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Article
Transient Neutropenia in Immunocompetent Infants with
Respiratory Syncytial Virus Infection
Tatsuya Korematsu and Hiroshi Koga *
Citation: Korematsu, T.; Koga, H.
Transient Neutropenia in
Immunocompetent Infants with
Respiratory Syncytial Virus Infection.
Viruses 2021,13, 301. https://
doi.org/10.3390/v13020301
Academic Editor: Oliver Schildgen
Received: 5 January 2021
Accepted: 13 February 2021
Published: 15 February 2021
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This article is an open access article
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conditions of the Creative Commons
Attribution (CC BY) license (https://
creativecommons.org/licenses/by/
4.0/).
Department of Pediatrics, National Hospital Organization Beppu Medical Center,
1473 Oaza-Uchikamado, Beppu, Oita 874-0011, Japan; tatsuya.korematsu@gmail.com
*Correspondence: koga.hiroshi.ab@mail.hosp.go.jp; Tel.: +81-977-67-1111
Abstract:
The incidence of neutropenia and the association between neutropenia and severity of
respiratory symptoms among infants with respiratory syncytial virus (RSV) infections remain to be
elucidated. This single-center, retrospective study included immunocompetent infants
(<10 months
old) with laboratory-confirmed RSV infection admitted to our center between January 2012 and
December 2019. Incidence of neutropenia (<1.0
×
10
9
/L) within 10 days of onset and risk factors
associated with subsequent neutropenia were evaluated. Among the 292 infants with RSV infec-
tion, including 232 (79%) with mild infection, neutropenia was observed in 31 (11%), with severe
neutropenia (<0.5
×
10
9
/L) in 3 (1.0%). No neutropenic infants developed serious infection or hema-
tological disorder. Infants without neutropenia showed age <3 months at onset in 34%, C-reactive
protein level <1.0 mg/L in 27%, and nasopharyngeal microbiota composition with any of Moraxella
catarrhalis,Streptococcus pneumoniae, or Haemophilus influenzae in 63%. In comparison, infants with
neutropenia showed age <3 months at onset in 74% (relative risk [RR] 2.15; 95% confidence interval
[CI] 1.65–2.81), C-reactive protein level <1.0 mg/L in 55% (RR 2.02; 95% CI 1.38–2.94), and microbiota
including Moraxella catarrhalis,Streptococcus pneumoniae, or Haemophilus influenzae in 15% (RR 0.24;
95% CI 0.10–0.61
). Multiple logistic regression analyses showed that younger age at onset and ab-
sence of that nasopharyngeal microbiota profile were associated with development of neutropenia. In
conclusion, age and airway microbiota are considered as risk factors for the development of transient
neutropenia among infants with RSV infection. However, the neutropenia seems not to develop
serious infection or hematological disorder.
Keywords:
host microbial interactions; leukopenia; neutrophils; respiratory tract infections; severity
of illness index
1. Introduction
Respiratory syncytial virus (RSV) continues to cause significant morbidity and mor-
tality among children and the elderly worldwide [
1
]. Approximately 33 million annual
episodes of RSV-associated lower respiratory infection occur among children <5 years,
resulting in 3 million hospital admissions and 60,000 in-hospital deaths [
2
]. Nearly half of
these admissions and deaths occur in infants <6 months [2].
To reduce the global burden of RSV infection, RSV vaccines and antivirals have
been developed and are currently in clinical trials [
3
]. Lumicitabine (ALS-008176 or JNJ-
64041575), an oral nucleoside analogue against RSV polymerase, has shown successful
results in phase I and II trials in adults [
4
]. However, adverse effects of neutropenia were
observed in a phase II trial of infants <3 years old, and the trial was terminated [
5
]. To
clarify the causal relationship, additional nonclinical study (monkey study) was undertaken
and showed potential clastogenic effects (data not shown). In clinical practice, neutropenia
subsequent to RSV infection, particularly persistent neutropenia, influences the decision to
perform a diagnostic work-up for serious infectious and hematological diseases.
