ICAM VCAMand Sepsis

Serum Soluble ICAM-1, VCAM-1,L-Selectin, and P-Selectin Levels as Markersof Infection and their Relation to ClinicalSeverity in Neonatal SepsisJose Figueras-Aloy, M.D., Ph.D.,1 Lilian Gomez-Lopez, M.D., Ph.D.,1

Jose-Manuel Rodrguez-Miguelez, M.D., Ph.D.,1

M. Dolors. Salvia-Roiges, M.D., Ph.D.,1 Iolanda Jordan-Garca, M.D., Ph.D.,1

Inmaculada Ferrer-Codina, M.D., Ph.D.,2 Xavier Carbonell-Estrany, M.D., Ph.D.,1

and Rafael Jimenez-Gonzalez, M.D., Ph.D.1

ABSTRACT

Adhesion molecules may play a role in the evolution and severity of neonatalsepsis. The purposes of this study were to determine whether serum soluble intercellularadhesion molecule (ICAM)-1, vascular cell adhesion molecule (VCAM)-1, L-selectin,and P-selectin levels are useful tools in the diagnosis of proven sepsis in newborn infants,and whether their levels are related to the clinical severity of the disease. A cohort of25 consecutive newborns meeting criteria for clinical sepsis, 10 hemoculture-negative(HC ) and 15 hemoculture-positive (HC ), were prospectively followed and com-pared with 12 healthy newborns (six 38 weeks of gestational age and six 39 weeks).Serum soluble (s)ICAM-1, sVCAM-1, sL-selectin, and sP-selectin concentrations weremeasured at the time of the septic workup, then followed by up to three determinations ineach newborn every third day. The Score for Neonatal Acute Physiology (SNAP)-IIseverity was assessed at the moment of highest clinical severity of the disease. At thebeginning of sepsis, sICAM-1 levels increased in both groups, being higher inHC sepsis than in HC ; sVCAM-1 only increased slightly in HC sepsis. SolubleICAM-1 levels were independently related to group of sepsis, and not to days of life. Thebest initial sICAM-1 cutoff level for diagnosing HC neonatal sepsis was 274 mg/L.The highest sICAM-1 levels were positively correlated with SNAP-II scores. SolubleL-selectin and sP-selectin did not change. Soluble ICAM-1 levels increased inHC and HC sepsis, but concentrations > 274 mg/L suggest HC sepsis. Theselevels were related to the clinical severity of the disease. Soluble VCAM-1 levelsincreased only slightly in HC sepsis. Soluble L-selectin and sP-selectin did not change.

KEYWORDS: Adhesion molecules, newborn, sepsis, septic shock

1Servicio Neonatologa, Institut Clnic de Ginecologia, Obstetrcia iNeonatologia; 2Agrupacio Sanita`ria Sant Joan de DeuHospitalClnic, Institut dInvestigacions Biome`diques August Pi i Sunyer(IDIBAPS), Universitat de Barcelona, Barcelona, Spain.

Address for correspondence and reprint requests: Prof. JoseFigueras-Aloy, Servicio Neonatologa. Hospital Clnic, C/ Sabino de

Arana 1, 08028 Barcelona, Spain.Am J Perinatol 2007;24:331338. Copyright # 2007 by Thieme

Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001,USA. Tel: +1(212) 5844662.

Accepted: March 6, 2007. Published online: June 12, 2007.DOI 10.1055/s-2007-981851. ISSN 0735-1631.

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The inflammatory response is essential in thedefense against microorganisms in neonatal infections.Circulating adhesion molecules promote the adherenceof circulating leukocytes to the endothelial cells of theblood vessel wall. The attached leukocytes migratethrough the endothelial cells to the inflammation site,attracted by other inflammatory mediators.1 Leukocytetransmigration starts along the endothelial lining in aselectin-based interaction intended to reduce the velocityrelative to the blood flow. There are three selectins:E-selectin, expressed on endothelial cells, P-selectin,expressed on endothelial cells and platelets, and L-selec-tin, expressed on leukocytes.2 Soluble (s)L-selectin in theplasma can reflect immune activation and is increased inmaternal chorioamnionitis and neonatal sepsis.3

