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Warisa Poonnarattanakul, M.D., Chompoonoot Boonsopa, M.D., Sarunya Srijuntongsiri, M.D.
Department of Pediatrics, Faculty of Medicine, Naresuan University, Phitsanulok 65000, ailand.
Comparison of Adjunctive Treatment with IgM-
Enriched IVIG and Antibiotics Alone in Treatment
of Neonatal Sepsis
ABSTRACT
Objective: e primary objective of this study was to compare the clinical and laboratory outcomes and the
mortality rate of neonatal sepsis treated with antibiotics and IgM-enriched IVIG as adjunctive therapy versus
antibiotic alone. In addition, the secondary objective was to determine the morbidities and safety following
the IgM-enriched IVIG treatment and the duration of mechanical ventilation and length of hospital stay.
Methods: A retrospective cohort study was conducted between January 2016 to December 2018 in Naresuan University
Hospital, ailand. All eligible neonates were divided into 2 groups. e control group received antibiotics alone.
e intervention group received both antibiotics and IgM-enriched IVIG. e clinical, laboratory parameters and
morbidities were collected and compared.
Results: ere were 28 neonates enrolled in the study. ere were 14 in each group. In the intervention group,
aer receiving the 3-day course of IgM-enriched IVIG concurrently with antibiotics, the patients had signicantly
decreased respiratory rates (p=0.022), increased mean arterial pressure (p=0.049) and increased serum pH (p=0.017).
e incidence of intraventricular hemorrhage, necrotizing enterocolitis, periventricular leukomalacia and patent
ductus arteriosus in preterm neonates were not found to be signicantly changed in both control and intervention
groups. No adverse eects recorded.
Conclusion: e use of IgM-enriched IVIG as adjunctive treatment in neonatal sepsis showed evidence of improvement
in some clinical and laboratory parameters in neonates presented with hypotension and DIC. e mortality rate
improvement was inconclusive and the use of IgM-enriched IVIG was not found to reduce morbidities in preterm
neonates.
Keywords: Neonatal sepsis; intravenous IgM-enriched IVIG; intravenous immunoglobulin; antibiotics (Siriraj
Med J 2021; 73: 84-91)
Corresponding author: Chompoonoot Boonsopa
E-mail: chompoonoot_pednu@outlook.com
Received 30 September 2020 Revised 16 November 2020 Accepted 17 November 2020
ORCID ID: http://orcid.org/0000-0003-2179-1561
http://dx.doi.org/10.33192/Smj.2021.12
INTRODUCTION
In 2015, the World Health Organization (WHO)
reported that there were almost 2.6 million newborn deaths
per year and most of them were caused by neonatal sepsis.
1
e Expert Meeting on Neonatal and Pediatric Sepsis in 2010
dened that neonatal sepsis is a condition of which clinical
manifestations and laboratory investigations compatible
with infection, although no evidence of infection (through
microbiological cultures or polymerase chain reaction
(PCR).
1
Premature birth and newborn with extremely low
birthweight are prone to have a severe infection. Moreover,
premature neonates are susceptible to pathogens especially
from gram-negative bacteria requiring maternal serum
immunoglobulin G (IgG) for opsonization to activate
phagocytic activity. However, maternal serum IgG is
inadequate in premature neonates and the immune system,
Poonnarattanakul et al.
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integumentary system, and thymus glands are not fully
developed.
2
ere were some evidence reported that the
use of intravenous immunoglobulins (IVIG) can enhance
immunity functions such as opsonization, complement
activity, antibody dependent-cytotoxicity, and neutrophil
chemoluminescence.
3-6
e newer studies found that the
IgM- enriched IVIG have a higher opsonization activity,
specic complement activation and phagocytic activity,
and more potent agglutination strength than IVIG.