Transient neutropenia can be observed in immunocompetent infants following viral in-
fections, including RSV infection [
6
–
8
]. However, the cumulative incidence of neutropenia
Viruses 2021,13, 301. https://doi.org/10.3390/v13020301 https://www.mdpi.com/journal/viruses
Viruses 2021,13, 301 2 of 10
in RSV-infected infants remains to be elucidated. The aim of this study was to determine
the incidence of neutropenia among infants with RSV infection and to investigate risk
factors for neutropenia following RSV infection. Our results provide insights into clinical
practice for RSV-infected infants and pathways to further clinical trials of RSV antivirals.
2. Methods
2.1. Study Design and Setting
This was a retrospective observational study of infants admitted to a single pediatric
center in Japan for RSV infection. Beppu Medical Center is a pediatric center for the
100,000 inhabitants of the city of Beppu, in the southeast of Japan. In this city, all pediatric
patients requiring emergency care or hospital admission are transported to our center.
This study protocol, based on the 2007 version of the Strengthening the Reporting of
Observational Studies in Epidemiology (STROBE) statement [
9
], was approved by the
ethics committee of Beppu Medical Center. Passive informed consent was obtained from
the parents of participants through the hospital website and bulletin board.
2.2. Study Participants
In this study, we used a global respiratory severity score (GRSS) [
10
], a clinical severity
score validated for full-term infants <10 months of age with RSV infection. Thus, we
reviewed the information of full-term infants who were <10 months old at the time of
hospitalization for RSV infection at our center between January 2012 and December 2019.
RSV infection was diagnosed based on rapid immunochromatographic antigen testing of
nasopharyngeal swabs or aspirates for RSV. The date of consecutive fever (>37.5
◦
C) or
respiratory symptom occurrence was considered as the first day of RSV infection. Infants
with at least one complete blood count performed within 10 days of illness were included.
Exclusion criteria were as follows: neutropenia diagnosed before onset of RSV infection,
other preceding hematological disorder, malignancy, immune disorder, inborn errors of
metabolism, administration of drugs associated with myelosuppression, administration
of palivizumab within the preceding month, or enrollment in a clinical trial for RSV
antiviral agents.
2.3. Data Collection and Definitions
Information about baseline characteristics, physical findings, laboratory data, and
treatments during the course of RSV infection were also obtained from the electronic
medical records of eligible infants. Clinical severity of RSV infection was assessed on
admission using a GRSS. GRSS is calculated using nine variables: general appearance;
wheezing; rales/rhonchi; chest wall retractions; cyanosis; lethargy; poor air movement;
worst room air SaO
2
; and maximum respiratory rate [
10
]. GRSS is reportedly associated
with length of hospital stay and to affect the CD8
+
T-cell profile in infants with RSV
infection [
10
,
11
]. Neutropenia in infants <1 year old is defined as an absolute neutrophil
count (ANC) <1.0
×
10
9
/L (severe: <0.5
×
10
9
/L) [
8
]. The nutritional condition of infants
was assessed by the z-score of weight-for-length, as calculated using the Anthro Survey
Analyser by the World Health Organization [
12
]. Abnormal values for body temperature
(>38.5
◦
C), heart rate (>180 beats/min), and respiratory rate (>34 breaths/min) were
defined according to systemic inflammatory response syndrome criteria for infants [13].
Analysis of microbial genomic sequences from nasopharyngeal aspirates in infants
with RSV infection demonstrated Streptococcus-, Moraxella-, and Haemophilus-dominant
profiles as the three major microbial profiles, and these nasopharyngeal microbiota profiles
were associated with the clearance of RSV [
14
]. Based on this report, the microbiota profile
was evaluated from bacterial cultures of nasopharyngeal aspirate in this study.
Viruses 2021,13, 301 3 of 10
2.4. Outcome Measures
The primary outcome measure was neutropenia in infants with RSV infection within
10 days of onset. Secondary outcome measures were the potential risk factors including
GRSS associated with the occurrence of neutropenia.
2.5. Follow-Up Assessment
Infants showing neutropenia during hospitalization for RSV infection were evaluated
for clinical signs of underlying serious infectious and hematological disorder, including
pancytopenia and peripheral blood blast cells. When no clinical signs suggested underlying
serious infectious or hematological diseases, infants with neutropenia were discharged
after recovery from RSV infection. The parents of infants with neutropenia were sent a
questionnaire in May 2020 to identify the recovery of neutropenia and subsequent onset of
any hematological disorder.
