Published online December 31, 2007
PEDIATRICS Vol. 121 No. 1 January 2008, pp. 129-134 (doi:10.1542/peds.2007-1308)
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ARTICLE

Hematologic Profile of Sepsis in Neonates: Neutrophil CD64 as a Diagnostic Marker

Vineet Bhandari, MD, DMa, Chao Wang, BSb, Christine Rinder, MDb and Henry Rinder, MDb

a Department of Pediatrics, Division of Perinatal Medicine
b Department of Laboratory Medicine, Yale University School of Medicine, New Haven, Connecticut


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 
OBJECTIVE. The goal was to determine the utility of neutrophil CD64 as a diagnostic marker for sepsis in neonates.

METHODS. A prospective study that enrolled consecutive infants with suspected sepsis was performed. Complete blood count with differential, blood culture, and CD64 index measurement were performed, and neutrophil CD64 indices were correlated with the diagnoses of confirmed and suspected sepsis.

RESULTS. There were 293 episodes of sepsis evaluations for 163 infants. Infants with sepsis episodes (confirmed or suspected; n = 40) were of greater gestational age (34.7 ± 0.9 weeks), compared with those (n = 123) with no sepsis (32.6 ± 0.5 weeks), but had similar birth weights (2325 ± 200 vs 1969 ± 94 g) and Apgar scores at 1 and 5 minutes. There was no difference in the duration of hospitalization for the 2 groups. As expected, the hematologic profiles of sepsis episodes (n = 128) were characterized by higher white blood cell counts, absolute neutrophil counts, absolute band counts, and immature/total neutrophil ratios but lower platelet counts. Sepsis episodes had higher neutrophil CD64 indices (5.61 ± 0.85 vs 2.63 ± 0.20). For all sepsis episodes, the CD64 index had an area under the curve, in receiver operating characteristic analysis, of 0.74; with a cutoff value of 2.30, the CD64 index in combination with the absolute neutrophil count had the highest negative predictive value (93%) for ruling out sepsis and 95% sensitivity for diagnosing sepsis. For culture-positive sepsis episodes, the CD64 index had the highest area under the curve (0.852) of all hematologic variables, with a sensitivity of 80% and a specificity of 79%, with a cutoff value of 4.02.

CONCLUSIONS. Neutrophil CD64 is a highly sensitive marker for neonatal sepsis. Prospective studies incorporating CD64 into a sepsis scoring system are warranted.

Key Words: newborn • infection • neutrophils • flow cytometry

Abbreviations: ANC—absolute neutrophil count • AUC—area under the curve

Sepsis in neonates hospitalized in the NICU is a global problem and is a significant contributor to morbidity and death.1–4 Most studies focus on infants of very low birth weight, given their immature immune system and the added contribution of a variety of risk factors.1,5,6 It is important to realize that even late-preterm infants have a compromised immune system and are susceptible to infections in the NICU.7,8

Early recognition and diagnosis of neonatal sepsis are difficult because of the variable and nonspecific clinical presentation of this condition. It is extremely important to make an early diagnosis of sepsis, because prompt institution of antimicrobial therapy improves outcomes. Isolation of bacteria from a central body fluid (usually blood) is the standard and most-specific method to diagnose neonatal sepsis.1,9,10 Bacteremia has been found to occur in 32.3% of infections, with mortality rates ranging from 15% to 50%.11 Studies have reported that, in most circumstances, if blood culture results are not reported as positive by 48 hours, then empiric institution of antibiotics may be discontinued.10,12–14

The problem of unnecessary exposure to antibiotics in this vulnerable population remains, creating an environment for emerging bacterial resistance and the potential for poor outcomes.15 Not surprisingly, attempts have been made to use physiologic parameters,16–18 hematologic indices,10,18–20 and cytokine profiles10,11,19,21–23 at the time of onset of the suspected sepsis episode to identify accurately neonates with sepsis. The role of cytokines as a diagnostic aid in neonatal sepsis has been reviewed.24,25 Despite the fact that a majority of the cytokine markers have high negative predictive values (ie, good for ruling out sepsis),24 these have not been adopted for general medical use. This is partly attributable to the larger amounts of blood required, the long interval to cytokine results (especially if enzyme-linked immunosorbent assay techniques are used), and the costs involved. The readily achievable complete blood count and leukocyte differential assays have relatively poor specificity for diagnosing sepsis. The associated band count and leftward shift of myeloid immaturity measurements may improve diagnostic yield, but their subjective measurement is problematic. Therefore, the need persists for improved diagnostic indicators of neonatal sepsis.