5,7
The diagnosis of neonatal sepsis is through
comprehensive assessment when a newborn exhibits at
least two clinical manifestations and two main laboratory
ndings. Clinical manifestations involve temperature
instability, cardiovascular instability, skin and subcutaneous
lesions (petechial rash, sclerema), respiratory instability,
gastrointestinal disturbances, and other non-specic
symptoms such as irritability and hypotonia. e main
laboratory ndings include but not limited to leukopenia
or leukocytosis, increased immature to total neutrophil
(I/T) ratio, thrombocytopenia, increased serum C- reactive
protein (CRP) or procalcitonin, glucose intolerance and
metabolic acidosis.
1
Timely antibiotic therapy of neonatal sepsis is
necessary without the need for positive microbiological
cultures to reduce the delay of treatment. Antibiotics are
still the most important specic treatment of neonatal
sepsis. Various studies reported substantial outcome
improvement, especially in severe cases who received
intravenous immunoglobulin (IVIG), and IgM-enriched
IVIG as adjunctive treatment.
2,4-6,8-19
However, in 2015,
the International Neonatal Immunology Study Group
(INIS Collaborative Group) and Cochrane Review
published that certain studies showed no distinction
in mortality rates between newborns with neonatal
sepsis treated with antibiotics alone compared to those
treated with both IVIG and antibiotics.
20
In contrast,
IgM-enriched IVIG proved to considerably reduce the
mortality rate of neonatal sepsis when incorporated as
a concomitant to antibiotics.
2-3,5,10-11,13,21-22
Newer studies
reported positive changes in symptoms and laboratory
results among severely underweight newborns with
suspected or conrmed neonatal sepsis aer receiving
IgM-enriched IVIG. IgM-enriched IVIG also found
to decrease mortality rates on day 7 and day 28.
13,21-23
Currently, there are very few studies involving the
eectiveness of IgM-enriched IVIG with antibiotics
for treatment of neonatal sepsis in ailand.
e primary objective of this study was to compare the
clinical and laboratory outcomes and the mortality rate of
neonatal sepsis treated with antibiotics and IgM-enriched
IVIG as adjunctive therapy versus antibiotic alone. In
addition, the secondary objective was to determine the
morbidities and safety following the IgM-enriched IVIG
treatment and the duration of mechanical ventilation
and length of hospital stay.
MATERIALS AND METHODS
The retrospective cohort study was conducted
between January 2016 to December 2018. Data were
collected from all infants in Naresuan University Hospital,
Phitsanulok, ailand. e Institutional Review Board
of Naresuan University (COA No. 296/2019 IRBNo.
0364/2020) approved this study. e inclusion criteria
were neonates with a gestational age of 24 to 40 weeks
and 500 to 4,000 grams birthweight diagnosed with
neonatal sepsis by ICD-10 and admitted in NICU. e
exclusion criteria were neonates with prenatal diagnosis
of chromosomal abnormalities, congenital anomalies
and congenital infections (TORCH). Neonates included
in the study received the standard antibiotic treatment
whereas some eligible neonates were given intravenous
IgM-enriched IVIG (Pentaglobin®) 5 ml/kg per day for
three consecutive days as an adjunctive treatment. e
subjects were divided into 2 groups. e rst group (the
intervention group) comprised of neonates who received
antibiotics and IgM-enriched IVIG as an adjunctive
treatment while the second group (the control group)
consisted of neonates who received antibiotics alone. e
decision to prescribe an adjunctive treatment depended
on the physician’s assessment and the family’s nancial
capability. Data records collected contains the demographic
details of the infants (gestational age, sex, birth weight,
mode of delivery, age at diagnosis of sepsis and age at
treatment initiated), maternal antenatal corticosteroid
and antibiotic uses, timing of membrane ruptured and
maternal chorioamnionitis. e clinical characteristics
collected at time of the sepsis diagnosis consists of
feeding intolerance, respiratory distress, hypotension
and Disseminated Intravascular Coagulation (DIC). e
data collected were analyzed according to the source of
infection, clinical and laboratory parameters, culture
results before and aer the treatment in both groups.
e clinical and laboratory information obtained from
the control group were 48-72 hours aer antibiotic
administration, whereas, data gathered in the intervention
group were 24 hours aer the 3-day course IgM-enriched
IVIG infusion. Other comorbidities and complications
recorded were grade 2 intraventricular hemorrhage,
necrotizing enterocolitis, periventricular leukomalacia,
and patent ductus arteriosus. Additional data monitored
were the duration of mechanical ventilation, length of
hospital stay, and mortality rate on the 7
th
day and 28
th
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Poonnarattanakul et al.
day. e notable IgM-enriched IVIG adverse eects
evaluated were hypotension, anaphylaxis, and rashes.
