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\begin{document}

\title{Corticosteroids for the management of parapneumonic pleural effusion in
children: a 15-year experience}



\author[1]{MATTHIEU THIMMESCH}%
\author[2]{Frédéric LEBRUN}%
\author[2]{Frédéric PIERART}%
\author[2]{Caroline GENIN}%
\author[2]{Isabelle LOECKX}%
\author[3]{André MULDER}%
\author[1]{Pierre DEMARET}%
\affil[1]{CHC MontLégia }%
\affil[2]{CHC MontLégia}%
\affil[3]{MontLégia}%


\vspace{-1em}



  
  \date{May 18, 2024}


\begingroup
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\selectlanguage{english}
\begin{abstract}
Objective: Description of the use of corticosteroids for the management
of parapneumonic pleural effusion in children. Methods: Retrospective
monocenter cohort study of all children hospitalized with a discharge
diagnosis of parapneumonic pleural effusion during a 15-year period.
Results: We documented 97 cases of parapneumonic effusion during the
study period, with a median age (interquartile range (IQR)) of 43
(33-61) months. Most of the children benefited from an evacuation of the
pleural effusion (89/97, 91.8\%): 21 patients (21.6\%) were treated with
needle thoracocentesis only, while a chest tube was inserted in 68
children (70.1\%). Thirty-two patients (33\%) were treated with
intrapleural fibrinolysis. Fifty-five children (56.7\%) received
corticosteroids for persistent fever. The median time (IQR) between
hospital admission and initiation of corticosteroids was 5.5 (4-7) days.
When corticosteroids were initiated, children were febrile since 9 (IQR
8-11) days. The fever ceased in a median (IQR) of 0 (0-1) day after
corticosteroids initiation. Only 1 patient required a video-assisted
thoracoscopy that was provided because of morphological reasons (morbid
obesity). No children treated with corticosteroids required surgery. All
children were discharged alive from hospital. The median (IQR) hospital
length of stay was 11 (8-14) days, with no difference between children
with and without corticosteroids. Conclusion: Our results indicate that
corticosteroids could be associated with a significant reduction in the
use of surgical procedures and with a prompt clinical improvement.
Corticosteroids could thus offer a non-invasive therapeutic alternative
for children with parapnemonic effusions when antibiotics and pleural
drainage are considered a failure.%
\end{abstract}%



\sloppy


\textbf{Introduction}

Pediatric community-acquired pneumonia (CAP) is a significant health
problem and a leading infectious cause of childhood morbidity and
mortality worldwide \textsuperscript{1}. Even though the once
significant mortality rates associated with CAP have decreased in the
industrialized world thanks to vaccines, accessible antibiotics and
advances in diagnostics and monitoring, some complications are still a
matter of concern, most commonly parapneumonic effusions that have been
increasing in Europe and the United States during the last
decades\textsuperscript{2}.

Parapneumonic effusion complicates up to 13\% of cases of hospitalized
pneumonia among children\textsuperscript{3}. It can be divided into
three stages: inflammatory exudate, clear in appearance, sterile (stage
I); purulent exudate resulting from translocation of white blood cells
into the fluid with deposition of fibrin in the pleural space (stage
II); organized empyema with formation of a thick membrane covering the
visceral pleura (stage III) \textsuperscript{4,5}. The management of
parapneumonic effusions remains an area of controversy, and various
therapeutic options are described \textsuperscript{6,7}. If conservative
treatment with antibiotics alone is a reasonable option for small
parapneumonic effusions, guidelines recommend evacuation of effusions
which are enlarging, compromising respiratory function and/or associated
with loculations; intrapleural fibrinolysis is usually suggested for
effusions of thick fluid with loculations or empyema; and surgery
(either thoracotomy with decortication or video-assisted thoracoscopic
surgery (VATS)) is recommended in case of failure of antibiotics, chest
tube drainage and fibrinolytics \textsuperscript{8,9}. However, surgery
is invasive and not without risks, requires general anesthesia as well
as a highly skilled pediatric surgical team, and is more expensive than
conservative management \textsuperscript{10}. Therefore, alternative
non-surgical strategies would be appealing in children failing
antibiotics, drainage and intrapleural fibrinolysis.

