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\begin{document}

\title{C-reactive protein is associated with severity in hospitalized children
with Respiratory Syncytial Virus bronchiolitis}



\author[1]{assaf adar}%
\author[1]{Aviv Goldbart}%
\author[1]{Nitzan Burrack}%
\author[1]{Neta Geva}%
\author[1]{Bracha Cohen}%
\author[1]{Inbal Golan-Tripto}%
\affil[1]{Soroka Medical Center}%


\vspace{-1em}



  
  \date{June 14, 2024}


\begingroup
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\selectlanguage{english}
\begin{abstract}
\textbf{Objective}: Acute bronchiolitis, primarily caused by Respiratory
syncytial virus (RSV), is the most common cause of hospitalization in
young children. Despite international guidelines supporting clinical
diagnosis, laboratory evaluations are often conducted with limited
validity. We aim to evaluate the association between C-reactive protein
(CRP) levels at admission and disease severity in children hospitalized
due to RSV bronchiolitis. \textbf{Study design:} This single center
retrospective cohort study included children (0-24 months old) who were
hospitalized due to RSV bronchiolitis (January 2018 -- March 2022) with
CRP levels taken upon admission. Clinical data and severity parameters
were extracted using MD-clone platform and the clinical research unit at
SUMC. \textbf{Results:} 1,874 children (mean age of 6.7 months, 59\%
males) with a median CRP level of 1.92mg/dL were included. Children with
elevated CRP (\textgreater{}1.92mg/dL) were significantly older (5.1 vs.
3.8 months, \emph{p\textless{}0.001}), had higher rates of pneumonia
(9.4\% vs. 4.3\%, \emph{p\textless{}0.001} \textbf{)}, urinary tract
infection (UTI), (2.2\% vs. 0.2\%, \emph{p\textless{}0.001}), acute
otitis media (AOM), (1.7\% vs 0.2\%, \emph{p\textless{}0.001}),
admissions to pediatric intensive care unit (PICU) (7.4\% vs 3.7\%,
\emph{p\textless{}0.001}), antibiotic treatment (49.8\% vs 37.2\%,
\emph{p\textless{}0.001}) and longer hospitalizations (3.83 vs 3.31
days, \emph{p=0.001}). Multivariable analysis predicted increased risk
for UTI, PICU admission, pneumonia, and longer hospitalization (relative
risk of 11.6, 2.25, 1.98, 1.44, respectively,
\emph{p\textless{}0.001})). CRP thresholds of 3.51, 1.9, and 2.81 mg/dL
for PICU admission, UTI, and pneumonia, were calculated using Youden's
index with AUC of 0.72, 0.62, and 0.61, respectively.
\textbf{Conclusions}: Elevated CRP levels at admission are associated
with increased disease severity and higher complication rates in
children hospitalized with RSV bronchiolitis.%
\end{abstract}%



\sloppy


\textbf{C-reactive protein is associated with severity in hospitalized
children with}

\textbf{Respiratory Syncytial Virus bronchiolitis}

Assaf Adar \textsuperscript{1,2}, Aviv D
Goldbart\textsuperscript{1,2,3}, Nitzan Burrack \textsuperscript{2,4},
Neta Geva\textsuperscript{1,2,5}, Bracha Cohen \textsuperscript{4},
Inbal Golan-Tripto \textsuperscript{1,2,3}

\textsuperscript{1}Department of Pediatrics, Soroka University Medical
Center, Beer-Sheva, Israel

\textsuperscript{2}Faculty of Health Sciences, Ben-Gurion University of
the Negev, Beer-Sheva, Israel

\textsuperscript{3}Pediatric Pulmonary Unit, Soroka University Medical
Center, Beer-Sheva, Israel

\textsuperscript{4}Clinical Research Center, Soroka University Medical
Center, Beer-Sheva, Israel

\textsuperscript{5}Department of Neonatology, Soroka University Medical
Center, Beer-Sheva, Israel

\emph{Corresponding author:} Dr. Inbal Golan-Tripto, Pediatric Pulmonary
Unit, Soroka University Medical Center, Faculty of Health Sciences, Ben
Gurion University, PO box 151, Beer Sheva, Israel. Tel: +972 8 6403064;
Fax: +972 8 6287163. E-mail: Inbalgt@Clalit.org.il

\emph{Keywords:} Bronchiolitis, Respiratory syncytial virus, C-reactive
protein, urinary tract infection, disease severity, hospitalization.

