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\begin{document}

\title{Paediatric empyema: are ultrasound characteristics at the time of
intervention predictive of treatment failure?}



\author[1]{Stuart Haggie}%
\author[2]{Hiran Selvadurai}%
\author[1]{Hasantha Gunasekera}%
\author[3]{Dominic Fitzgerald}%
\author[1]{David Lord}%
\author[1]{Murthy Chennapragada}%
\affil[1]{Children's Hospital at Westmead}%
\affil[2]{The Children\'s Hospital at Westmead}%
\affil[3]{The Children's Hospital at Westmead}%


\vspace{-1em}



  
  \date{June 14, 2024}


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\selectlanguage{english}
\begin{abstract}
Background: Parapneumonic effusions and empyema are the most frequent
complication of paediatric pneumonia. Treatment options include chest
drain and fibrinolytics (CDF) or thoracoscopic surgery. CDF is
considered less invasive, more cost effective though with higher rates
of reintervention. Pleural fluid characteristics on ultrasound may
identify cases at increased risk of treatment failure with primary CDF.
Methods: A retrospective cohort 2011-2018 of complicated pneumonia
managed with primary CDF. Cases were reviewed using ultrasound criteria
to describe pleural fluid. We compared ultrasound findings and treatment
failure. Results: We report 137 cases with a median age 3.8 years and
43\% female. Treatment failure occurred for 32/137 (23\%) cases. The
interobserver reliability was substantial for the number of septations
(Kappa 0.72, 95\% CI 0.6 to 0.8), moderate for the size of the largest
locule (Kappa 0.55, 95\% CI 0.4 to 0.7) and fair for the level of
echogenicity (Kappa 0.22, 95\%CI 0.1 to 0.3), pleural thickening (Kappa
0.28, 95\% CI 0.2 to 0.4), maximum effusion depth (Kappa 0.37, 95\%CI
0.2 to 0.5) and radiologist's risk for reintervention (Kappa 0.32, 95\%
CI 0.2 to 0.5). Hyperechoic pleural fluid was associated with treatment
failure, with cases nearly five times more likely than anechoic fluid to
have a reintervention (OR 4.9 95\%CI 1.7 to 14.2, p=0.04). Treatment
failure was not associated with other variables. Conclusion: We did not
find an association between ultrasound characteristics and treatment
failure for complicated pneumonia managed with primary CDF.
Inter-observer agreement of ultrasound findings was difficult despite
more objective criteria.%
\end{abstract}%



\sloppy


\textbf{Paediatric empyema: are ultrasound characteristics at the time
of intervention predictive of treatment failure?}

Stuart Haggie\textsuperscript{1,2} MBBS, FRACP, Hiran
Selvadurai\textsuperscript{1,2} MBBS, FRACP, PhD, Hasantha
Gunasekera\textsuperscript{2} MBBS, DCH, MIPH (Hons), FRACP, PhD,
Dominic A. Fitzgerald\textsuperscript{1,2} MBBS, FRACP, PhD, David Lord
MBBS, FRANZCR\textsuperscript{2,3} , S.Murthy Chennapragada MBBS,
FRANZCR\textsuperscript{2,3}

\emph{\textsuperscript{1}Department of Respiratory Medicine, The
Children's Hospital at Westmead, Sydney, NSW, Australia, 2145}

\emph{\textsuperscript{2}Children's Hospital Westmead Clinical School,
Faculty of Medicine and Health, The University of Sydney, NSW,
Australia, 2145}

\emph{\textsuperscript{3}Paediatric Interventional Radiology, Division
of Medical Imaging, The Children's Hospital at Westmead, Sydney, NSW,
Australia, 2145}

\textbf{Financial Disclosure} : The authors have no financial
relationships relevant to this article to disclose.