Recently, attention has been directed to the leukocyte cell surface antigens as diagnostic markers of sepsis.26 Neutrophil surface CD64, the high-affinity Fc receptor, is quantitatively upregulated during infection and sepsis, under the influence of inflammatory cytokines; this increase in surface density occurs in a graded manner dependent on the intensity of the cytokine stimulus, and CD64 expression is stable for >24 hours.27 Technological advances in flow cytometry have made it possible to quantitate neutrophil CD64 rapidly, with precision, and, importantly for neonates, with minimal blood volumes,26 but CD64 expression has not been studied extensively in ill preterm neonates.

We hypothesized that neutrophil surface CD64 expression would be a sensitive index for the detection of neonatal sepsis. Our goal in this prospective study was to enroll consecutive infants undergoing sepsis evaluation from the NICU and to measure the neutrophil CD64 index in blood as an adjunct to our previously validated hematologic scoring system for detecting neonatal sepsis.10,19,28


   METHODS
TOP
 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 
Patients
This study was approved by the Yale University School of Medicine Human Investigation Committee. This prospective study was conducted in the Yale-New Haven Children's Hospital newborn special care unit. Consecutive patients (May 2005 to July 2006) undergoing sepsis evaluation (as deemed necessary by the attending neonatologist) were enrolled. The length of antibiotic therapy varied on the basis of the severity of the illness and the discretion of the attending neonatologist.

Two or more of the following clinical features were used to identify patients for sepsis evaluations: (1) respiratory compromise, that is, tachypnea (respiratory rate of >60 breaths per minute), increased apnea (cessation of respiration for ≥20 seconds, occurring at a rate of ≥2 times per hour), severe apnea (any single episode requiring positive pressure ventilation), increased ventilatory support (with no other obvious cause, eg, pneumothorax), or desaturation (pulse oximetry readings of ≤85%); (2) cardiovascular compromise, that is, bradycardia (heart rate of <100 beats per minute), pallor, decreased perfusion (capillary refill of ≥3 seconds or cold extremities), or hypotension; (3) metabolic changes, that is, hypothermia (rectal temperature of <36°C), hyperthermia (rectal temperature of >38°C), feeding intolerance (increased gastric residuals of >30% of food volume in ≥2 feedings within 24 hours), glucose instability (blood glucose level of <45 mg/dL or >125 mg/dL), or metabolic acidosis (pH <7.25); or (4) neurologic changes, that is, lethargy, hypotonia, or decreased activity. These clinical features were validated in an earlier study to be strongly suggestive of infection.10

As part of the evaluation, blood was drawn for a complete blood count, including manual differential, blood culture, and CD64 index. The following previously validated hematologic criteria10,19,28 were used as indicators for sepsis: (1) absolute neutrophil count (ANC) of <7500 or >14500 cells per mm3, (2) absolute band count of >1500 cells per mm3, (3) immature/total neutrophil ratio of >0.16, and (4) platelet count of <150000 cells per mm3.