Statistical analysis
Data were analyzed using SPSS version 22 (IBM
Corp., Armonk, NY). Continuous data were shown as
mean ± standard deviation (SD). Categorical data were
shown as frequency and percentage. e pair t-test was
used to compare the results before and aer treatment.
Independent T-test, Chi-square tests and Fisher’s exact
test were used to compare data between control and
intervention groups. The comparison of changes of
parameters between the two groups was performed by
mixed linear regression. e absolute dierences between
the two groups of treatment with the p- value < 0.05 are
considered to be statistically signicant.
RESULTS
ere were 166 neonates diagnosed with neonatal
sepsis from 1,860 infants born between January 2016
and December 2018. ere were 14 neonates in the
intervention group given IgM-enriched IVIG as an
adjunctive treatment while the other 152 received antibiotic
alone. e 14 neonates in control group were taken from
the 152 neonates through by blocked randomization.
Table 1 provides the demographic details and information
of each group. Aer comparing between the two study
groups, there were no dierences found related to patient
characteristics and timing of antibiotic received.
Table 2 shows the clinical characteristics at the time
of neonatal sepsis diagnosis. ese clinical characteristics
were quite similar between these two groups. 9 out of 14
(64.3%) patients in the intervention group had hypotension,
whereas 2 out of 14 (14.3%) in the control group (p-value
0.007). Disseminated intravascular coagulation (DIC)
was frequently found in the intervention group (9 vs. 0
with P-value <0.001). Necrotizing enterocolitis (NEC)
and hospital-acquired pneumonia (HAP) were found
to be the source of infection in the intervention group
(5 vs. 0 with P-value 0.014). Early neonatal sepsis was
found more in the control group (9 vs. 14 with P-value
0.014).
Aer the 3-day course of IgM-enriched IVIG along
with antibiotics, patients in the intervention group had
signicantly decreased respiratory rates (68.18±10.94
vs. 60.80±4.13 with p-value 0.022), increased mean
arterial pressure (MAP) (40.36±15.36 vs. 46.43±15.04 with
p-value 0.049) and serum pH (7.28±0.11 vs. 7.36±0.09
with p-value 0.017) comparable to the value prior to
treatment. In the control group, white blood cell count
was signicantly decreased aer antibiotic treatment
(15,709.29±1,601.15 vs. 10,792±1,206.88 with p-value
0.041) as shown in Table 3.
ere was no remarkable dierence in microbiological
culture values aer treatment was administered in both
study groups (Table 4).
Duration of mechanical ventilation and length of
hospital stay in the intervention group were found to be
longer than those in the control group (50.85±12.62 vs.
8.14±5.71 with P- value 0.007, 97.00±16.93 vs. 21.79±8.80
with P-value 0.001). No dierence in mortality rate at
day 7 and day 28 was recorded in both groups (0(0%)
vs. 0(0%)). Aer the mixed linear regression analysis,
the estimated dierence between the intervention and
control groups on account of the duration of mechanical
ventilation and length of hospital stay (adjusted for
changes in respiratory rate, mean arterial pressure, and
pH) was 29.03 days (95%CI -7.10 to 65.17, p = 0.108) and
42.98 days (95%CI -1.99 to 87.95, p = 0.060) respectively,
resulting to insignicant change between groups as
shown in Table 5.
Aer performing subgroup analysis, the results of
morbidities in preterm neonates were shown in Table 6.
e incidence of intraventricular hemorrhage at least
grade 2, necrotizing enterocolitis, periventricular
leukomalacia and patent ductus arteriosus were not
found to be signicantly changed in both groups.
