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Original ArticleNasal aNthropometry of INdIaN NeoNates Original Article

DOI: 103126/JNPS.V4113

Adel Moideen1, Ayesha Erum Hadi2, Apurv Barche3, Sneha Jaganathan Andrade3, Aditya Verma3, Leslie 
Edward Lewis3, Jayashree Purkayastha3

1Department of Nephrology, University of Toronto, Toronto, Ontario, Canada
2Department of Radiodiagnosis, McMaster University, Hamilton, Ontario, Canada
3Department of Paediatrics, Kasturba Medical College Manipal, Manipal Academy of Higher Education (MAHE) Karnataka - 576104, 
India.

Role of Neutrophil CD64 in the Diagnosis of Neonatal Sepsis

Introduction: Neutrophil surface CD64 (Cluster of differentiation 64), the high-
affinity Fc receptor, is quantitatively up-regulated during infection and sepsis. 
The diagnostic utility of NCD64 as a reliable marker of neonatal sepsis has 
not been explored so far. Hence this study has been conducted to compare 
NCD64 with other currently used infection markers including total leucocyte 
count, platelet count, absolute neutrophil count (ANC), band:neutrophil ratio 
and highly sensitive C reactive protein (hs-CRP). 

Methods: Consecutively born neonates between March 2014 to November 
2014 were enrolled with documented sepsis (n = 81), clinical sepsis (n = 35), 
and no sepsis (n = 87).  NCD64 was analyzed by flow cytometry.  

Results: Sepsis episodes had a higher median CD64 index of 10.35 (Range: 
15.88, 6.87) as against 2.97 (Range: 5.53, 1.64) in the control group (p < 
0.001). The percentage of NCD64 positive cells was also significantly higher in 
the sepsis group compared to the control group (63.90 ± 2.67 vs 15.07 ± 1.95; 
p = 0.001). In the ROC curve analysis NCD64, percentage of NCD64 positive 
cells had the highest AUC (AUC-0.914) using a cutoff of 28.01%, followed by 
CD64 mean fluorescence intensity (MFI) with an AUC of 0.850 using a cutoff 
of 5.54. NCD64 was significantly elevated in the groups with documented and 
clinical sepsis (p < 0.001). 

Conclusions: NCD64 is a highly sensitive marker for neonatal sepsis. 
Prospective studies incorporating NCD64 into a sepsis scoring system are 
warranted. 

Abstract

*Corresponding Author
Jayashree Purkayastha
Professor,
Department of Paediatrics,
Kasturba Medical College Manipal,
Manipal Academy of Higher Education 
(MAHE)
Karnataka - 576104, India.
Email: jayashreepurkayastha@yahoo.com

Article History 
Received On : 18 Sep, 2021
Accepted On : 17 Aug, 2022

Funding sources: None

Conflict of Interest: None

Keywords: CD64; hs-CRP; Neonatal sep-
sis; Neutrophil

Online Access

DOI:
https://doi.org/10.3126/jnps.v42i2.39821

Introduction
Neonatal sepsis is a clinical syndrome of bacteremia with systemic signs and symptoms 
of infection with in the first 28 days of life. In a country like India and other developing 
countries, neonatal sepsis is the single most important cause of neonatal deaths in the 
community, accounting for over half of them. Successful treatment depends on early 
initiation of appropriate antibiotic therapy, but early diagnosis of neonatal bacterial 

Copyrights & Licensing © 2022 by author(s). This is an Open Access article distribut-
ed under Creative Commons Attribution License (CC BY NC )



J Nepal Paediatr Soc | VOL 42 | ISSUE 02 |MAY-AUG,  202272

Original Article Neutrophil CD64 iN NeoNatal sepsis

infections is difficult because clinical signs are non-specific and 
may initially be subtle.1,2 

Neonatal sepsis is categorized as early or late onset. Although 
advances in neonatal intensive care have led to improved 
survival of very low birth weight (VLBW) infants, late-onset sepsis 
continues to be an important cause of morbidity and mortality.3-5 
Very few modalities are available for investigating neonatal 
sepsis. As such, positive blood cultures still remain the gold 
standard for the diagnosis of sepsis, but many times the cultures 
may be negative even in a symptomatic neonate. When blood 
culture is negative we have to depend on other parameters for 
the diagnosis of neonatal sepsis. These tests should be fast and 
reliable. One of these is neutrophil CD64 which is supposed to be 
very specific for neonatal sepsis. CD64 (Cluster of differentiation 
64) is a type of integral membrane glycoprotein known as an 
Fc receptor that binds monomeric IgG-type antibodies with high 
affinity; more commonly known as Fc-gamma receptor 1 (Fc≤R1).6 
It is expressed at low concentration on the surface of non-
activated neutrophils making normal ranges easy to define and 
independent of ethnic background, genetic influences or gender.6 
Its up-regulation is induced by granulocyte colony stimulating 
factor (G-CSF) and interferon gamma (INF-y) within four to six 
hours of stimulation, five to 10 fold increase during 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.6 