\textbf{List of Abbreviations:}

AB Acute bronchiolitis

AOM Acute otitis media

BPD Bronchopulmonary dysplasia

CLD Chronic lung disease

CRP C-reactive protein

ED Emergency department

IQR Interquartile range

LOS Length of stay in the hospital

MOS Minimal Oxygen Saturation

PICU Pediatric intensive care unit

RDS Respiratory distress syndrome

RSV Respiratory syncytium virus

SD Standard Variation

SUMC Soroka University Medical Center

UTI Urinary tract infection

\textbf{ABSTRACT}

\emph{Objective} : Acute bronchiolitis, primarily caused by Respiratory
syncytial virus (RSV), is the most common cause of hospitalization in
young children. Despite international guidelines supporting clinical
diagnosis, laboratory evaluations are often conducted with limited
validity. We aim to evaluate the association between C-reactive protein
(CRP) levels at admission and disease severity in children hospitalized
due to RSV bronchiolitis.

\emph{Study design:} This single center retrospective cohort study
included children (0-24 months old) who were hospitalized due to RSV
bronchiolitis (January 2018 -- March 2022) with CRP levels taken upon
admission. Clinical data and severity parameters were extracted using
MD-clone platform and the clinical research unit at SUMC.

\emph{Results:} 1,874 children (mean age of 6.7 months, 59\% males) with
a median CRP level of 1.92mg/dL were included. Children with elevated
CRP (\textgreater{}1.92mg/dL) were significantly older (5.1 vs. 3.8
months, \emph{p\textless{}0.001} ), had higher rates of pneumonia (9.4\%
vs. 4.3\%, \emph{p\textless{}0.001} \textbf{)} , urinary tract infection
(UTI), (2.2\% vs. 0.2\%, \emph{p\textless{}0.001} ), acute otitis media
(AOM), (1.7\% vs 0.2\%, \emph{p\textless{}0.001} ), admissions to
pediatric intensive care unit (PICU) (7.4\% vs
3.7\%,\emph{p\textless{}0.001} ), antibiotic treatment (49.8\% vs
37.2\%,\emph{p\textless{}0.001} ) and longer hospitalizations (3.83 vs
3.31 days, \emph{p=0.001} ). Multivariable analysis predicted increased
risk for UTI, PICU admission, pneumonia, and longer hospitalization
(relative risk of 11.6, 2.25, 1.98, 1.44,
respectively,\emph{p\textless{}0.001} )). CRP thresholds of 3.51, 1.9,
and 2.81 mg/dL for PICU admission, UTI, and pneumonia, were calculated
using Youden's index with AUC of 0.72, 0.62, and 0.61, respectively.

\emph{Conclusions} : Elevated CRP levels at admission are associated
with increased disease severity and higher complication rates in
children hospitalized with RSV bronchiolitis.

\textbf{Statements and declarations}

\emph{Funding}

The authors declare that no funds, grants, or other support were
received during the preparation of this manuscript.

\emph{Competing interests}

The authors have no relevant financial or non-financial interests to
disclose.

\emph{Author contributions}

IGT contributed to the study's conception and design. AA and NB were
responsible for material preparation and data collection. Statistical
analysis was performed by NB and BC. The initial draft of the manuscript
was written by AA, and all authors provided feedback on earlier versions
of the manuscript. All authors reviewed, edited, and approved the final
manuscript.

\emph{Ethics approval}

The study protocol was approved by the local ethical review board of
SUMC (0296-21-SOR).

\textbf{INTRODUCTION}

Acute bronchiolitis (AB) is a lower respiratory tract infection that
affects approximately 20\% of all children, resulting in hospitalization
for 2-3\% of them under 12 months of age. Mortality from AB occurs
predominantly in developing countries. In developed countries it is
associated with various complex chronic conditions and sociodemographic
risk factors.