2.6. Statistical Analysis
Descriptive statistics were used to summarize basic and clinical characteristics, as
percentages. Bivariate associations were assessed using Pearson’s
χ2
test or Fisher’s
exact test. Wilcoxon rank-sum test was used to compare continuous variables. Patient
characteristics, GRSS, laboratory data, and treatment during the course of RSV infection
were compared between infants with and without neutropenia. Logistic regression analysis
was used to identify independent risk factors for neutropenia. The multivariate model
was adjusted for GRSS, potential confounders on univariate analysis (p< 0.05), and factors
previously reported as relevant to neutropenia, such as age and sex [8,15].
JMP version 14 software (SAS Institute Inc., Cary, NC, USA) was used for all statistical
analyses. Values of p< 0.05 were considered significant. Measures of effect are presented
as the risk ratio or odds ratio with 95% confidence interval (CI).
3. Results
3.1. Basic Characteristics
During the study period, a total of 308 infants <10 months old were admitted to our
hospital because of RSV infection. RSV infection was confirmed by rapid immunochromato-
graphic antigen testing in all infants. Among these infants, complete blood counts were
performed within 10 days of onset in the 298 infants who met the inclusion criteria, then six
infants were excluded (due to palivizumab administration within 1 month in five infants;
and participation in a clinical trial of RSV antiviral in one infant). A total of 292 infants
were subsequently considered eligible for this study. Among the 292 infants, 60 (21%) had
GRSS scores of >3.5 [
10
], a threshold for predicting hospitalization, and 232 (79%) had
less severe GRSS scores of
≤
3.5. All 292 infants underwent complete blood counts and
differential evaluations at admission and 70 (24%) underwent two times or more blood
tests within 10 days of onset.
The ethnicity of the 292 eligible infants comprised 290 (99%) Asian (286 Japanese,
2 Korean, 1 Chinese, and 1 Uzbek), 2 (0.7%) white, and no black. A seasonal trend
in admissions of RSV-infected infants was observed as an increase from September to
December in 151 infants (52%) and a decrease from April to July in 32 (11%).
Among the 292 infants with RSV infection, median age at admission was 4.2 months
(interquartile range [IQR] 2.1–7.3 months). Neutropenia with ANC <1.0
×
10
9
/L was identi-
fied in 31 (11%) of these 292 infants, including severe neutropenia with
ANC <0.5 ×109/L
in 3 (1.0%). In addition, neutropenia with ANC <1.0
×
10
9
/L was observed in 32 (8.7%)
of the 368 complete blood counts performed within 10 days of illness. The incidence of
neutropenia according to the day of illness in a series of complete blood counts is illustrated
in Figure 1. Neutropenia was observed in approximately 5–15% of blood samples from
days 2 through 9 of illness in RSV-infected infants.
Viruses 2021,13, 301 4 of 10
Viruses 2021, 13, x FOR PEER REVIEW 4 of 10
the 368 complete blood counts performed within 10 days of illness. The incidence of neu-
tropenia according to the day of illness in a series of complete blood counts is illustrated
in Figure 1. Neutropenia was observed in approximately 5–15% of blood samples from
days 2 through 9 of illness in RSV-infected infants.
Figure 1. Distribution of absolute neutrophil count (ANC) and proportion of neutropenia <1.0 ×
109/L in respiratory syncytial virus (RSV)-infected infants according to day of illness. Each box
bounds the interquartile range of ANC, divided by the median. Solid line denotes the proportion
of neutropenia.
Bacterial cultures of nasopharyngeal aspirates were collected from 234 (81%) of 292
infants (26 with neutropenia, 208 without neutropenia). Blood cultures collected from 26
infants were all negative. During hospitalization, apnea was observed in five infants
(1.7%). In total, 289 infants (99%) were treated with inhaled bronchodilator or nebulized
hypertonic saline, 282 (97%) with intravenous fluid administration, 88 (30%) with oxygen
therapy, 58 (20%) with antibiotic administration, 14 (4.8%) with corticosteroid administra-
tion, nine (3.1%) with high-flow nasal cannula, and one (0.3%) with endotracheal intuba-
tion. None of the infants developed subsequent leukemia or other bone marrow disorder,
or died during the course of RSV infection.