Intercellular adhesion molecule (ICAM)-1, amember of the cell surface immunoglobulin superfamilyof adhesion receptors,2 takes part in lymphocyte-medi-ated adhesion, cytotoxic T-cell activity, and antigenpresentation.4 ICAM-1 is also a ligand for lymphocytefunction-associated antigen (LFA)-1 and macrophage-associated complex (MAC)-1.5 The soluble form ofvascular cell adhesion molecule (sVCAM)-1 is, likesICAM-1, a reliable marker of immune activation andresponse. Moreover, sVCAM-1 has been reported to bea potent angiogenic agent.6 High levels of adhesionmolecules have been found in different disease states,especially inflammation7 and infection.4,811

Serum sICAM-1, sVCAM-1, sL-selectin, andsP-selectin levels may be useful tools for the diagnosisof sepsis in newborn infants. The aims of this study wereto evaluate whether adhesion molecule concentrationsincrease at the beginning of sepsis and during the daysfollowing and can be used to differentiate hemoculture-positive (HC ) sepsis from hemoculture-negative(HC ) sepsis and normal newborns, and also to deter-mine whether the degree of alteration of adhesionmolecule concentrations is related to the clinical severityof the disease.

PATIENTS AND METHODSAll the newborns admitted consecutively to the neonatalintensive care unit (NICU) over 21 months with thediagnosis of suspected sepsis were enrolled in the study.Parental informed consent was obtained. The study wasapproved by the Neonatology Ethics Committee.

Inclusion CriteriaThe diagnosis of suspected sepsis was accepted when anewborn showed one or more clinical signs of infectionand at least one biological sign. In this case, a hemocul-ture was drawn and antibiotherapy was started. Clinicalsigns of infection were: respiratory distress, apnea, vomit-ing, abdominal distention, hypothermia or fever, leth-

argy, seizures, purpura, hyperglycemia, or hypotension.The biological signs included fewer than 5000 leuko-cytes/mL, immature-to-total neutrophil ratio greaterthan 0.20, and/or C-reactive protein more than 40 mg/L.Hemoculture-positive (HC ) or proven sepsis wasaccepted if a positive hemoculture was obtained in a new-born with suspected sepsis. If a newborn presented asuspected sepsis but the hemoculture was negative, thediagnosis of hemoculture-negative (HC ) sepsis wasaccepted only after excluding intracranial hemorrhage,drug withdrawal, and cardiac disease; antibiotherapy wasthen maintained for at least 7 days.

Exclusion CriteriaPatients with severe congenital anomalies, metabolicdiseases, or chromosomal disorders were excluded.

Groups Analyzed

CONTROL GROUP

Twelve healthy newborns with unconfirmed risk ofperinatal infection (mother colonized by Streptococcusagalactiae) were considered as controls. Only one extrablood extraction for determining adhesion molecules wasperformed during the first infectious disease workup. Fortwo of the newborns, the extractions were repeated up tothree times approximately every third day.

STUDY GROUP

Twenty-five patients were identified and enrolled withthe diagnosis of suspected sepsis. At the time of clinicalsuspicion of sepsis and when the blood was drawn forhemoculture, 1 mL was taken to determine adhesionmolecules, and up to three determinations in each new-born were performed approximately every third day.According to hemoculture results, this group was sub-divided into two groups: (1) HC sepsis (10 patients)and (2) HC sepsis (15 patients, 3 of whom presentedclinical severity criteria such as death due to the infection,repeated seizures, disseminated intravascular coagulation[DIC], or shock, and in need of mechanical ventilation assupport treatment). No meningitis was diagnosed. Onepatient died due to the infection (1 of 25, 4%).

Variables AnalyzedGestational age and birthweight were considered in allthe newborns, as well as C-reactive protein, immature-to-total neutrophil ratio, and Score for Neonatal AcutePhysiology (SNAP)-II.12 This severity score was per-formed in each newborn when the highest level ofclinical severity was reached. In addition, for each ofthe three periods considered in the evolution of theseptic process (initial, middle, and final), the time of

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blood extraction to determine adhesion molecule wasrecorded.

Serum Soluble ICAM-1, VCAM-1, L-Selectin,and P-Selectin DeterminationBlood (1 mL) was collected in pyrogen-free tubes,centrifugated immediately after clotting, and nonhe-molyzed serum samples were divided into four aliquotsand stored frozen at 408C. Serum levels of adhesionmolecules were measured by commercially availableenzyme-linked immunoadsorbent assays (ELISAs)(R&D Systems, Minneapolis, MN). The sensitivitylimits were as follows: sL-selectin, 0.3 mg/L; sP-selec-tin, 0.5 mg/L; sICAM-1, 0.35 mg/L; and sVCAM-1,2 mg/L.