No adverse effects consisting of hypotension,
anaphylaxis and rash found during and 24 hours aer
IgM- enriched IVIG therapy.
DISCUSSION
is study was initiated to evaluate the ecacy of
IgM-enriched IVIG as adjunctive treatment for neonatal
sepsis in ailand. A previous study conducted by Kola
E, et al. showed that neonates with sepsis who received
IgM-enriched IVIG had a signicant increase in survival
rate and a signicant reduction in length of hospital stay
as compared to neonates who were given antibiotics
and placebo.
12
In Capasso et al. study, similar ndings
were also reported regarding the IgM-enriched IVIG
therapy in infants and showed a reduction in short - term
mortality in neonates (OR 0.16; 95% CI 0.3-0.7).
2,13,21
In
the meta-analytical study conducted by Kreymann et al.,
they found that from 12 trials on 710 neonates, polyvalent
immunoglobulins ( IgGAM) had a signicant eect
on mortality in sepsis and septic shock.
5
On the other
hand, Ohlsson A and Lacy JB reported no evidence for
the reduction of mortality or other relevant outcomes of
3,973 neonates who received IVIG. In addition, subgroup
analysis for IgM- enriched IVIG from this study was
performed (N = 266) and there was no indication that
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TABLE 1. Demographic data.
Characteristics
Intervention Control
n=14 (%) n=14 (%)
P-value
Gestational age (week)
< 37 12 (85.7) 10 (71.4) 0.357
≥37 2(14.3) 4(28.6)
Sex 0.131
Male 9 (64.3) 5 (35.7)
Female 5 (35.7) 9 (64.3)
Birth weight (gram) 0.115
< 2,500 11 (78.6) 7 (50.0)
≥2,500 3(21.4) 7(50.0)
Mode of delivery 0.303
Normal labor 3 (21.4) 1 (7.1)
Cesarean section 10 (71.4) 13 (92.9)
Vacuum extraction 1 (7.2) 0 (0.0)
Antenatal corticosteroid received 7 (50.0) 2 (14.3) 0.103
Maternal prolonged PROM (>18 hour) 1 (7.1) 5 (35.7) 0.065
Maternal received antibiotic 2 (14.3) 6 (42.9) 0.094
Maternal chorioamnionitis 2 (14.3) 0 (0.0) 0.142
Timing of antibiotic received (hour) 7.77±2.85 8.43±2.87 0.871
its use would signicantly reduce mortality in infants
with suspected infection (Risk ratio 0.68; 95% CI 0.39-
1.20).
20
However, the results of this study only revealed
the mortality outcome.
Our study did not nd a dierence in the mortality
rate as there were no recorded deaths on day 7 and
day 28. e length of hospital stay was longer in the
intervention group. is may be caused by the more
severity (hypotension and DIC) in the intervention group
at time of sepsis. However, the duration of mechanical
ventilation and the length of hospital stay were insignicant
between groups as revealed in the mixed linear regression
analysis.
In a study conducted by Salihoglu O, et al., I/T
ratio and CRP level were signicantly decreased and
a substantial increase in the pH and base excess were
recorded following IgM- enriched IVIG therapy.
22
is
result is similar to this study as the intervention group had
signicantly decreased respiratory rates, increased mean
arterial pressure (MAP) and serum pH aer treatment.
Whereas no signicant decline in preterm morbidities
was observed in both groups.
It is inconclusive to state that IgM-enriched IVIG
provides benets to any specic microbial organism as
presented in this current study. Furthermore, randomization
between groups could not be performed because of the
retrospective nature of the study. us, it may be dicult
to compare the baseline characteristics such as severity
of neonatal sepsis between groups. Further prospective
study with precise protocols should be conducted to
substantiate the results of this current study.
is research study was designed to oer information
about the new adjunctive treatment for neonatal sepsis,
therefore providing physicians feasible treatment alternatives
in the care of patients with neonatal sepsis.