Inflammation plays a key role in the genesis of parapneumonic
effusion\textsuperscript{11}. Corticosteroids have well-known
anti-inflammatory properties, based on which they have been successfully
studied in several infectious diseases including bacterial meningitis
and community-acquired pneumonia of the adult \textsuperscript{12,13}.
However, even though their use may be attractive, corticosteroids are
not included in the recommendations for the management of complicated
parapneumonic effusion, probably because evidence to support this
approach is still lacking. Despite this, aiming to favor a less invasive
approach than surgery, we have introduced corticosteroids in the
therapeutic armamentarium used in managing children with complicated
parapneumonic effusion admitted to our hospital. We prescribe
corticosteroids to children with persisting fever despite pleural
drainage and fibrinolysis, or to febrile children with effusions that
are organized and loculated to such an extent that chest drainage is not
an option. We report here our 15-year experience with this strategy.

\textbf{Methods}

Study design, study site and population

This is a 15-year monocenter retrospective study conducted in the
pediatric department of a community general hospital in Li\selectlanguage{ngerman}ège, Belgium.
Approximately 3000 children are hospitalized each year in our 85-bed
pediatric department for numerous medical or surgical reasons (with the
exclusion of organ transplantation and cardiac surgery).

We retrospectively searched for children (0-15-years-old) admitted to
our pediatric department between January 1\textsuperscript{st}, 2002,
and June 30st, 2017 and coded in the hospital database with the
diagnosis of pleural effusion, pleurisy or empyema. We also listed all
the children for whom a chest drainage system (Pleur-Evac®) had been
delivered by the hospital pharmacy during the study period. The medical
charts of the selected children were reviewed, and only children with
pleural effusion in the context of an infectious respiratory disease (as
documented in the medical chart) were retained for analysis.

Data collection

Data were retrospectively extracted from medical charts by three
investigators (M.T., F.L. and P.D.). Baseline data included medical
history, age, main complaints and clinical findings at hospital
admission. Tachycardia was defined according to the age based on the
following thresholds: 180 beat per minute (bpm) for infants, and 160 bpm
for children aged 1-16-years. The increased work of breathing was
documented as per medical notes, based on a subjective assessment by the
treating physician (no scale measurement).

Data collected during the hospital stay included the use of at least one
dose of corticosteroid (prednisone or methylprednisolone) as part of the
management of the pleural effusion, the use of respiratory support
techniques (high-flow oxygen therapy, noninvasive ventilation,
mechanical ventilation), the number of chest imaging exams and the use
of painkillers. We also collected data to characterize the pleural
effusion, including the time of diagnosis, the presence of fibrin in the
effusion (according to the chest ultrasound protocol), the time and type
(needle thoracocentesis, chest tube) of evacuation (if any), the
duration of drainage (if any), the total volume drained, the use of
intrapleural fibrinolysis, as well as the leucocyte count of the pleural
effusion. We also collected the total duration of fever (defined as a
temperature \selectlanguage{english}[?] 38degC), the highest C-reactive protein (CRP) level as well
as the highest leukocyte count. Finally, we recorded the duration of the
hospital stay.

Statistical analyses

Descriptive statistics were reported as frequencies and percentages or
as median (interquartile range). Statistical analyses were conducted to
compare children with and without corticosteroids: continuous variables
were compared using Student \emph{t} test if normally distributed (as
attested by the Shapiro-Wilk test) or Wilcoxon test if not, and the
chi-square statistic was used for categorical variables. Results were
considered statistically significant when the \emph{p} value was less
than 0.05.

\textbf{Results}

We documented 97 cases of parapneumonic effusion admitted to our
hospital during the study period. Fifty-five of them (56.7\%) received
corticosteroids.

Baseline characteristics

The median age (IQR) at hospital admission was 43 (33-61) months for the
whole cohort, with no difference between children who were going to
receive corticosteroids or not (p=0.667) (Table 1). Most of the included
children were previously healthy, even though 27.8\% reported a previous
respiratory disease. The main complaints at hospital admission were
fever (97.9\%), asthenia (82.5\%), cough (67\%), dyspnea (39.2\%),
abdominal pain (39.2\%) and chest pain (23.7\%), with no difference
between children about to receive corticosteroids or not. Only a
minority of children showed tachycardia at hospital admission (13.7\%),
and oxygen saturation at baseline was normal for the majority of the
children (median (IQR) 96 (94-98) \% for the whole cohort) with no
difference for children about to receive corticosteroids or not
(p=0.341).

Corticosteroids use

Methylprednisolone was used for each of the 55 children with
corticosteroids, at an initial median (IQR) dose of 2 (1.9-2) mg/kg/day.
The median time (IQR) between hospital admission and initiation of
corticosteroids was 5.5 (4-7) days. When corticosteroids were initiated,
children were febrile since 9 (IQR 8-11) days. The fever ceased in a
median (IQR) of 0 (0-1) day after corticosteroids initiation. Three
patients required more than 1 course of corticosteroids because of fever
recurrence when corticosteroids were ceased. The median duration (IQR)
of corticosteroid therapy was 8.5 (4-13.3) days.