Data AnalysisDue to the small sample in each group, the quantitativevariables are expressed as median and interquartilerange (IQR): percentile 25 to percentile 75. The influ-ences of gestational age and birthweight on sICAM-1,sVCAM-1, sL-selectin, and sP-selectin concentrationswere studied only in the control group. These adhesionmolecules were also considered in the initial compar-ison between the control group and the HC andHC septic groups. For the sequential data for sI-CAM-1, sVCAM-1, sL-selectin, and sP-selectin lev-els, only septic groups were considered. Nonparametricanalyses were used in the group comparison; theKruskal-Wallis test was performed for the cross-sec-tional evaluation, and the Friedman test was performedfor the longitudinal evaluation. When considered ap-propriate, post hoc comparisons using the Mann-Whitney U test were also performed. The Spearmancorrelation was applied to determine the possible rela-tionship between sICAM-1, sVCAM-1, sL-selectin,and sP-selectin levels and birthweight and gestationalage in the control group; in the study groups it was used

to evaluate the possible relation between the highestvalues of sICAM-1, sVCAM-1, sL-selectin, sP-selec-tin, C-reactive protein, immature-to-total neutrophilratio and SNAP scores. Univariate analysis of variancewas performed to analyze the different influences ofthe variable sepsis group (control, HC septic, orHC septic) and two covariables (gestational age anddays of life at blood extraction) on the initial sICAM-1levels. The same was done for sVCAM-1 levels. Todetermine whether initial sICAM-1 levels were reliableearly markers of infection in newborns, we comparedHC sepsis newborns and non-HC sepsis new-borns (control group and HC sepsis group), and weobtained a receiver-operator characteristic (ROC)curve of sICAM-1 and determined the best cutoff level(i.e., one with the highest sensitivity and the highestpositive likelihood ratio). Differences were consideredsignificant if the P value was < 0.05.

RESULTSThirty-seven newborns, ranging in age from 1 hour to32 days (median 24 hours; IQR, 14 to 264 hours), werestudied. The control group included 12 newborns, 6 at38 weeks gestational age (WGA) or less and 6 at 39WGA or more. There was no correlation betweensVCAM-1, sL-selectin, sP-selectin, and gestationalage or birthweight. A positive correlation betweensICAM-1 and gestational age was found (r 0.623,P 0.041), but there was no significant difference be-tween sICAM-1 levels in 38 WGA and 39 WGAnewborns (153 mg/L; IQR, 144 to 156 versus 164 mg/L;IQR, 158 to 194, respectively).

The bacteria isolated in the 15 newborns withhemoculture-positive sepsis were: five Staphylococcusepidermidis, two Enterococcus faecalis, five Streptococcusagalactiae, two Enterobacter cloacae, and one Klebsiellaoxytoca. The HC sepsis group had lower gestationalage and birthweight than the other groups, althoughthe differences were not significant (Table 1). However,

Table 1 Characteristics of Newborns Studied

1 Control Group(n12)

2 HCSepsis Group(n 10)

3 HCSepsis Group(n15) P*

Gestational age (wk) 38.5 (3740) 40 (3640) 37 (3239) NS (0.113)

Birthweight (g) 3037 (26253835) 3365 (28403612) 2350 (13903120) NS (0.124)

Days of life

Initial blood extraction 1 (11) 2.5 (23) 10 (314) < 0.001 (a)

Middle blood extraction 5.5 (56) 6 (58) 13 (518) NS (0.185)

Final blood extraction 9 9.5 (911) 20 (1024) NS (0.114)

C-reactive proteiny (mg/L) 6 (328) 71 (4087) 61 (50121) < 0.001 (b)Immature-to-total neutrophil ratioy 0.015 (0.00.04) 0.106 (0.050.22) 0.041 (0.030.14) 0.001 (c)

*Kruskal-Wallis test. Post hoc Mann-Whitney U test (P < 0.05) results were: (a) 1 to 2, 1 to 3, 2 to 3; (b) 1 to 2,1 to 3; (c) 1 to 2, 1 to 3.yHighest values are shown.Median (interquartile range [IQR]: percentile 25 to percentile 75).HC , hemoculture-negative; HC , hemoculture-positive; NS, not significant.

ADHESION MOLECULES IN NEONATAL SEPSIS/FIGUERAS-ALOY ET AL 333

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the HC sepsis groups blood samples were obtainedlater than from the other groups (Table 1), the differ-ence being significant only in the first sample.C-reactive protein and immature-to-total neutrophilratio were high in both the HC and HC sepsisgroups, although the differences were not significant(Table 1).