The purpose of this study was to measure the Neutrophil CD64 
in blood as an adjunct to our previously validated hematologic 
scoring system for detecting neonatal sepsis.

Methods
In this prospective observational study, all neonates presenting 
with clinical features suggestive of sepsis at the neonatal 
intensive care unit of a tertiary care hospital from March 2014 
to November 2014 were eligible for inclusion. Neonates who 
had received antibiotic therapy for < 72 hours were excluded. 
Informed consent was taken from all parents prior to the inclusion 
in the study. This study was approved by the Research Ethics Board 
of the institution. Neonates were selected for the study if they 
had two or more of the following clinical features:7 Respiratory 
changes- tachypnea, apnea, increased ventilatory support, or 
desaturation; Cardiovascular changes - heart rate variability, 
pallor, decreased perfusion or hypotension; Metabolic changes 
- hypothermia, hyperthermia, feed intolerance, glucose instability 
(Hypo / hyperglycemia), or unexplained metabolic acidosis; 
Neurologic changes - lethargy, poor suck, convulsion, hypotonia 
or decreased activity; Skin infections - abscess, pyoderma, 
bruising.

As part of the evaluation, detailed history with clinical 
examination was done and demographic, clinical and laboratory 
data were collected for all the neonates. In all the cases, 
neonatal details like date of birth, gestational age, gender and 
birth weight were collected. Antenatal details including parity, 
gestational age, presence of maternal fever, prolonged rupture 
of membranes (PROM), chorioamnionitis, urinary tract infection 
(UTI) and pretreatment with antimicrobials whenever relevant 
were collected. Mode of delivery, place of birth, resuscitation 

methods and Apgar score were recorded. Blood was drawn for 
a complete blood count along with blood culture, CRP, NCD64 
and CD64 index. Neonatal age at the time of obtaining blood 
culture, physical examination details and antibiotic pretreatment 
were also recorded. All blood cultures were collected by using 
standard sterile techniques. The Bactec microbial detection system 
(Becton-Dickinson, Sparks, MD) was used to detect positive blood 
cultures. The details of the organism isolated and the timing of the 
positive signal were obtained from the microbiology department. 
Each positive blood culture result was grouped as either drawn 
< 72 hours (Early onset) or ≥ 72 hours of life (Late-onset). Other 
investigations like urine routine, chest X-ray and cerebrospinal 
fluid (CSF) study were done as and when required. Accordingly, 
neonates were grouped as blood culture positive and negative 
sepsis, and no sepsis and were followed up.

The following hematological criteria were used as indicators of 
sepsis: TLC: < 5,000 / cu.mm or < 20,000 / cu.mm, ANC: 
Considered low if below normal for age as per the Manroe’s 
chart for term and Mouzinho’s chart for VLBW infants, I:T ratio: < 
0.3 in term and < 0.2 in preterms, platelet count: < 1,50,000/
cu.mm.  Measurement of NCD64 index: 50 µL of heparinised 
whole blood was incubated for 30 minutes at room temperature 
with a saturating amount of phycoerythrin conjugated NCD64 
in dark condition. This was followed by ammonium chloride-
based red cell lysis (For 12 - 15 mins). The counting beads were 
added to the sample and mixed thoroughly. Sample was acquired 
in FACS Calibur using Cell quest pro software. A minimum of 
10,000 cells data was saved. The saved data was analysed. The 
study data was processed using SPSS V16.0. For the analysis 
of baseline characteristics of study group, descriptive statistics 
was used. Median values were described with interquartile range 
of 75th percentile - 25th percentile. For the variables following 
normal distribution curve, mean and standard error mean 
were computed. The chi-square test was used in the analysis 
of categorical variables between groups. Receiver operating 
characteristic curves were generated and analyzed for the area 
under the curve (AUC). Significance was assessed at 5% level 
of significance. A p-value of < 0.05 was considered statistically 
significant.