\textbf{Keywords} : Imaging, Infections: Pneumonia

\textbf{Corresponding author} : Dr. Stuart Haggie, Department of
Respiratory Medicine, The Children's Hospital Westmead, Sydney, NSW,
Australia, 2145. +6129845 0000. stuart.haggie@health.nsw.gov.au

\textbf{Short Title:} Ultrasound and empyema treatment failure



\textbf{Abstract:}

Background\textbf{:} Parapneumonic effusions and empyema are the most
frequent complication of paediatric pneumonia. Treatment options include
chest drain and fibrinolytics (CDF) or thoracoscopic surgery. CDF is
considered less invasive, more cost effective though with higher rates
of reintervention. Pleural fluid characteristics on ultrasound may
identify cases at increased risk of treatment failure with primary CDF.

Methods: A retrospective cohort 2011-2018 of complicated pneumonia
managed with primary CDF. Cases were reviewed using ultrasound criteria
to describe pleural fluid. We compared ultrasound findings and treatment
failure.

Results: We report 137 cases with a median age 3.8 years and 43\%
female. Treatment failure occurred for 32/137 (23\%) cases. The
interobserver reliability was substantial for the number of septations
(Kappa 0.72, 95\% CI 0.6 to 0.8), moderate for the size of the largest
locule (Kappa 0.55, 95\% CI 0.4 to 0.7) and fair for the level of
echogenicity (Kappa 0.22, 95\%CI 0.1 to 0.3), pleural thickening (Kappa
0.28, 95\% CI 0.2 to 0.4), maximum effusion depth (Kappa 0.37, 95\%CI
0.2 to 0.5) and radiologist's risk for reintervention (Kappa 0.32, 95\%
CI 0.2 to 0.5). Hyperechoic pleural fluid was associated with treatment
failure, with cases nearly five times more likely than anechoic fluid to
have a reintervention (OR 4.9 95\%CI 1.7 to 14.2, p=0.04). Treatment
failure was not associated with other variables.

Conclusion: We did not find an association between ultrasound
characteristics and treatment failure for complicated pneumonia managed
with primary CDF. Inter-observer agreement of ultrasound findings was
difficult despite more objective criteria.

\textbf{Background} :

Parapneumonic effusion and empyema thoracis are the most common
complications of paediatric community acquired
pneumonia.\textsuperscript{1} Distinguishing parapneumonic effusions
from a empyema is difficult and thoracocentesis is not recommended in
pleural effusions associated with infection.\textsuperscript{4} Without
pleural fluid microscopy, biochemistry and culture results, the
clinician's ability to precisely discern a parapneumonic effusion from
empyema is limited. An invasive drainage procedure is considered for
patients with respiratory compromise, a continued fever or an enlarging
pleural collection despite optimised medical management (supplemental
oxygen and intravenous antibiotics)\textsuperscript{4} reported rates of
intervention range from 26-78\%.\textsuperscript{2,3}

Primary invasive treatment options include chest drainage and
fibrinolytic therapy (CDF) or video assisted thoracoscopic surgery
(VATS). Since 2006 four randomised controlled trials comparing primary
CDF and VATS for the management of paediatric empyema have reported no
difference in clinical outcomes (length of stay and procedural
reintervention rate).\textsuperscript{5-8} However, a recent
meta-analysis including these trials as well as several large
retrospective cohorts, has reported a 15\% higher reintervention rate in
cases treated with primary CDF vs. VATS (23.9\% vs
8.7\%).\textsuperscript{9} CDF is preferred where possible as it is less
invasive and more cost effective than VATS.\textsuperscript{10} Over the
last 10 years, a trend toward increasing CDF and decreasing VATS as the
primary intervention for paediatric empyema has been
reported.\textsuperscript{11} Further research is needed to better
select cases at high risk of reintervention following CDF, ultrasound
assessment of pleural fluid may support clinicians in deciding between
these interventions.

