CRP N/A .38 I/T ratio + sE-selectin 9.2 .48 Abbreviations: ANC, absolute neutrophil count; CRP, C-reactive protein; I/T, immature neutrophil to total leukocytes count; N/A, data not available; sE-selectin, soluble E-selectin; TLC, total leukocytes count.
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