Results
We included 116 neonates who had clinical features of sepsis, 
after excluding 40 neonates who had received antibiotics for 
< 72 hours prior to admission. Of the enrolled 116 neonates, 
blood culture was positive in 81 neonates (Documented sepsis) 
and 35 were grouped as culture negative sepsis (Clinical sepsis). 
The blood culture positive and negative groups were further sub-
grouped as early onset sepsis (EOS) and late onset sepsis (LOS). 
Healthy term and preterm neonates for whom blood was drawn 
for routine serum bilirubin estimation, with no evidence of sepsis 
were selected as controls. Flowchart (Figure 1) shows the study 
recruitment done.



J Nepal Paediatr Soc | VOL 42 | ISSUE 02 |MAY-AUG,  2022 73

Original ArticleNeutrophil CD64 iN NeoNatal sepsis

Table 1. Comparison of AUC values of various hematological 
parameters from Receiver Operating Characteristic (ROC) curves

Variable AUC Mean ± SE
(95% Confidence interval)

Platelet 0.721 ± 0.036 (0.650 - 0.792)

ANC 0.645 ± 0.038 (0.570 - 0.720)

I:T ratio 0.645 ± 0.038 (0.570 - 0.720)

hs-CRP 0.826 ± 0.028 (0.771 - 0.882)

CD64 MFI 0.850 ± 0.039 (0.791 - 0.908)

% NCD64 positive cells 1.914 ± 0.019 (0.878 - 0.951)

Figure 1. Study flow chart

Table 2. Baseline characteristics of study population

Variable Sepsis (Cases)
N = 116

No sepsis (Controls)
N = 87

Sex – Male
          Female

84 (72.4%)
32 (27.6%)

55 (63.2%)
32 (36.8%)

Singleton
Multiple

112 (96.6%)
4 (3.4%)

84 (96.6%)
3 (3.4%)

Age at sepsis evaluation:
(Mean ± SEM, weeks)

35.99 ± 0.43 35.53 ± 0.39

Inborn
Outborn

22 (19%)
94 (81%)

41 (47.1%)
46 (52.9%)

Gestation:
Preterm (≤ 33 weeks)
Late preterm (34 - 36 weeks)
Term (≥ 37 weeks)

26 (22.4%)
18 (15.5%)
72 (62.1%)

24 (27.6%)
19 (21.8%)
44 (50.6%)

Mode of delivery:
Vaginal
Assisted vaginal
LSCS

(37.9%) 44
(3.4%) 4
(58.6%) 68

24 (27.6%)
3 (3.4%)
60 (69.0%)

Age at sepsis evaluation:
< 72 hrs
< 72 hrs

(32.8%) 38
(67.2%) 78

72 (82.8%)
15 (17.2%)

Asphyxia: Present   
               Absent                   

(19%) 22
(81%) 94

10 (11.5%)
77 (88.5%)

PROM: Present   
           Absent                                              

(16.4%) 19
(83.6%) 97

18 (20.7%)
69 (79.3%)

Blood culture yield in the early onset sepsis group was 60.5% 
as against the blood culture yield of 74.4% in the late onset 
sepsis group. Of 116 septic neonates, pathogenic organisms 
could be isolated from 81 (70%) cases: 19 - Coagulase-negative 
staphylococcus (CONS), 19 - Klebsiella pneumoniae, nine 
- Candida, seven - Enterobacter, six – Escherichia coli, five - 
Burkholderia, three - Methicillin resistant staphylococcus aureus 
(MRSA), three - Streptococcus, two - Pseudomonas, one - non 
fermenting gram negative bacilli (NFGNB), two - Serratia, two - 
Staphylococcus aureus, one - Acinetobacter and one - Kodamea 
spp. On the basis of the sepsis scoring system using hematologic 
variables, septic neonates (n = 116) were characterized by 
significantly higher white blood cell counts, ANC’s and immature 
/ total neutrophil ratios, compared with the control group (n = 
87), as well as lower platelet counts (p < 0.05 for all comparisons) 
(Table 3).         