Pleural effusion

Most of the children benefited from an evacuation of the pleural
effusion (89/97, 91.8\%): 21 patients (21.6\%) were treated with needle
thoracocentesis only, while a chest tube was inserted in 68 children
(70.1\%) (Table 2). Chest tube insertion and intrapleural fibrinolysis
occurred less frequently in children about to receive corticosteroids
(chest tube 61.8\% \emph{versus} 81.0\%, p=0.041; intrapleural
fibrinolysis 25.5\% \emph{versus} 42.9\%, p=0.07). The duration of chest
drainage did not differ between children with and without
corticosteroids (median (IQR) 5 (3-8.25) \emph{versus} 5 (3-6),
p=0.184). The total volume evacuated through the chest tube tended to be
higher for children without corticosteroids (median (IQR) 480 (300-805)
mL \emph{versus} 390 (137-579) mL), this discrepancy almost reaching the
statistical significance threshold (p=0.07).

Biochemical analyses of the pleural effusion were inconstant and their
results did not differ between children about to receive corticosteroids
or not: proteins were measured in 79/89 samples (88.8\%) (median (IQR)
45 (39.8-48.7) g/L for the whole cohort), LDH in 64 (71.9\%) (median
(IQR) 3124 (879-9367)U/L), glucose in 57 (64\%) (median (IQR) 0.22
(0.01-0.67)g/L), amylase in 15 (16.9\%) and pH in only 8 samples (9\%).
Cytology was more frequently analyzed: the leucocyte and the red blood
cell counts were requested in 78 (87.6\%) and in 73 (82\%) samples
respectively and they did not differ between children with and without
corticosteroids (median (IQR) 5200 (1000-17800) red blood cells /mm3 and
6800 (1500-21100) white blood cells /mm3 for the whole cohort).

Surgery

Only 1 patient required a VATS that was provided because of
morphological reasons (morbid obesity) compromising our usual
``non-surgical'' chest tube insertion. This patient did not receive
corticosteroids. No children treated with corticosteroids needed
surgery.

Organ support

The proportion of children admitted to the PICU / middle care during the
hospital stay was lower for children receiving corticosteroids
(60.9\%\emph{versus} 90.5\%, p=0.011), and the duration of PICU / middle
care stay was shorter for children with corticosteroids than for those
without corticosteroids (median (IQR) 5.5 (4-9.3) \emph{versus} 8.5
(5.8-14.3) days, p=0.017) (Table 2).

Organ support therapies were rare: only 1 patient (1\%) received
high-flow oxygen therapy, no patient received noninvasive ventilation, 4
patients (4.1\%) were mechanically ventilated and 2 patients (2.1\%)
required inotropic and vasopressive support.

Medical imaging

The number of chest X-rays was lower for children with corticosteroids
than for those without (median (IQR) 2 (2-4) versus 4 (2-6), p=0.01),
while the number of chest ultrasounds and chest computed tomography
scans did not differ between the 2 groups.

Inflammation

The total duration of fever was 10 (8-13) days for the whole cohort,
with no difference between children with and without corticosteroids.
There was a marked inflammatory response as assessed by a high CRP level
(median peak (IQR) 270 (202-370) mg/L) and an increased leukocyte count
(median peak (IQR) 20200 (16700-27200) leukocytes /mm3), with no
difference between children with and without corticosteroids.

Pain control

All but one child received paracetamol during the hospital stay, most of
children received ibuprofen (95.9\%), and 76 (78.4\%) children received
at least one dose of tramadol. Morphine was prescribed to 8 (8.2\%)
children. The use of painkillers did not differ between children with
and without corticosteroids.

Outcome

All children were discharged alive from hospital: 92 children were
discharged home, and 5 were discharged to another hospital (the
referring hospital). The median (IQR) hospital length of stay (for
children discharged home) was 11 (8-14) days, with no difference between
children with and without corticosteroids.

\textbf{Discussion}

In our cohort of 97 children with parapneumonic effusion, 55 (56.7\%)
received corticosteroids because of refractory fever. The fever ceased
within the day following corticosteroids initiation for most of the
treated children and none of them required subsequent surgery. Hospital
stay characteristics and outcomes were the same for children with and
without corticosteroids. All the children were discharged alive and well
from hospital.