3.2. Potential Risk Factors for Neutropenia
Among the 292 infants, a comparison of clinical manifestations between those with
and without neutropenia is summarized in Table 1. Comorbidities were observed in 10
infants without neutropenia, including congenital heart defects in four, central nervous
system abnormalities in three, cleft lip and palate in one, osteogenesis imperfecta in one,
and anhidrotic ectodermal dysplasia in one. Younger age at onset, lower C-reactive pro-
tein level, and less frequent identification of any of Moraxella catarrhalis, Streptococcus pneu-
moniae, or Haemophilus influenzae in nasopharyngeal aspirates were observed in infants
with neutropenia, compared to those without neutropenia. Median ANC and C-reactive
protein level on admission were higher in the 135 infants with any of these three bacteria
identified from nasopharyngeal aspirates (4.0 × 109/L and 8.1 mg/L) than in the 99 infants
without such a microbiota profile (2.0 × 109/L and 0.9 mg/L, p < 0.0001 and p < 0.0001,
respectively). Age at onset of RSV infection <3 months represented an absolute risk in-
crease of 40% for subsequent neutropenia (number needed to diagnose = 2.5 infants). No
significant difference in corticosteroid use and severity of RSV infection as evaluated by
GRSS was apparent between groups.
Figure 1.
Distribution of absolute neutrophil count (ANC) and proportion of neutropenia <1.0
×
10
9
/L in respiratory
syncytial virus (RSV)-infected infants according to day of illness. Each box bounds the interquartile range of ANC, divided
by the median. Solid line denotes the proportion of neutropenia.
Bacterial cultures of nasopharyngeal aspirates were collected from 234 (81%) of 292 in-
fants (26 with neutropenia, 208 without neutropenia). Blood cultures collected from 26 in-
fants were all negative. During hospitalization, apnea was observed in five infants (1.7%).
In total, 289 infants (99%) were treated with inhaled bronchodilator or nebulized hypertonic
saline, 282 (97%) with intravenous fluid administration, 88 (30%) with oxygen therapy,
58 (20%) with antibiotic administration, 14 (4.8%) with corticosteroid administration, nine
(3.1%) with high-flow nasal cannula, and one (0.3%) with endotracheal intubation. None of
the infants developed subsequent leukemia or other bone marrow disorder, or died during
the course of RSV infection.
3.2. Potential Risk Factors for Neutropenia
Among the 292 infants, a comparison of clinical manifestations between those with
and without neutropenia is summarized in Table 1. Comorbidities were observed in
10 infants without neutropenia, including congenital heart defects in four, central nervous
system abnormalities in three, cleft lip and palate in one, osteogenesis imperfecta in
one, and anhidrotic ectodermal dysplasia in one. Younger age at onset, lower C-reactive
protein level, and less frequent identification of any of Moraxella catarrhalis,Streptococcus
pneumoniae, or Haemophilus influenzae in nasopharyngeal aspirates were observed in infants
with neutropenia, compared to those without neutropenia. Median ANC and C-reactive
protein level on admission were higher in the 135 infants with any of these three bacteria
identified from nasopharyngeal aspirates (4.0
×
10
9
/L and 8.1 mg/L) than in the 99 infants
without such a microbiota profile (2.0
×
10
9
/L and 0.9 mg/L, p< 0.0001 and p< 0.0001,
respectively). Age at onset of RSV infection <3 months represented an absolute risk
increase of 40% for subsequent neutropenia (number needed to diagnose = 2.5 infants). No
significant difference in corticosteroid use and severity of RSV infection as evaluated by
GRSS was apparent between groups.
Viruses 2021,13, 301 5 of 10
Table 1. Comparison of clinical manifestations between RSV-infected infants with and without neutropenia <1.0 ×109/L.