When we analyzed sICAM-1 levels in the initialperiod, significant differences appeared between controland HC sepsis or HC sepsis (Table 2). Newbornswith HC sepsis had higher sICAM-1 concentrationsin the initial and middle periods than the HC septicand control group newborns (Table 2 and Fig. 1). Thesame analysis applied to sVCAM-1 concentrations

Table 2 Adhesion Molecules Concentrations During the Septicemic Process

Control Group (1) HCSepsis Group (2) HCSepsis Group (3) P*

sICAM-1 (mg/L)

Initial (11)y 156 (150194)** (10)y 242 (226331)** (14)y 394 (342600)** < 0.001 (a)Middle (2)y 214 (126302)** (10)y 271 (221371)** (15)y 418 (326646)** 0.008 (b)Final (1)y 274** (8)y 278 (213366)** (10)y 458 (323568)** NS (0.146)

sVCAM-1 (mg/L)

Initial (12)y 856 (742960)** (10)y 768 (629861)** (14)y 1153 (7261307)** 0.027 (c)Middle (2)y 895 (6961095)** (10)y 887 (7251040)** (15)y 1094 (8091354)** NS (0.111)Final (1)y 1005** (8)y 897 (7781069)** (10)y 1072 (9311279)** NS (0.235)

sL-selectin (mg/L)

Initial (12)y 580 (523717)** (10)y 637 (553696)** (14)y 681 (541757)** NS (0.580)Middle (2)y 419 (338500)** (10)y 746 (647812)** (15)y 700 (586806)** NS (0.096)Final (1)y 434** (8)y 808 (665856)** (10)y 790 (6281076)** NS (0.235)

sP-selectin (mg/L)

Initial (9)y 272 (152288)** (7)y 224 (168318)** (9)y 244 (170324)** NS (0.791)Middle (2)y 300 (237364)** (8)y 187 (141238)** (10)y 289 (187316)** NS (0.126)Final (1)y 338** (7)y 458 (160562)** (7)y 268 (240344)** NS (0.842)

*Kruskal-Wallis test. Post hoc Mann-Whitney U test (P< 0.05) results were: (a) 1 to 2, 1 to 3, 2 to 3; (b) 1 to 3, 2 to 3; (c) 2 to 3.yNumber of cases.**Median (interquartile range [IQR]: percentile 25 to percentile 75).The Friedman test was not significant except for sL-selectin in the HC sepsis group (P0.010).HC , hemoculture-negative; HC , hemoculture-positive; sICAM, soluble intercellular adhesion molecule; sVCAM, soluble vascular celladhesion molecule; s, soluble; NS, not significant.

Figure 1 sICAM-1 concentrations (median,values) in newborns studied, differentiatingbetween HC sepsis, HC sepsis and con-trol groups. sICAM, soluble intercellular adhe-sion molecule; HC , hemoculture-positive;HC , hemoculture-negative.


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showed significant differences in the initial period be-tween HC sepsis and HC sepsis (Table 2). Thehighest value of sICAM-1 correlated positively withthe highest value of sVCAM-1 (r 0.625; P < 0.001).There were no significant differences in sL-selectin andsP-selectin either at the beginning or during the sepsisperiod (Table 2).

SNAP-II scores correlated positively with thehighest value of sICAM-1 concentrations in each septi-cemic newborn (r 0.537, P 0.006) (Fig. 2), but notwith the highest value of sVCAM-1. Bacteria weresimilar (P 0.637) in the subgroup with a highSNAP-II score (16 to 105; 3 Gram-positive bacteriaand 1 Gram-negative bacteria) and in the subgroup witha low SNAP-II score (0 to 5, 9 Gram-positive bacteriaand 2 Gram-negative bacteria). The highest value ofC-reactive protein in each septicemic newborn corre-lated positively with the highest value of the immature-to-total neutrophil ratio (n 25; r 0.590, P 0.002).There was also a correlation between the value ofC-reactive protein in each septicemic newborn and thevalue of the immature-to-total neutrophil ratio in thefirst blood sample when sepsis was suspected (n 25,r 0.523, P 0.007). However, these values didnot correlate with the concentrations of sICAM-1,sVCAM-1, or SNAP-II scores.