Table 3. Haematological profile of cases and controls

Variable Sepsis
(Cases)

N = 116
Median

(75th, 25th IQR)

No sepsis
(Controls)
N = 87
Median

(75th, 25th IQR)

p value

Hemoglobin
(gm / dL)

14.7
(17.07, 12.55)

16.2
(18.2, 14.40)

 0.006

Total count
(cu. mm)

9700
(16700, 5853)

12900
(18900, 9738)

 0.001

ANC
(cu. mm)

3810
(8197.50,1795.50)

6365
(11300, 3870)

 0.001

Platelet count
(Lakhs / cu.mm)

1.03
(2.63, 0.34),

2.36
(2.86, 1.75)

 0.001

I:T ratio 0.115
(0.33, 0.00)

0.00
(0.10, 0.00)

 0.002

hs-CRP
(mg / L)

47.5
(120.82, 9.2)

4.5
(8.90, 1.1)

 0.001

CD64 MFI 10.35
(15.88, 6.87)

2.97
(5.53, 1.64)

0.001

There was statistically significant difference in the hs-CRP levels in 
the sepsis group compared to the control group (47.5 with range: 
120.8 - 9.2 vs 4.5 with range: 8.9 - 1.1; p = 0.001). Those with 
sepsis also demonstrated significantly higher CD64 MFI (Mean 
Fluorescence Intensity) values than those with no sepsis (10.35 
with range: 6.87-15.88 vs 2.97 with range 1.64 - 5.53; p = 
0.001) (Table 3). 



J Nepal Paediatr Soc | VOL 42 | ISSUE 02 |MAY-AUG,  202274

Original Article Neutrophil CD64 iN NeoNatal sepsis

Figure 2.  ROC curves for percentage NCD64 positive cells and 
CD64 index    

The mean time taken for hs-CRP, NCD64 and blood culture 
positivity was analysed and it was observed that mean time taken 
for hs-CRP positivity was 0.798 ± 0.33 hours which was the least, 
followed by NCD64 (2.802 ± 0.038 hours). Mean time taken for 
blood culture positivity was 55.315 ± 3.022 hours which was 
significantly longer. As treatment cannot be withheld in a neonate 
with suspected sepsis waiting for blood culture report, the role 
of hs-CRP and NCD64 becomes important as they give faster 
clue with regard to sepsis. In the receiver operating characteristic 
curves for the various hematologic parameters (hs-CRP and 
NCD64) percentage of NCD64 positive cells had the highest 
AUC (AUC-0.914) using a cutoff of 28.01%, followed by CD64 
MFI with an AUC of 0.850 using a cutoff of 5.54.

Table 4. Sensitivity, specificity, PPV and NPV of various sepsis 
markers using optimal cutoff values

A B C D E

TLC 21 99 96 48

ANC 25 93 83 48

Platelet 62 83 83 62

I:T ratio 36 89 81 51

hs-CRP 75 83 85 71

CD64 MFI 86 76 83 81

% nCD64 positive 
cells

85 81 85 81

Note: A = Variable, B = Sensitivity (%), C = Specificity (%), D = Positive 
predictive value (%), E = Negative predictive value (%)

The assessment of individual markers indicated that NCD64 
has the highest overall sensitivity and negative predictive value 
(NPV) for the prediction of sepsis. We chose the calculated cutoff 
value of 28.01% NCD64 positive cells and CD64 MFI of 5.54 
to be the optimal point, as it would permit a very high sensitivity 
(86%) and NPV (81%) and simultaneously be able to maintain an 
acceptable specificity < 75%. The cutoff value CRP ≥ 10 mg / L 
currently adopted in the neonatal unit provided only a sensitivity 
and specificity of 75% and 83% respectively. Thus, neutrophil 

CD64 and hs-CRP could be used in conjunction for early detection 
of sepsis owing to its faster result. NCD64 index at a cut-off value 
of ≥ 5.54 was positive in 86% of blood culture positive neonates 
(p value - 0.001) while at a cut-off value of 28.01% NCD64 
positive cells, blood culture positive neonates were 83% (p value 
- 0.001). CD64 index at a cut-off value of ≥ 5.54 was able to 
detect 85% of EOS and 87% of LOS neonates while at a cut-off 
value of 28.01% NCD64 positive cells,72% EOS and 91% of 
LOS neonates were detected. 

Discussion
It is difficult to recognize the neonates with sepsis before receipt 
of the blood culture results and this remains a challenge. Currently 
blood culture is the most effective method for diagnosing neonatal 
sepsis. However, the sensitivity of this method is low and using 
it as a gold standard in the diagnosis of septicemia is met with 
many difficulties. A study by Magudumana et al showed that 
fewer than 10% of neonates evaluated and treated for sepsis had 
blood culture positive sepsis.8 As there is a possibility of sepsis 
even in the absence 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. 