AB classically presents with increased respiratory effort and wheezing,
often accompanied by systemic manifestations such as fever or apnea, a
common symptom in neonates. a common disease is of 14-21 days with peak
symptoms at days 3-5. guidelines recommend avoiding laboratory or
radiographic evaluations. Nonetheless, these are often performed in
various clinical settings.

The most common viral pathogen associated with bronchiolitis is
Respiratory Syncytial Virus (RSV), which accounts for 50-80\% of cases,
and is associated with more severe disease. Co-infections with other
viruses are seen in up to 30\% of cases. Secondary bacterial infections,
such as AOM, Pneumonia, and UTI (37-74\%, up to 32\%, 1-7\%
respectively) (7,9) have been reported in hospitalized patients.
(7,9--11). Respiratory failure requiring invasive or non-invasive
ventilation occurs in 3-19\% of hospitalized children, usually in PICU
settings.

C-reactive protein (CRP), an acute phase reactant which is synthesized
in the liver, acts as a mediator between the innate and acquired immune
systems. Peaking 48-72 hours after the onset of an inflammatory
response, it is a common clinical tool for diagnosis and monitoring of
inflammatory responses. Only a few studies have examined the relevance
of CRP in RSV bronchiolitis. These studies identified a correlation
between higher CRP levels and an increased risk of severe disease
particularly in cases of radiologically confirmed pneumonia, or the
diagnosis of sepsis in PICU settings.

In this study, our objective is to investigate the correlation between
CRP levels on admission and the severity of RSV bronchiolitis, as well
as any related complications in hospitalized children. Additionally, we
aim to propose specific cutoff values for CRP levels that are indicative
of different severity outcomes, such as the incidence of secondary
infections, prolonged length of stay in the hospital (LOS), and the need
for PICU admission.

\emph{METHODS}

Study design

This is a retrospective cohort study conducted at Soroka University
Medical Center (SUMC), a tertiary hospital in southern Israel where
approximately 450 children are hospitalized annually due to RSV
bronchiolitis, many of whom undergo initial workup, including CRP
levels. Clinical, demographic, and laboratory data were extracted from
Clalit Health Services (CHS) electronic medical records using Clalit's
Data sharing platform powered by MD-clone (www.mdclone.com). The
institution's computational unit extracted data on mechanical
ventilation, oxygen supply, and oxygen saturation of the enrolled
patients. The study protocol was approved by the local ethical review
board of SUMC (0296-21-SOR).

Subjects

This study included children aged less than 2 years of age who were
hospitalized between January 2018 and March 2022 due to acute
bronchiolitis, with a positive RT-PCR for RSV on a nasal swab during the
first week since admission and a CRP level measurement taken during the
first 72 hours from admission. The exclusion criteria were major genetic
or chromosomal abnormalities, immunodeficiencies, cyanotic heart
conditions, neurologic diseases, hypotonia, and chronic lung diseases.

Clinical outcomes

Clinical outcomes included LOS, minimal oxygen saturation (MOS), rate of
PICU admissions, and rates of secondary bacterial infections. LOS was
calculated from the ED admission to discharge from the hospital.
Prolonged LOS was defined as longer than the
75\textsuperscript{th}percentile. MOS was the lowest recorded oxygen
saturation in room air during hospitalization. PICU admission and
assisted ventilation with continuous positive airway pressure (CPAP) or
non-invasive positive pressure ventilation were also noted. The
diagnoses of secondary infections, such as pneumonia, UTI, AOM,
meningitis, and bacteremia, as well as the use of steroids or
antibiotics during hospitalization, were extracted from the patient's
electronic medical records.

Statistical analysis

The study evaluated children's clinical and demographical
characteristics based on their CRP levels above or below the median.
Results from the univariate analysis were presented as mean \selectlanguage{ngerman}± SD for
normally distributed variables or as a median with interquartile range
(IQR) for variables not meeting the normal distribution assumption.
Categorical variables were presented as counts and proportions of
available data. Differences in quantitative variables between groups
were analyzed using ANOVA or the nonparametric Wilcoxon rank sum test.
Categorical parameters were compared using
Chi-square\selectlanguage{greek}\textbf{χ\textsuperscript{2}}\selectlanguage{english} or Fisher's exact test.
Quasi-Poisson regression modeling was used for multivariable analysis to
investigate the association between the CRP value and clinical outcomes.
The optimal cutoff values for CRP were determined using Youden's index
with the R pROC package. The predictive ability of these cutoffs for
severe clinical outcomes was evaluated using the receiver operating
characteristic curve (ROC), and the area under the curve (AUC) was
calculated to measure this ability. Statistical significance was
indicated by a \emph{P} value of 0.05 in all analyses. All statistical
analyses were performed using R software (version 4.0.2), developed by
the R Foundation for Statistical Computing, in Vienna, Austria
(http://www.R-project.org).