Recommended management of pediatric parapneumonic effusions

The treatment of choice for parapneumonic effusion in children remains a
matter of controversy in the literature and in clinical practice, and
the management of this disease remains largely center
dependent\textsuperscript{14}.

All children with parapneumonic effusion should be admitted to the
hospital \textsuperscript{8}. The majority of the children included in
our study were hospitalized in PICU / middle care. However, contrary to
adult empyema, parapneumonic effusions in childhood are associated with
a low mortality and the vast majority of children recover
completely\textsuperscript{15}. The high admission rate to PICU in our
cohort is explained by our admission policies rather than by the
severity of the disease.

Although it has been reported than approximately 20 to 50\% of the
parapneumonic effusions can be treated with intravenous antibiotics
alone, there is some evidence that early evacuation of the pleural
effusion may be beneficial \textsuperscript{16,17}. The role of needle
thoracocentesis in the management of pediatric parapneumonic effusions
remains unclear, and some advocate that it should be reserved for cases
where non-infective causes of parapneumonic effusions are being
considered \textsuperscript{15}. However, needle aspirations have
advantages: it less invasive than a chest tube, it is relatively easy
and safe to perform in older children who can tolerate the procedure
with a local anesthetic and sedation, and the sample collected via this
minimally invasive procedure can be analyzed for diagnostic
clarifications. Therefore, a single simple needle thoracocentesis may be
considered for the management of some free-flowing parapneumonic
effusion. However, repeated taps are not recommended, and a drain should
be inserted once it is clear a second tap is required; moreover, chest
tube is recommended over simple thoracocentesis for loculated and/or
purulent effusions \textsuperscript{8,9}. In our cohort, one fifth
(21.6\%) of the children were successfully managed with simple needle
thoracocentesis, confirming that this less-invasive strategy may be
appropriate for selected cases.

In a large cohort study including 14225 pediatric empyema-related
hospital discharges aiming to describe trends in the number and type of
empyema-related procedures in the United States between 2008 and 2014,
there was an increase in the proportions of patients coded for chest
tube placement as the only procedure (from 14.6\% to 20.9\%), for 2
chest tube procedures (from 0.9\% to 3.5\%), and for chest tube
placement as part of their management along with other therapeutic
strategies (from 24.8\% to 30.6\%) \textsuperscript{18}. In another
cohort of 192 Australian children with a diagnosis of empyema, 174
(90.6\%) were managed by primary chest drainage, among which 49 (28.1\%)
required subsequent VATS. In this study, the authors failed to identify
risk markers of VATS at the time of insertion of the primary chest tube,
which highlights the difficulties in identifying patients at risk of
drainage failure. They observed, however, that each day of fever after
the chest tube insertion was associated with an increased risk of
VATS\textsuperscript{19}. Our results are within the range suggested by
these 2 recent studies: 70.1\% of the children included in our study
were managed with a chest tube. Such discrepancies between the reported
proportion of primary chest drainage may be explained by differences in
patient characteristics, as well as differences in management strategies
since the priority of the available therapeutic interventions is not
clearly defined.

Pediatric data on intrapleural fibrinolysis are scarce, but indicate
that instillation of a fibrinolytic agent through the chest tube may be
of interest by reducing the hospital length of stay\textsuperscript{20}.
Therefore, intrapleural fibrinolysis is recommended for parapneumonic
effusions of thick fluid with loculations and/or empyema (overt pus)
\textsuperscript{8}. The agent, dosage, concentration, dwell time,
interval and total doses have not been proven with comparative data and
are subject for future investigation\textsuperscript{9}. In our cohort,
only 32/68 (47.1\%) of the children with a chest tube received
intrapleural fibrinolysis, while fibrin was found in the pleural
ultrasound of 77.7\% of the children and while the median leucocyte
count (IQR) of 6.8 (1.5-21.1) x
10\textsuperscript{3}/mm\textsuperscript{3} indicates that most of the
effusions were purulent. Our practice is thus not totally in accordance
with the aforementioned recommendation, maybe because the level of
evidence for this recommendation is weak.