Neutropenic Infants (n= 31) Non-neutropenic Infants (n= 261) Relative Risk (95%CI) pValue
Basic Characteristics
Female infant 18 (58) 113 (43) 1.34 (0.96–1.87) 0.12
Age < 3 months at onset 23 (74) 90 (34) 2.15 (1.65–2.81) <0.0001 *
Weight-for-length z-score < −2 0 (0) 15 (5.8) not applicable 0.38
Admission before day 5 of illness 22 (71) 156 (60) 1.19 (0.93–1.52) 0.23
Vital Signs and Oxygen Saturation
on Admission
Axial temperature > 38.5 ◦C 2 (6.5) 39 (15) 0.43 (0.11–1.70) 0.28
Heart rate > 180 beats/min 0 (0) 18 (6.9) not applicable 0.23
Respiratory rate > 34 breaths/min 25 (81) 185 (71) 1.14 (0.94–1.37) 0.25
Arterial oxygen saturation < 95% 2 (6.5) 37 (14) 0.46 (0.12–1.80) 0.40
Laboratory Findings on Admission
Absolute lymphocyte count < 1.5 ×109/L 0 (0) 2 (0.8) not applicable 1.0
C-reactive protein < 1.0 mg/L 17 (55) 71 (27) 2.02 (1.38–2.94) 0.0015 *
Consolidation on chest radiography 2 (6.5) 52 (20) 0.32 (0.08–1.26) 0.086
Culture of Nasopharyngeal Aspirate
Moraxella catarrhalis 1 (3.9) †87 (42) ‡0.09 (0.01–0.63) <0.0001 *
Streptococcus pneumoniae 1 (3.9) †51 (25) ‡0.16 (0.02–1.09) 0.013 *
Haemophilus influenzae 2 (7.7) †45 (22) ‡0.36 (0.09–1.38) 0.12
Any of these 3 bacteria 4 (15) †131 (63) ‡0.24 (0.10–0.61) <0.0001 *
Treatments
Antibiotic use during course of RSV
infection 5 (16) 57 (22) 0.74 (0.32–1.70) 0.64
Corticosteroid use during course of RSV
infection 1 (3.2) 14 (5.4) 0.60 (0.08–4.42) 1.0
Hospital stay >7 days 4 (13) 58 (22) 0.58 (0.23–1.49) 0.35
Severity of RSV Infectio
GRSS on admission > 3.5 8 (26) 52 (20) 1.30 (0.68–2.47) 0.44
CI: confidence interval; GRSS: global respiratory severity score; RSV: respiratory syncytial virus. * p< 0.05;
†
Denominator of 26 (bacterial cultures were not performed in 5);
‡
denominator of 208 (bacterial
cultures were not performed in 53).
Viruses 2021,13, 301 6 of 10
Multiple logistic regression analysis was performed to evaluate associations between
neutropenia and relevant factors such as sex, age at onset, C-reactive protein level, na-
sopharyngeal microbiota profile, and GRSS (Table 2). Neutropenia within 10 days of onset
in RSV-infected infants was associated with younger age at onset and identification of any
of the three bacterial species mentioned above in cultures of nasopharyngeal aspirate, but
was no longer associated with sex, C-reactive protein level, or GRSS.
Table 2.
Logistic regression analysis for predicting neutropenia <1.0
×
10
9
/L in infants with RSV infection.
Odds Ratio (95%CI) pValue
Any of the 3 bacteria †identified in cultures of
nasopharyngeal aspirate 0.11 (0.03–0.35) <0.0001 *
Age at onset of RSV infection, per
1-month increment 0.81 (0.65–0.97) 0.020 *
GRSS on admission, per 1-point increment 0.92 (0.67–1.24) 0.59
C-reactive protein, per 1-mg/L increment 1.02 (0.99–1.05) 0.10
Female infant 1.49 (0.61–3.70) 0.38
CI: confidence interval; GRSS: global respiratory severity score; RSV: respiratory syncytial virus. * p< 0.05;
†Moraxella catarrhalis,Streptococcus pneumoniae, or Haemophilus influenzae.
3.3. Follow-up Assessment
For the 31 neutropenic infants, 21 questionnaires (68%) were returned. Median follow-
up period was 3.6 years (IQR 1.8–5.0 years). None of the 21 infants developed hematological
disorder or other serious diseases after hospital discharge. Complete blood count was
performed in 19 (90%) of the 21 infants after discharge, and all 19 infants had recovered
(ANC >1.5 ×109/L) from neutropenia.