\emph{RESULTS}

A total of 2,301, children under the age of two were hospitalized due to
RSV bronchiolitis, of which 1,874 were included in the study (Figure 1).
Patients' mean age was 6.7 months (SD \selectlanguage{ngerman}± 5.9), 55.9\% were male and
62.6\% were of Bedouin origin. The mean hospital LOS was 3.57 days. 104
children were admitted to the PICU (5.5\%), with an average PICU LOS of
5 days (SD ± 4.4 days). The mean MOS was 89\%. Additionally,
approximately one-quarter of the children had co-infection with a second
virus, with adenovirus present in 8.9\% of cases (Table 2b). additional
demographic and clinical parameters are presented in Table 1.

The cohort was divided into a low-CRP group and a high-CRP group based
on the median CRP value of 1.92 mg/dL (Table 2a). The two groups had
similar gender, ethnicity, gestational age, and prior diagnosis of RDS.
The high-CRP group had a significantly higher mean CRP level of 14 mg/dL
compared to 1 mg/dL in the low-CRP group (p\textless{}0.001). Children
in the high-CRP group were older (7.3 vs. 6.0 months, p\textless{}0.001)
and had slightly lower birthweight (3,087 vs. 3,141 grams, p=0.047).
Additionally, they had longer hospital LOS (3.83 days VS. 3.31, p=0.001)
and a lower prevalence of BPD in their medical history (0.2\% vs 1\%,
p=0.034).

Children in the higher-CRP group had lower minimal saturation (88\% vs.
89\%\emph{, p=0.002} ), a higher rate of prolonged LOS (defined as \selectlanguage{english}[?] of
75\% of LOS percentile, 4.3 days) (28.9\% vs.
21.0\%\emph{p\textless{}0.001} ), and a higher incidence of pneumonia
(9.4\% vs. 4.3\%, \emph{p\textless{}0.001} ), UTI (2.2\% Vs.,
0.2\%\emph{p\textless{}0.001} ), and AOM (1.7\% Vs.
0.2\%\emph{p\textless{}0.001} ). Viral co-infection was more common in
the low-CRP group (28.1\% Vs. 25.2\% \emph{p\textless{}0.001} ), while
adenovirus infection was more common in the high-CRP group (10.5\% Vs.
7.4\% \emph{p\textless{}0.001} ). The PICU admission rate was twice as
high in the high-CRP group (7.4\% Vs. 3.7\% \emph{p\textless{}0.001} ).
We observed a higher rate of antibiotic treatment in the high-CRP group
(49.8\% Vs. 37.2\% \emph{p\textless{}0.001} ). No significant
differences in hyponatremia rates, bacteremia, glucocorticosteroid use,
ventilation duration, or readmission rates were found between the two
groups.

After adjusting for age and sex in a multivariable regression model, it
was found that the high-CRP group had a higher risk for PICU admission
(RR = 2.25 CI 1.40, 3.71 \emph{p=0.001} ), UTI (RR = 11.6, CI 3.67,
61.4\emph{p\textless{}0.001} ), pneumonia (RR = 1.98 CI 1.39,
2.87\emph{p\textless{}0.001} ), and prolonged LOS (RR = 1.44 CI 1.23,
1.70\emph{p\textless{}0.001} ) (Table 3, Figure 2).

The optimal cutoff values of CRP for predicting severity outcomes,
calculated using Youden's index, were 1.9 mg/dL with an AUC of 0.72 for
predicting UTI, 2.81 mg/dL with an AUC of 0.62 for predicting pneumonia,
and 3.51 mg/dL with an AUC of 0.61 for predicting PICU admission (Figure
3).