Primary VATS is associated with good clinical outcomes and low rates of
reintervention \textsuperscript{19}. A recent meta-analysis suggested
that VATS may be associated with a lower reintervention rate and shorter
post-procedural length of stay than primary chest tube and
fibrinolysis\textsuperscript{7}. However, the level of evidence is low,
and the authors of this meta-analysis acknowledge that chest drainage
with fibrinolysis may be effective in more than 75\% of cases.
Furthermore, VATS require minimally invasive surgery expertise which is
not routinely available. The place of VATS in the management of
parapneumonic effusions in children is thus not clearly defined. In our
cohort, only 1 child (1\% of the whole cohort) was treated with VATS.
This only VATS was required because insertion of a chest tube at the
bedside was technically challenging (morbid obesity). No child received
VATS because of a failure of non-surgical management. This proportion of
children requiring surgery is remarkably low, considering that others
have reported that the need for surgical rescue interventions for
parapneumonic empyema in children remained as high as
20\%\textsuperscript{21}. Our finding is probably explained by the use
of corticosteroids if chest drainage was deemed not possible
(multiloculated effusion not drainable) or as soon as chest drainage was
considered a failure (persisting fever).

Corticosteroids for the management of pediatric parapneumonic effusions

In a randomized controlled trial conducted in Spain and including 60
children hospitalized with community acquired pneumonia and pleural
effusion, the use of dexamethasone (0.25mg/kg/ 6 hours for 48
hours)\emph{versus} placebo reduced the time to recovery by almost 3
days with no apparent increase in serious adverse events. In that study,
more patients receiving placebo than receiving dexamethasone needed
eventual pleural drainage (16\% \emph{versus} 5\%), but the study was
underpowered to determine statistical significance for this
analysis\textsuperscript{22}.

To date, no other studies have assessed the role of corticosteroids in
the management of parapneumonic effusion in children. However, this
question makes sense, especially when the inflammatory response is
clinically evident. Indeed, the anti-inflammatory properties of
corticosteroids no longer need to be demonstrated \textsuperscript{23}.
Beneficial effects of corticosteroids have been observed in several
infectious processes where inflammation may play a key role, including
respiratory diseases: in patients hospitalized with community-acquired
pneumonia, the use of (methyl)prednisone reduces treatment failure and
improves recovery, and meta-analysis of the few available randomized
trials suggest that corticosteroids are associated with a reduction in
mortality, in need for mechanical ventilation and in hospital length of
stay; moreover, the use of dexamethasone in patients hospitalized with
coronavirus disease 2019 (COVID-19) recently resulted in lower 28-day
mortality among those receiving respiratory
support\textsuperscript{13,24-26}. But corticosteroids have also
potential drawbacks, as they can cause systemic
immunosuppression\textsuperscript{27}. Corticosteroid treatment in
influenza is associated with increased mortality and hospital-acquired
infection, even though the evidence relates mainly to high
corticosteroid doses and is of low quality with a high potential for
confounding by indication\textsuperscript{28}.

Considering the lack of evidence, our approach is rather cautious and
conservative: we use corticosteroids as a rescue therapy when
antibiotics and pleural drainage are considered a failure, only after a
few days of intravenous antibiotics and only if no lung abscess has been
found on chest tomodensitometry. With this strategy, no children
underwent surgery in our cohort for failure of the medical management.

Limitations and strengths

Our study has several limitations. First, it is single center, which
limits its external validity. Second, the retrospective design increases
the risk of information bias. Third, the use of corticosteroids was not
strictly protocolized so that the criteria for initiating
corticosteroids may have varied from one child to another. Fourth, we
only collected data during the hospital stay: therefore, we cannot
exclude that corticosteroids are associated with worse outcomes after
hospital discharge. However, even though children with parapneumonic
effusions may have severe clinical, radiological and lung function
abnormalities during the acute phase of the disease, favorable and
complete recovery is the rule in the months following
infection\textsuperscript{29,30}. Therefore, the benefits of
corticosteroids should be expected during the hospital stay or maybe in
the immediate post-hospital phase, but not in the long term. Fifth,
microbiological, clinical and management changes may have occurred
during the 15-year study period, and data observed 15 years ago may not
be representative of what occurs nowadays. The main strengths of our
study are the size of our cohort, and most importantly the fact that our
study is the first to describe the successful use of corticosteroids in
the management of parapneumonic effusion when non-surgical management is
considered a failure.

\textbf{Conclusion}

Corticosteroids may be an important part of the therapeutic
armamentarium for children with parapneumonic effusion. Obviously, lots
of questions have to be answered: what molecule (if any) should be used,
what posology, when to initiate the treatment (in the early phase of the
disease, or later?), what duration of treatment, what patients would
benefit from this treatment? As a first step in addressing these
questions, our data, despite their limitations, indicate that
corticosteroids could be associated with a significant reduction in the
use of surgical procedures and with a prompt clinical improvement.
Corticosteroids could thus offer a non-invasive therapeutic alternative
for children with parapneumonic effusions when antibiotics and pleural
drainage are considered ineffective.

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