4. Discussion
This study elucidated the incidence and the risk factors of transient neutropenia in
infants with RSV infection. Among immunocompetent infants with RSV infection, 11%
of the infants showed the transient neutropenia (ANC <1.0
×
10
9
/L), and the transient
neutropenia demonstrated a correlation with age at onset and nasopharyngeal microbiota
profile (presence of M. catarrhalis,S. pneumoniae, or H. influenzae). Among RSV-infected
infants with transient neutropenia, no subsequent serious secondary infections, bone
marrow disorders, or deaths were observed. Our results suggest that comorbid neutropenia
is a transient phenomenon without developing severe infection or hematologic malignancy
among infants with RSV infection.
4.1. RSV Infection and Neutropenia
The estimated incidence of transient neutropenia among RSV-infected infants is 11% in
this study, which raises concerns about potential serious bacterial infection or bone marrow
disorder, particularly in prolonged neutropenia. The incidence of serious bacterial infection
has been reported as 3.7–4.2% among young febrile infants with viral infections [
16
,
17
],
2.1–8.5% among immunocompetent children with febrile neutropenia [
7
,
18
], and 1.1–7.0%
among young infants with RSV infection [
17
,
19
,
20
]. These risks are uncommon, but
non-negligible. Based on these results, targeted antibiotic treatment may be needed in
RSV-infected infants with febrile neutropenia. Prophylactic antibiotic administration may
provide clinical benefit for RSV-infected infants with febrile neutropenia [
18
], especially
in young or ill-appearing infants [
19
,
20
]. Bone marrow disorders, including leukemia or
myelodysplastic syndrome, were found in 1.5–2.5% of previously healthy, infected children
with febrile neutropenia, and all of them showed chronic neutropenia >2 months
[6,21]
.
Given the safety concerns, a diagnostic work-up of underlying serious etiologies is neces-
sary for RSV-infected infants with febrile or prolonged neutropenia. Prophylactic antibiotic
use may then be withheld from RSV-infected infants with afebrile neutropenia.
Viruses 2021,13, 301 7 of 10
4.2. Age-Related Prevalence of Neutropenia
Normal values for ANC vary by age and ethnicity [8]. Except for the first two weeks
after birth, 1.0
×
10
9
/L is used as the lower limit of normal for ANC during the first year of
life, with 1.5
×
10
9
/L thereafter [
8
]. Benign ethnic neutropenia has been described in black
individuals [
8
,
15
], but no such individuals were present in this study. In our study, the
cumulative incidence of neutropenia (<1.0
×
10
9
/L) was 11% among RSV-infected infants,
higher than <5% among infants from the general population [
8
]. Febrile neutropenia
was reported as a serious adverse event in the clinical trial of lumicitabine, a nucleoside
analogue against RSV polymerase, in RSV-infected children <3 years old [
5
]. However,
neutropenic complications have not been reported in adult clinical trials of lumicitabine or
other nucleoside polymerase inhibitors, such as PC786 or EDP-938 [22,23].
4.3. Inflammatory Effect of Airway Microbiota in RSV Infection
In the present study, transient neutropenia occurring in infants with RSV infection
showed an association with nasopharyngeal microbiota, including M. catarrhalis,S. pneumo-
niae, or H. influenzae. Both ANC and C-reactive protein levels were higher in RSV-infected
infants with such microbiota than in those without. These results indicate that nasopha-
ryngeal microbiota profile can potentially induce systemic inflammation and neutrophil
recruitment. The effects of the airway microbiota profile on inflammatory response and on
the severity of RSV infection have been studied. Nasopharyngeal microbiota comprising
H. influenzae or Streptococcus have shown correlations with overexpression of inflammation-
related genes and the need for hospitalization in RSV-infected children <2 years old [
24
].
In addition, nasopharyngeal microbiota with H. influenzae was associated with delayed
clearance of RSV and the need for intensive care and for prolonged hospitalization in RSV-
infected infants [
14
,
25
]. Airway microbiota, including Moraxella or Haemophilus, evoked
the release of cytokines and chemokines among non-infected healthy neonates and among
RSV-infected infants, contributing to the development of recurrent wheezing until 3 years
of age [26,27].