\emph{DISCUSSION}

This study evaluated the association between CRP levels and measures of
disease severity in infants who were hospitalized due to acute RSV
bronchiolitis. The findings revealed that infants with elevated CRP
levels were older, had lower MOS, longer LOS, and higher rates of
secondary infections such as pneumonia, UTI, and AOM. Additionally,
there were more likely to receive antibiotics and require
hospitalization in the PICU. The study also proposes cutoff values for
CRP that could predict the likelihood of UTI, pneumonia, and PICU
admission.

The mean age of the children was 6.7 months, with a male predominance,
and most were term infants, while 10.8\% were born prematurely. These
results align with previous medical literature regarding the demographic
characteristics of pediatric patients with RSV bronchiolitis and those
treated at the SUMC. Younger age is a known risk factor for severity in
RSV, and indeed older age was a protective factor, according to the
regression model. A relative immaturity of the immune system, supported
by studies that demonstrate a severe RSV infection associated with lower
levels of Interferon-gamma (IFN-\selectlanguage{greek}γ\selectlanguage{english}) and lower fever due to inappropriate
inflammatory response, could explain a more severe course of the disease
in younger children. Our study revealed a significant correlation
between elevated CRP and older children (rather than younger children),
indicating the independent role of CRP in association with more severe
disease. This finding is further supported by the lack of influence of
prematurity and gestational age, which are prominent risk factors for
severe disease, on CRP as a severity marker. This holds true even for
premature infants under 35 weeks who routinely receive Palivizumab
during RSV season. Additionally, we observed equal distribution of CRP
levels, sex, and ethnicity in both the higher and lower CRP groups.

LOS

Although the length of hospitalization is an important aspect of RSV
bronchiolitis, it has not been well studied. Mean LOS varies greatly,
ranging from 2-3 days in the USA to 5-6 days in Europe and low-income
countries. A recent study investigating the correlation between CRP
levels and RSV bronchiolitis severity found no association with
prolonged hospitalization. However, that study had a relatively small
cohort with a relatively long mean hospitalization length of 5 days. Our
study, on the other hand, found that children with elevated CRP had an
average extended hospitalization length of half a day. In a
multivariable model, children in the higher-CRP group had a 1.5 times
higher risk of being hospitalized for an extended period
(75\textsuperscript{th} percentile, or 4.3 days).

PICU admissions

Multivariate analysis revealed a positive association between CRP and an
increased risk of PICU admission due to respiratory failure. Studies
report an admission rate of 3-27\% with variability in invasive
ventilation usage, which correlates with younger age, especially those
under 3 months. A recent study reported a PICU admission rate of 27\%,
with only 3.5\% requiring invasive ventilation, and 96\% utilizing high
flow nasal cannula. This non-invasive ventilation method is routinely
used in the PICU and was integrated into our pediatric wards in the
middle of the study period. This may have contributed to the low rate of
PICU admission in our study of 5.5\%. Although few studies have examined
the association between CRP and PICU admission, a preliminary study of
177 patients found an association between PICU admission and a mean CRP
of 3.9 mg/dL when most patients had RSV bronchiolitis. However, another
study failed to demonstrate such an association. Our study demonstrated
an association between elevated CRP and PICU admission, reflected by a
relative risk of 2.25 in a multivariable model. The suggested cutoff
value's ability to differentiate between children admitted to PICU was
limited (Figure 3). However, we found that a cutoff value of 3.295 was
useful for children under three months old (AUC 0.68).

Secondary bacterial infections

Secondary bacterial infections are a known complication of RSV
bronchiolitis, of which UTI is the most extensively studied. However,
many of these studies have used various UTI definitions with differing
levels of sensitivity and specificity. For instance, a recent
meta-analysis reported that 3.1\% of children with bronchiolitis were
also diagnosed with a UTI. Many studies included only children under
three months of age and not 24 months. Early detection of UTI can
profoundly impact the clinical outcome of hospitalized infants.

In our cohort, 23 patients (1.2\%) were diagnosed with UTI, with a
relative risk of 11 for the high CRP group in a multivariable analysis.
However, this association was highly sensitive but not specific. The
highest AUC was in children 3-12 months old with a threshold of 3.42
mg/dL (AUC 0.79), although further investigation is needed since UTI
incidence in our cohort was very low.