There are a variety of rapid tests which are helpful for screening 
of neonatal sepsis. White blood cell count and differential count, 
acute phase reactants like CRP, micro ESR, agglutination tests, 
pro-inflammatory and anti-inflammatory cytokine level estimation, 
DNA sequence test like polymerase chain reaction (PCR), are 
used depending on their sensitivity and specificity. Leucopenia 
(< 5000 / cu. mm) is more specific for neonatal sepsis.9 Absolute 
neutropenia (< 1000 / cu.mm) is more predictive of neonatal 
sepsis than neutrophilia.10 A hematologic scoring system has been 
introduced by Rodwell et al in 1988 by using seven hematological 
parameters.11 Among the various cytokines studied, interleukin-6 
(IL-6) has emerged as an early marker of neonatal sepsis. The 
cutoff values for IL-6 to diagnose sepsis ranges between 18 to 
31 pg / ml.8,12-14 Serial measurement of CRP is probably of more 
value than expensive and time consuming determination of IL-6 
plasma concentration in the evaluation of neonatal sepsis.15 One 
of the newer acute phase markers of infection is procalcitonin 
(PCT), the pro-hormone of calcitonin, which occurs in very low 
concentrations in the serum of healthy people.16  Recently numerous 
cell surface antigens have been studied as potentially promising 
biomarkers of infection, including CD11b, CD69 and CD64.17

There is a significant increase in the CD64 expression on the 
surface of neutrophils in response to bacterial infection in 
neonates, similar to that seen in older children as well as adults.18 
The quantification of NCD64 is rapid (< 60 minutes) and only 
minimal blood volume is used. For the present study, no additional 
blood was drawn from neonates. NCD64 is constitutively 
expressed on antigen presenting cells (Monocytes, macrophages 
and dentritic cells), to a lesser extent to eosinophils, but only to a 
very low extent on resting neutrophils.6,19-21 Several studies have 
indicated that quantification of the neutrophil / polymorphonuclear 
cell (PMN) NCD64 is a worthwhile candidate for evaluation as 
a more sensitive and specific indicator of sepsis than the other 
available diagnostics tests. Majority of the studies have shown 
that NCD64 has high diagnostic specificity and sensitivity.22-24. 
Therefore, we focused on NCD64 as a diagnostic adjunct to 



J Nepal Paediatr Soc | VOL 42 | ISSUE 02 |MAY-AUG,  2022 75

Original ArticleNeutrophil CD64 iN NeoNatal sepsis

standard hematologic indices in our study. A smaller study in 
critically ill neonates and infants by Groselj-Grenc et al used the 
standardized CD64 index for the first time and demonstrated its 
superiority over all other infection markers. They also pesented 
evidence that NCD64 was the best individual marker for bacterial 
sepsis in children.25 Bhandari et al26 conducted the third largest 
study in neonates with suspected sepsis and also these authors 
found that  CD64 index had the best diagnostic performance for 
culture-positive sepsis compared with all traditional hematologic 
assays. The study by Bhandari et al showed a sensitivity of 
70% and a specificity of 62% with a cutoff value of 2.30.26 In 
another study performed over 100 patients in NICU, the NCD64 
index was found again to be the best with the highest sensitivity, 
with no difference between NCD64 and MFI.27 In the present 
study, we found that NCD64 positive cells and NCD64 index 
had the highest AUC, compared to the other routinely used 
hematologic parameters. Here, the cutoff CD64 index of 5.54 
by itself yielded a sensitivity of 86% and a specificity of 76% 
for diagnosing sepsis. NCD64 index could detect 85% of early 
onset sepsis neonates and 87% of late onset sepsis neonates. 
In addition, the results of CD64 are available in a much shorter 
time than blood culture results which could reduce the injudicious 
use of antibiotics. However, ours is a relatively smaller study and 
hence larger, multicentric studies are warranted to implement it 
in neonatal sepsis. However critical issues like availability at all 
centers and cost must be evaluated carefully.

Conclusions
The NCD64 index and percentage of NCD64 positive cells were 
significantly elevated during neonatal sepsis episodes and were 
the most diagnostic and faster measure of confirmed sepsis. It 
also additionally identifies a separate group among culture-
negative sick neonates and may be useful to guide early antibiotic 
administration.

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https://doi.org/10.1111/j.1651-2227.2005.tb03072.x