4.4. Potential Role of Airway Microbiota Composition in Neutropenic Phenomenon
Our results demonstrated that nasopharyngeal microbiota composition without M.
catarrhalis,S. pneumoniae, or H. influenzae correlated with increased incidence of tran-
sient neutropenia and was not correlated with the severity of RSV infection in infants.
This suggests that decreased circulating neutrophil counts do not necessarily imply im-
munosuppression. RSV can be detected in peripheral blood in children, and infects bone
marrow stromal cells in children and adults [
28
,
29
]. RSV infection in infants also enhances
the release of hematopoietic cytokines, inflammatory cytokines, and proinflammatory
chemokines in nasal lavage fluids [
30
]. The release of these proinflammatory cytokines and
chemokines induced by RSV infection has an effect on the recruitment and the migration
of neutrophils to inflammatory sites. Decreased circulating neutrophils in the peripheral
blood of infants with RSV infection are therefore considered to result from facilitated trans-
migration and extravasation [
31
], in addition to the effect of transient myelosuppression
or neutrophil apoptosis. This postulated mechanism is consistent with the infrequent
occurrence of serious bacterial infections among immunocompetent children with febrile
neutropenia [
7
,
18
]. Transient neutropenia in RSV-infected infants has been reported to per-
sist for approximately 30 days [
6
]. Further research is required to reveal the pathogenesis
of transient neutropenia in infants with RSV infection.
4.5. Limitations
This type of retrospective observational study has inherent limitations. First, the
timing and the frequency of collecting blood samples within 10 days of illness were not
the same for all participants. This may underestimate the incidence of benign neutropenia
in RSV-infected infants. Second, 32% of patients did not complete follow-up assessment
in this study, and missing data were not included in the analyses. We could not confirm
Viruses 2021,13, 301 8 of 10
the recovery of neutropenia in all RSV-infected infants with neutropenia. Duration of
neutropenia was thus not analyzed in this study. Missed diagnoses of serious infection,
bone marrow disorder, and malignancy following neutropenia in RSV-infected infants were
presumed to be rare, because all children requiring emergency care or hospital admission
in this city were transported to our center. Third, subtypes of RSV were not identified in
the present study. The subtype of RSV has an effect on disease severity, and possibly on
ANC, through the enhanced release of proinflammatory cytokines and chemokines [
32
].
Finally, 80% of infants included in this study showed mild severity of RSV infection (GRSS
≤
3.5) [
10
]. Our study results have limited generalizability to infants with severe RSV
infection or with non-Asian ethnicity.
5. Conclusions
Among infants hospitalized due to predominantly mild RSV infection, 11% showed
transient neutropenia <1.0
×
10
9
/L within 10 days of onset. However, no development of
serious disease was observed in the neutropenic infants. Age at onset and nasopharyngeal
microbiota profile were associated with the development of transient neutropenia. These
risk factors for benign neutropenia in RSV-infected infants should thus be considered in
clinical practice and clinical trials for RSV antivirals. Further investigation is needed to
determine the pathogenesis and the optimal management of transient neutropenia among
children with RSV infection.
Author Contributions:
Conceptualization: T.K. and H.K.; methodology: T.K. and H.K.; formal
analysis: H.K.; data curation: T.K.; original draft preparation: T.K.; review and editing: H.K. All
authors have read and agreed to the published version of the manuscript.
Funding: This research received no external funding.
Institutional Review Board Statement:
The study was conducted according to the STROBE state-
ment, and approved by the Institutional Ethics Committee of Beppu Medical Center (BMC2019-015).
Informed Consent Statement:
Passive informed consent was obtained from the parents of partici-
pants through the hospital website and bulletin board.
Data Availability Statement: Not applicable.
Conflicts of Interest:
This research did not receive any specific grant from funding agencies in the
public, commercial, or not-for-profit sectors.
Abbreviations
ANC absolute neutrophil count
GRSS global respiratory severity score
RSV respiratory syncytial virus
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