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TABLE 2. Clinical characteristics at time of neonatal sepsis diagnosis and source of infection.
Intervention Control
n=14 (%) n=14 (%)
P value
Clinical characteristics at time of neonatal sepsis diagnosis
Feeding intolerance 7 (50.0) 5 (35.7) 0.445
Respiratory distress 12 (85.7) 13 (92.9) 0.541
Cyanosis/desaturation 6 (42.9) 5 (35.7) 0.699
Hypotension 9 (64.3) 2 (14.3) 0.007*
Apnea 2 (14.3) 2 (14.3) 1.000
Abdominal distension 6 (42.9) 2 (14.3) 0.094
Jaundice 3 (21.4) 3 (21.4) 1.000
Bradycardia 1 (7.1) 1 (7.1) 1.000
Lethargy 2 (14.3) 1 (7.1) 0.541
Disseminated intravascular coagulation (DIC) 9 (64.3) 0 (0.0) <0.001*
Source of infection
Necrotizing enterocolitis (NEC) 5 (35.7) 0 (0.0) 0.014*
Early neonatal sepsis 9 (64.3) 14 (100.0) 0.014*
Septicemia (hemoculture positive) 3 (21.4) 0 (0.0) 0.067
Congenital pneumonia 5 (35.7) 4 (28.6) 0.686
Hospital acquired pneumonia (HAP) 5 (35.7) 0 (0.0) 0.014*
TABLE 3. Clinical and laboratory parameters.
Clinical and IgM- enriched IVIG treatment (n=14) Control (n=14)
laboratory parameters Before After P-value Before After P value
Body temperature (°C) 37.16± 0.78 37.09±0.78 0.727 37.16±0.44 37.29±0.31 0.334
Respiratory rate (bpm) 68.18±10.94 60.80±4.13 0.022* 61.21±10.14 55.79±9.74 0.150
Heart rate (bpm) 169.79±34.22 164.21±12.53 0.520 157.00±22.87 143.00±27.22 0.198
Systolic blood pressure (mmHg) 57.14±17.83 62.43±17.39 0.111 60.14±8.18 60.36±8.88 0.928
Mean arterial pressure (mmHg) 40.36±15.36 46.43±15.04 0.049* 46.29±9.24 45.07±9.64 0.666
Diastolic blood pressure (mmHg) 32.36±14.90 37.43±14.68 0.068 38.50±10.18 36.36±9.60 0.494
SpO
2
(%) 87.79±12.78 91.86±6.32 0.286 95.57±9.20 95.86±8.01 0.923
pH 7.28±0.11 7.36±0.09 0.017* 7.28±0.06 7.34±0.09 0.135
pO
2
41.65±19.40 41.22±14.13 0.940 74.30±18.63 51.60±6.30 0.296
pCO
2
56.43±17.59 46.29±11.00 0.093 42.87±5.62 51.60±19.92 0.146
HCO
3
(mEq/L) 26.36±7.18 25.56±4.07 0.560 20.54±3.28 22.89±4.59 0.182
Base excess -0.31±2.22 0.77±1.41 0.538 -6.00±3.97 -2.40±4.67 0.062
WBC count (/mm
3
) 12,012.14 8,472.14 0.133 15,709.29 10,792 0.041*
±1,897.50 ±2,155.73 ±1,601.15 ±1,206.88
Platelet count (/mm
3
) 191,321.43 199,071.43 0.812 259,714.29 257,555.56 0.884
±25,912.66 ±29,303.35 ±23,819.47 ±42,699.89
Hemoglobin (g/dL) 12.59±0.50 12.26±0.45 0.658 17.06±2.21 17.23±1.97 0.428
I:T ratio 0.37±0.07 0.17±0.09 0.127 0.25±0.08 0.14 NA
C- reactive protein (mg/dL) 7.83±5.02 11.30±5.70 0.645 1.79±0.89 2.89±0.24 0.401
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TABLE 4. Microbiological cultures.
TABLE 5. Outcome measurement.