Lobar/alveolar pneumonia is another important complication of RSV
bronchiolitis, but its definition varies in the literature and is based
on clinical and radiographic features, often assisted by laboratory
markers. A recent study from our center has demonstrated that RSV is
associated with community-acquired pneumonia in a multivariable model in
50\% of cases, most notably in children under 2 years of age (62\%),
indicating a significant role in its pathogenesis. This finding is
supported by the decline in pneumonia and RSV prevalence during the
COVID-19 pandemic despite persistent nasopharyngeal carriage of \emph{S.
pneumoniae.}

Several studies have assessed the association of elevated CRP with
pneumonia in the context of RSV. One multinational study reported that
increased CRP levels (\textgreater{}4mg/dL) were associated with
bacterial rather than viral pneumonia in otherwise healthy children.
However, another study showed only a slightly elevated CRP level in
bacterial pneumonia (1.06 Vs. 0.62 mg/dL). In a prospective study of
children with bronchiolitis in a PICU setting, elevated CRP and
procalcitonin levels were significantly associated with pneumonia or
sepsis. These results are similar to our study in the association of CRP
with severe disease, but differ in the study population, which only
isolated RSV in 65\% of patients and only included severe cases, who
often have other predisposing conditions that excluded them from our
study. Our study found that elevated CRP was associated with secondary
pneumonia (9\% in the high-CRP group vs. 4.3\% in the low group) with a
relative risk of 1.98 in a multivariable analysis. However, we found
that CRP had limited predictive ability, as the AUC for the suggested
cutoff was low.

The main strength of our research is the large cohort size, which is
larger than previous studies that have assessed CRP in acute
bronchiolitis in children. Additionally, being a single tertiary medical
center, SUMC was able to maintain a consistent clinical approach, with
standardized protocols for hospitalization, discharge, antibiotic
stewardship, and laboratory and radiologic evaluation, which further
strengthens the reliability and validity of our findings.

Limitations of this study include its retrospective nature, as the
inclusion and exclusion criteria may have resulted in the exclusion of
mild cases who were likely discharged without CRP measurement, as well
as critically ill patients with severe risk factors. Also, our
definition of secondary infection was based on the electronic medical
records, which were determined by the treating physicians and not based
on interpretation of radiological findings, with fixed criteria. As
such, there may be potential for under or overdiagnosis. Furthermore, an
elevated CRP level may have influenced the given pneumonia diagnosis,
which was also based on inflammatory markers and not merely based on
radiologic findings. Lastly, our medical documentation system prevented
us from further analyzing data on the use of high-flow nasal cannula in
the pediatric ward setting, which was implemented in 2020.

This study was conducted with the aim of providing clinicians an easy
and accessible tool to aid decision making and management of
hospitalized children with RSV bronchiolitis. Specifically, we sought to
determine the usefulness of CRP levels measured at ED admission as an
early detection method for severe disease. Our findings demonstrate that
CRP can be a valuable tool for informing decisions related to
hospitalization, diagnostic evaluation, and communication with parents
about the anticipated duration of hospitalization.

\emph{CONCLUSIONS}

Elevated CRP levels upon hospital admission are associated with severe
disease in RSV bronchiolitis, leading to increased risks of prolonged
hospitalization, PICU admission, and secondary bacterial infection.
Since it is widely available and commonly used, CRP can aid
decision-making in emergency departments.

\emph{REFERENCES}

\emph{Legend}

\textbf{Table 1.} Demographic and clinical characteristics of the study
population (N = 1,874)

Table 2a. Demographics and background diseases of the study population,
according to CRP

Table 2b. clinical characteristics of the study population, according to
CRP

Table 3. Multivariable Model adjusted to age for different clinical
outcomes.

\textbf{Figure 1.} Flowchart of the Study population

\textbf{Figure 2.} Multivariable model for different clinical outcomes

\textbf{Figure 3.} ROC curves for predicting UTI (A), Pneumonia (B),
PICU admission (C), and prolonged LOS (D), using the Youden's
index\textbf{.}

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