Univariate analysis of variance of sICAM-1 levelsrelated to the variable sepsis group being considered with

three categories (control group, HC septic group, andHC septic group) and two covariables (gestational ageand days of life at blood extraction) showed that themodel was valid (R2 0.585, P< 0.001) and that theonly independent significant factor was the sepsis groupbeing considered (P 0.002). The covariable days of lifeat blood extraction did not reach statistical significance(P 0.836). A similar analysis performed on sVCAM-1levels showed that the model was not as good as theprevious one (R2 0.414, P< 0.001) and that the mostsignificant factor was, again, the sepsis group beingconsidered (P 0.023).

According to our sICAM-1 determinations atthe beginning of the neonatal sepsis, a cutoff level of274 mg/L predicted HC neonatal sepsis with sensi-tivity of 100%, specificity of 85.7% (confidence interval[CI] 95%: 70.7 to 100%), positive predictive value of82.3%, negative predictive value of 100%, accuracy of91.4%, and positive likelihood ratio of 7.0 (CI 95%:2.45 to 19.95). Area under the curve was 0.939(P< 0.001) (Fig. 3).

DISCUSSIONAccurate new markers of neonatal sepsis are needed.Early appropriate diagnosis of sepsis will help to ensurethat newborns treated with antibiotics are only thosewith clinical symptoms and truly suspicious biological

Figure 2 Correlation between sICAM-1concentrations and SNAP-II scores. sICAM,soluble intercellular adhesion molecule; HC ,hemoculture-positive; HC , hemoculture-ne-gative; SNAP, Score for Neonatal Acute Phy-siology.


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parameters. The 25 patients from our study group hadsuspected sepsis. When hemoculture was positive, sepsiswas accepted as proven. If hemoculture was negative,other conditions were ruled out and antibiotherapy wasmaintained for at least 7 days because the attendingphysician considered that the syndrome was probablydue to sepsis. A SNAP-II score was determined whenthe septic process reached the highest severity.12

Our study and control groups were small andcannot be considered completely homogeneous in termsof gestational age and birthweight, especially at the timeof the first blood extraction. However, soluble adhesionmolecule levels were not influenced by birthweight, andwe found no significant differences between 38 WGAand 39 WGA infants in the control group. Studying168 noninfected newborns, Austgulen and colleagues4

also found no relation between sICAM-1 and sVCAM-1 and gestational age. However, in a study of 28 new-borns > 38 WGA and 15 newborns between 35 and 38WGA, Phocas and colleagues13 found a reduction ofsICAM-1 levels in > 38 WGA infants, although thedifference was small. Increasing postnatal age in new-borns has a positive effect on sICAM-1 and sVCAM-1values from days 1 to 5 and then to day 30 of life7,13,14

The most likely reason for the increase in sICAM-1

and sVCAM-1 after birth is the change from a relativelyhypoxic intrauterine environment to the more oxygen-rich extrauterine environment. Moreover, there is animmature or deficient antioxidant defense mechanism,15

which leads to relative enhanced lipid peroxidationand oxidative stress,16 resulting in a proinflammatorystate. This physiological increase is especially noted insICAM-1. Malamitsi-Puchner and colleagues17 repor-ted that in healthy neonates serum levels of sVCAM-1and sL-selectin did not change during early neonatal life.

In our study, at the beginning of neonatal sepsis,sICAM-1 increased in both the HC and HC sepsisgroups, although its levels in HC sepsis were higher.High sICAM-1 has been considered a good marker ofinfection in newborns.4,10,11,18,19 Later, sICAM-1 andsVCAM-1 increased with age in control and sepsisgroups. This finding is difficult to interpret because thecases were older than the controls at the time of the firstblood sample. However, we believe that the initialsICAM-1 and sVCAM-1 increases in our HC septi-septicemic newborns were due to the inflammatoryprocess and not to the time of blood sampling. Univariateanalysis of variance of sICAM-1 levels showed that theonly independent significant factor was the sepsis groupbeing considered (control group, HC septic group, or

Figure 3 ROC curve of sICAM-1 levels and HC sepsis.sICAM, soluble intercellular adhesion molecule; HC , hemo-culture-positive; HC , hemoculture-negative; SNAP, Scorefor Neonatal Acute Physiology; ROC, receiver-operator char-acteristic.


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HC septic group), whereas days of life at blood sam-pling and gestational age did not show any statisticalsignificance.