IgM- enriched IVIG treatment (n=14) Control (n=14)
Laboratory Before After Before After
n (%) n (%)
P value
n (%) n (%)
P value
Hemoculture 1.000 0 (0.0) 0 (0.0) NA
Staphylococcus aureus 1 (7.1) 1 (7.1) 0 (0.0) 0 (0.0)
Staphylococcus spp. 1 (7.1) 1 (7.1) 0 (0.0) 0 (0.0)
Gram negative bacilli 1 (7.1) 1 (7.1) 0 (0.0) 0 (0.0)
Sputum culture 0.376 NA
Acinetobacter baumannii 3 (21.4) 4 (28.5) 0 (0.0) 1 (7.1)
Enterococci spp. 1 (7.1) 1 (7.1) 0 (0.0) 0 (0.0)
Pseudomonas aeruginosa 2 (14.3) 1 (7.1) 0 (0.0) 0 (0.0)
Stenotrophomonas maltophilia 1 (7.1) 1 (7.1) 0 (0.0) 0 (0.0)
Staphylococcus coagulation negative 1 (7.1) 0 (0.0)
Urine culture 0 (0.0) 0 (0.0) NA 0 (0.0) 0 (0.0) NA
Cerebrospinaluidculture 0(0.0) 1(7.1) 0.733 0(0.0) 0(0.0) NA
Fungus 0 (0.0) 0 (0.0) NA
Hemoculture for fungus 0 (0.0) 1 (7.1) 0.733 0 (0.0) 0 (0.0) NA
Sputum for fungus 0 (0.0) 1 (7.1) 0.733 0 (0.0) 0 (0.0) NA
Urine for fungus 0 (0.0) 0 (0.0) NA 0 (0.0) 0 (0.0) NA
Outcome measurement IgM-enriched IVIG treatment Control (n=14) P- value
(n=14)
Duration of mechanical ventilation (day) 40.33 ±15.82 11.30 ± 7.89 0.108
a
Length of hospital stay (day) 70.78 ±18.17 27.80 ±11.93 0.060
a
Mortality rate
At day 7 (n (%)) 0 (0.0) 0 (0.0) NA
At day 28 (n (%)) 0 (0.0) 0 (0.0) NA
a
adjusted for changes in respiratory rate, mean arterial pressure, pH
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Poonnarattanakul et al.
TABLE 6. Morbidities in preterm.
Morbidity IgM- enriched IVIG treatment Control
(n=12) (n=10)
Before After P value Before After P value
n (%) n (%) n (%) n (%)
Intraventricularhemorrhagegrade≥2 6(50.0) 6(50.0) 1.000 0(0.0) 1(10.0) 0.305
Necrotizing enterocolitis 5 (41.7) 5 (41.7) 1.000 0 (0.0) 1 (10.0) 0.305
Periventricular leukomalacia 0 (0.0) 0 (0.0) NA 0 (0.0) 0 (0.0) NA
Patent ductus arteriosus 6 (50.0) 5 (41.7) 0.682 0 (0.0) 1(10.0) 0.305
CONCLUSION
Following a 3-day course of IgM-enriched IVIG
concurrently with antibiotics, improvements in clinical
and laboratory parameters were recorded. Mortality
rate was inconclusive as there was no reported patient
death on day 7 and day 28. However, improvements
on respiratory rates, mean arterial pressure (MAP) and
serum pH are benecial indicators to monitor sepsis
in neonates and there were found to be improved aer
using IgM-enriched IVIG as adjunctive treatment in
the neonates presented with hypotension and DIC.
Nevertheless, the use of IgM-enriched IVIG was not
found to reduce morbidities in preterm neonates.
ACKNOWLEDGEMENTS
is work was supported in part by a service grant
from the Faculty of Medicine, Naresuan University,
ailand. We gratefully acknowledge Judely Marish
C. Canete for review of the manuscript and Kornthip
Jeephet for assistance with statistical analysis.
Conict of interest: is study was funded by Faculty
of Medicine, Naresuan University. e authors have no
nancial relevant to this article to disclose.
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