All blood cultures were collected by using standard sterile techniques, according to protocol. The Bactec microbial detection system (Becton-Dickinson, Sparks, MD) was used to detect positive blood cultures. This is a closed automated system that uses a chemical sensor to detect increases in carbon dioxide production produced by the growth of microorganisms. The sensor is monitored every 10 minutes for increased fluorescence, which is proportional to the amount of carbon dioxide present. Infants whose culture results were positive were diagnosed as having confirmed sepsis. Of infants with negative culture results, those with a positive sepsis score (≥2 of the hematologic criteria enumerated above) were categorized as having suspected sepsis, whereas the remaining infants were categorized as having no sepsis.10,19,28

CD64 Index
Neutrophil CD64 expression was measured as described previously.29 Briefly, 50 µL of whole blood or phosphate-buffered saline–diluted whole blood was incubated for 10 minutes at room temperature with a saturating amount of fluorescein isothiocyanate-conjugated anti-CD64 monoclonal antibody or isotype control (Leuko64 kit; Trillium Diagnostics, Scarborough, ME), followed by ammonium chloride-based red cell lysis. Samples were washed once and resuspended in 0.5 mL of phosphate-buffered saline with 0.1% bovine serum albumin. Flow cytometric analysis was accomplished by using a Becton-Dickinson FACScan system to collect data on the logarithm of green (fluorescein isothiocyanate) fluorescence and linear right-angle side and forward scatter for a minimum of 50000 leukocytes. Interassay standardization and CD64 quantitation were performed by using fluorescein isothiocyanate calibration beads (Leuko64; Trillium Diagnostics, Scarborough, ME). Data analysis was performed by using light scatter gating to define the neutrophil population, and the neutrophil CD64 index was quantified as mean equivalent soluble fluorescence units by using QuickCal for Winlist (Verity Software House, Topsham, ME); correction for nonspecific antibody binding was performed by subtracting values for the isotype control.

Statistical Analyses
Comparisons between the sepsis and no-sepsis groups were performed by using Student's t test or {chi}2 analysis, as appropriate. All analyses were performed by using GraphPad Prism 3.02 (GraphPad Software, San Diego, CA). Receiver operating characteristic curves were generated and analyzed for the area under the curve (AUC); pairwise comparisons were performed by using MedCalc for Windows 9.2.0.2 (MedCalc Software, Mariakerke, Belgium). A P value of <.05 was considered statistically significant.


   RESULTS
TOP
 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 CONCLUSIONS
 REFERENCES
 
There were 293 episodes of sepsis evaluations among 163 infants. Infants with sepsis episodes (confirmed or suspected; n = 40) were of greater gestational age than those with no sepsis (n = 123; mean ± SEM: 34.7 ± 0.9 vs 32.6 ± 0.5 weeks; P = .03) but had similar birth weights (2325 ± 200 vs 1969 ± 94 g) and similar Apgar scores at 1 and 5 minutes (Table 1). There were no differences in numbers of days of positive pressure ventilation, nasal continuous positive airway pressure therapy, or supplemental oxygen therapy or duration of hospitalization between groups (Table 1).


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  		TABLE 1 Characteristics of Neonatal Population

 
On the basis of the sepsis scoring system using hematologic variables, sepsis episodes (n = 128) were characterized by significantly higher white blood cell counts, ANCs, absolute band counts, and immature/total neutrophil ratios, compared with nonseptic episodes (n = 165), as well as lower platelet counts (P < .001 for all comparisons) (Table 2). Those with sepsis episodes also demonstrated significantly higher CD64 index values than did those with no sepsis (5.61 ± 0.85 vs 2.63 ± 0.20; P = .0002) (Table 2). For all sepsis episodes, the CD64 index had an AUC of 0.739; use of a cutoff CD64 index of 2.30 by itself yielded a sensitivity of 70% and a specificity of 62%, with a negative predictive value of 73%. Table 3 shows the sensitivity, specificity, positive predictive value, and negative predictive value of all hematologic data alone and in combination with the CD64 index (cutoff value: 2.30). Combining this CD64 index cutoff value with the predefined ANC criteria listed above yielded the highest sensitivity of 95% and the highest negative predictive value of 93%. The sensitivity and predictive values were not calculated for combinations of multiple hematologic indices because the basis for defining sepsis in this study was ≥2 positive hematologic indices; this a priori definition would produce a positive bias toward higher predictive values. Therefore, we examined only single variables with and without the experimental CD64 index.