DAlquen and colleagues20 recently found thatcord blood serum concentrations of sICAM-1 werehigher in a group with chorioamnionitis and funisitiswhen compared with a group with only chorioamnionitisor controls, probably due to the higher inflammatoryresponse when funisitis is present. However, cord serumsICAM-1 determinations have no diagnostic relevancein neonatal infection.21,22

Whalen and colleagues19 reported that, in chil-dren with sepsis-induced multiple organ failure, plasmasICAM-1 concentrations independently predicted num-ber of organ failures, development of more than threeorgan failures, and mortality. Xanthou and colleagues10

reported that sICAM-1 rose in the peripheral blood ofboth asphyxiated and infected neonates in the first 5 daysof life; sICAM-1 levels were higher in severe cases. Inaddition, increased C-reactive protein levels were foundin perinatally infected but not perinatally asphyxiatedneonates. In our study, throughout the sepsis period,only sICAM-1 remained significantly higher in infantswith HC sepsis. In addition, the highest values ofsICAM-1 correlated positively with the SNAP-II se-verity score system in septic newborns. Austgulen andcolleagues,4 who studied 24 infected newborns and 168noninfected newborns, proposed an sICAM-1 cutoff of250 mg/L (sensitivity of 80% and specificity of 61%),whereas Hansen and colleagues,23 who studied 45 in-fected newborns and 45 noninfected newborns, raisedthe cutoff to 300 mg/L. Our data suggest that the bestinitial cutoff would be 274 mg/L, with no false-negativesand a very low rate of false-positives. Edgar and col-leagues24 studied 46 newborns and reported that a lowlevel of serum sICAM-1 might help exclude infection.Our results support this suggestion because the negativepredictive value of 100% that we obtained means that allthe newborns with sICAM-1 concentrations below 274mg/L will not be affected by HC sepsis.

In relation to C-reactive protein, a recognizedmarker of neonatal infections, Apostolou and col-leagues25 studied 20 infected newborns (10 full-termand 10 preterm) and 20 noninfected newborns (10 full-term and 10 preterm). They demonstrated that increasedsICAM-1 levels could be detected early in both full-term and premature neonates with sepsis, while C-reactive protein levels were concurrently within thenormal range. Hansen and colleagues23 showed thatfor identification of infection in newborns less than5 days old, sICAM-1 and C-reactive protein in combi-nation are better primary markers than C-reactive pro-tein alone. We could not demonstrate a relation betweenC-reactive protein levels or immature-to-total neutro-phil ratio and sICAM-1 and sVCAM-1 concentrations,probably because adhesion molecules increased earlier.

In our study, sVCAM-1 concentrations only in-creased at the beginning of the sepsis and in theHC sepsis group. Whalen and colleagues19 also re-ported an increase in sVCAM-1 on the first day of sepsis,whereas Austgulen and colleagues4 found no increase ineither full-term or preterm septic newborns. These differ-ences are probably due to the small increase in sVCAM-1,and therefore justify analyzing sICAM-1 first.

According to our data, sL-selectin and sP-selectindid not change either at the beginning or, indeed, at anytime during the sepsis period. Kourtis and colleagues3

reported slightly higher levels of sL-selectin in earlyneonatal sepsis (median 1331 versus 1149 mg/L;P 0.026). The selectins are the first adhesion moleculesto increase, with a very quick return to normal values.Very early blood samples are needed to detect anychange.

Assessments of sICAM-1 levels in newborn in-fants without perinatal asphyxia or after 5 days of lifemay provide further evidence of enhanced inflammatoryresponses. The results of adhesion molecule expressionwere not available to the treating clinician during themanagement of the infant. A high sICAM-1 value(> 274 mg/L) would mean probable HC sepsis(82.3% of positive predictive value) and therefore anti-biotherapy would be justified. If the sICAM-1 value islow (< 274 mg/L), the probability of not havingHC sepsis is 100%, and, in case of good clinicalevolution, antibiotics could be withdrawn or not started.However, the final decision will depend on blood cultureresults and evolution of clinical signs and biologicalmarkers (C-reactive protein, immature-to-total neutro-phil ratio). Soluble ICAM-1 may not be a good indicatorof favorable evolution because during the HC sepsisthe values may even increase (Fig. 1). Further studies todetermine the biological significance of soluble adhesionmolecule levels in newborns and whether their assess-ments can be used as a tool to guide clinical care arewarranted.

In conclusion, sICAM-1 determination seems tobe a good indicator of neonatal sepsis, especially ofHC sepsis, and its severity. Soluble VCAM-1 con-centrations only increase slightly in HC sepsis, andsL-selectin and sP-selectin do not change.

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ICAM VCAMand Sepsis