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  		TABLE 2 Characteristics of Sepsis Episodes

 

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  		TABLE 3 Sensitivity, Specificity, Positive Predictive Value, and Negative Predictive Value (Expressed as Percentage) for Hematologic Data Alone and in Combination With CD64 Index

 
There were 10 confirmed sepsis episodes with positive culture results: 4 involved coagulase-negative staphylococcal species, 2 Escherichia coli, and 1 each group B streptococci, Klebsiella oxytoca, Klebsiella pneumoniae, and Enterobacter spp. For these confirmed sepsis episodes, the CD64 index had the highest AUC (AUC: 0.852), in the receiver operating characteristic analysis, among all laboratory measures (Fig 1 and Table 4). Pairwise comparisons of receiver operating characteristic curves for the various hematologic parameters and the CD64 index showed no significant differences in comparison with absolute band count or immature/total neutrophil ratio, with a trend toward a higher value of the CD64 index in comparison with platelet count (P = .086) and a significantly higher value in comparison with ANC (P = .009). The cutoff CD64 index of 4.02 by itself yielded a sensitivity of 80% and a specificity of 79% for diagnosing culture-positive sepsis episodes.


Figure 1
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  		FIGURE 1 ROC-curve analysis of hematologic parameters in confirmed sepsis episodes (n = 10). CD64 had the highest AUC (0.852). Plt indicates platelet count.

 

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  		TABLE 4 Comparison of AUC Values From Receiver Operating Characteristic Curves

 

   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
CONCLUSIONS
 REFERENCES
 
It is difficult to identify neonates with sepsis before receipt of the blood culture results. Because there is a possibility of sepsis even in the presence of negative blood culture results (for example, if the neonate had been exposed to antibiotics in utero), clinicians may opt to continue antibiotic treatment on the basis of the clinical profile. In a multicenter study, Fanaroff et al30 reported the incidence, presenting features, and risk factors for late-onset sepsis in very low birth weight infants. A total of 2416 infants were studied, but only 395 with culture-proven sepsis developed septicemia, at a median age of 17 days. The clinical features of the infants with sepsis included apnea (55%); feeding intolerance, abdominal distention, and guaiac test-positive stools (43%); increased respiratory support (29%); and lethargy and hypotonia (23%). Another study used similar clinical findings to identify neonates with sepsis.10 With the exception of increased episodes of apnea and bradycardia, however, clinical criteria were unable to distinguish infected infants from uninfected infants (using the standard criterion of positive blood culture results).10 Similar to the studies described above, the most common organism implicated in neonatal sepsis in the present study was coagulase-negative Staphylococcus.1,5,10,30,31

Studies using peripheral/core temperature differences to identify infants with sepsis have shown promise but have not been validated with larger numbers of infants.16,32 Griffin et al17 used heart rate characteristics to predict neonatal infection and death, but this requires confirmation.

Many efforts have focused on the use of hematologic parameters to increase the diagnostic yield for neonatal sepsis. Rodwell et al33 evaluated the role of hematologic findings as a screening test for neonatal sepsis; in that study, 298 infants were evaluated for sepsis, and 27 had culture-proven sepsis (similar to rates in the current study). Twenty-six (96%) of those 27 had ≥3 hematologic criteria present at the time of the sepsis episode. It was concluded that the presence of ≥3 hematologic scores was 96% sensitive and 78% specific. These criteria had a positive predictive value of 31% and a negative predictive value of 99%. Modified Rodwell criteria have been used in other studies to differentiate infants with and without sepsis.10,19,28 One must keep in mind, however, the wide variability in the diagnostic accuracy of leukocyte indices in neonatal sepsis,34 especially the band count and its derived immature/total neutrophil ratio.

Measurement of cytokine levels has also been investigated as a means to increase the diagnostic yield for neonatal sepsis. Among the various cytokines, most studies have confirmed the utility of interleukin-6 as an early marker of neonatal sepsis.10,11,24,35–46 The cutoff values for interleukin-6 to diagnose sepsis have ranged from 18 to 31 pg/mL.10,11,44,45 Interleukin-8, in contrast, has not lived up to its initial promise as a diagnostic marker for neonatal sepsis.10,24,47,48 It is also important to note that, although manual immunoassays can yield results in 1.5 to 4 hours, readily available automated processes for measurement of cytokine levels are necessary if cytokine values are to be used to facilitate clinical decisions to initiate or to discontinue antibiotic therapy.25 The lack of automation and the costs involved in manual immunoassays have hindered the acceptance of these measurements in general clinical practice. Acute-phase reactants (for example, procalcitonin and C-reactive protein) have also been studied as markers of neonatal sepsis.22,23,34,45,48 Unfortunately, because these acute-phase reactants have similar diagnostic properties, no single marker has been found to have a significant advantage over the others.26

A variety of leukocyte surface markers have been assessed for their potential as markers for neonatal sepsis (reviewed in ref 26). There is a substantial increase in CD64 expression on the surface of neutrophils in response to bacterial infection in neonates, similar to that seen in older children and adults.49 Expression of CD64 has been found to be a highly specific indicator of neonatal sepsis, but it had a low sensitivity in one study.50 CD64 levels have been found to have high sensitivity (95%–97%) and negative predictive value (97%–99%) for early- and late-onset infection in infants of very low birth weight, using cutoff values of 6136 and 4000 phycoerythrin molecules bound per cell, respectively.51,52 Addition of interleukin-6 or C-reactive protein levels enhanced the sensitivity and specificity to 100%.52 Therefore, we focused on CD64 as a diagnostic adjunct to standard hematologic indices in our study.

The quantitation of CD64 is rapid (<60 minutes) with the use of flow cytometry and uses minimal blood volume. In fact, for the present study, no extra blood was obtained from the neonates to perform this test; the samples sent for the complete blood count proved adequate. In the present study, we found the CD64 index to have the highest AUC, compared with commonly used hematologic parameters (including band count and immature/total neutrophil ratio), for diagnosing confirmed neonatal sepsis. This finding alone justifies additional prospective studies of CD64 in neonatal sepsis evaluations. Moreover, CD64 showed surprising utility in all sepsis episodes, even given the a priori use of other hematologic indices to establish that definition. In fact, the combination of the CD64 index and the ANC criterion, without any other hematologic indices, demonstrated 95% sensitivity for all sepsis episodes and a 93% value for predicting which episodes did not fit septic criteria. These findings strongly suggest that the objective CD64 index could replace the band count (and its derived immature/total neutrophil ratio) as a hematologic indicator of sepsis. Moreover, the high negative predictive value of the CD64/ANC combination suggests that these 2 values could be efficacious in guiding decisions to withhold antibiotic therapy. Future studies are warranted for direct comparison of the CD64 index with the band count and immature/total neutrophil ratio, to determine whether the former may supplant these subjective criteria in conjunction with the ANC.


   CONCLUSIONS
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
REFERENCES
 
The CD64 index was elevated significantly during neonatal sepsis episodes and was the most-diagnostic measure of confirmed sepsis; in conjunction with the ANC, the CD64 index showed promise for replacing the subjectively measured band count and immature/total neutrophil ratio. Before this test can be accepted, however, critical issues such as availability and cost must be evaluated carefully in routine clinical settings. In accord with other reports, our findings suggest that the CD64 index be incorporated into sepsis scoring systems for neonates and evaluated prospectively for its incremental (or replacement) diagnostic value.


   ACKNOWLEDGMENTS
 
This study was supported by a grant from Trillium Diagnostics.

We thank the NICU nurses for their invaluable assistance.


   FOOTNOTES
 
Accepted Jun 29, 2007.

Address correspondence to Vineet Bhandari, MD, DM, Department of Pediatrics, Division of Perinatal Medicine, Yale University School of Medicine, LCI 401B, PO Box 208064, New Haven, CT 06520-8064. E-mail: vineet.bhandari{at}yale.edu


   REFERENCES
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 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 

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PEDIATRICS (ISSN 1098-4275). ©2008 by the American Academy of Pediatrics

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