Ultrasound is a core imaging modality in the management of complicated
pneumonia, it is fast, non-ionizing, portable and inexpensive tool able
to confirm the diagnosis of a pleural effusion and guide pleural
catheter insertion to the most favourable drainage
site.\textsuperscript{4,12,13} A 2009 review of paediatric pleural
effusion imaging concluded that ultrasound cannot accurately predict the
Light's stage (Exudative, Fibrinopurulent or Organised) of a pleural
collection. However paediatric data is lacking and the authors concluded
ultrasound was useful in assessing disease
severity.\textsuperscript{14}Prospective clinical trials comparing
primary CDF and VATS have included sonographic criteria of pleural fluid
to recruit cases despite this evidence gap.\textsuperscript{5,6,8}

A prospective randomised trial comparing VATS and CDF for the management
of children with empyema reported no association between ultrasound
characteristics (fluid echogenicity or the presence of septations) and
duration of hospitalisation.\textsuperscript{15} There is currently
insufficient data to determine whether ultrasound characteristics can
predict treatment failure in primary CDF for paediatric complicated
pneumonia.

\textbf{Aim} :

We postulated treatment failure would be more likely in cases with
ultrasound findings consistent with highly organised pleural effusions,
managed with primary CDF. We sought to compare treatment failure
outcomes with a detailed ultrasound criteria for pleural fluid.

\textbf{Methods} :

We report a retrospective cohort of paediatric empyema cases, identified
by ICD-10 diagnostic and procedural codes, admitted to the largest
tertiary paediatric children's hospital in Sydney, Australia from
2011-2018. Each record was assessed for suitability by SH, records were
only included with a clinical diagnosis of empyema, referred for primary
CDF with no prior drainage procedure and with available ultrasound
images. During the study cases routinely received 48 hours intravenous
treatment with broad spectrum antibiotics prior to an invasive drainage
procedure, unless a more urgent intervention for respiratory compromise
was required.

All ultrasounds were performed at our centre, and the last chest
ultrasound prior to intervention was reviewed for each case. Ultrasounds
were described according to a prior agreed criteria, independently by
two senior consultant paediatric interventional radiologists blinded to
the subsequent clinical outcome. Ultrasound images were obtained using a
combination of sector probes of frequency ranging between 2-9 MHz and
linear probes of frequency ranging between 4 to 15 MHz. These images
were stored on the PACS (Siemens, Erlangen, Germany). The stored images
were reviewed and graded according to predefined novel criteria. The
criteria was modified from a previously described (largely qualitative)
pleural fluid assessment \textsuperscript{14} by expert consensus from
the radiologists participating in this study, to include more objective
parameters. We described the pleural fluid characteristics of:
echogenicity, the number of septations (defined as an echogenic strand
like appearance arising from a pleural surface), the presence of
loculations (defined as a pocket of fluid bordered by septations), the
visceral pleural thickness and the maximal interpleural depth of fluid.
Each radiologist also made a subjective assessment of whether they
considered the case a high risk for reintervention. The ultrasound
criteria are presented in table 1 and demonstrative images in figure 1.

We compared interobserver agreement between radiologists using Cohen's
kappa coefficient for dichotomous variables and a weighted kappa
statistic for ordinal variables. This approach was used to report
disagreement between two raters on an ordinal scale, as disagreement
between extreme categories was considered more important than
disagreement on neighbouring categories. We used McHugh's descriptions
of kappa inter-observer reliability. \textsuperscript{16} A p value of
\textless{}0.05 was considered statistically significant. We pooled the
radiologists' observations for each ultrasound characteristic and
compared these to the clinical outcome of reintervention. We used the
paired t-test for continuous variables and ?\textsuperscript{2} test for
categorical variables. Treatment failure was defined as any repeat
invasive procedure following primary CDF, which included VATS,
thoracoscopy or repeat chest drainage. All analyses were performed in
SAS version 9.4 (SAS Institute; Cary, North Carolina, USA).

\textbf{Results} :

152 cases were identified from ICD-10 codes, 15 cases were excluded from
the analysis with (2/15) requiring parenchymal drainage for necrotising
pneumonia (without an effusion) and (13/15) due to absent or inadequate
ultrasound images to review. There were 137 cases in the final analysis.
The median age was 3.8 years (IQR 2.0 -- 5.9y) and 43\% were female. The
mean duration of fever at the time of CDF insertion was 7.3 days (range
1-16 days).The baseline characteristics of cases managed with primary
CDF alone and those with reintervention are presented in table 2. There
were no differences between the cohorts. Treatment failure occurred for
32/137 (23\%) cases. The indications for a repeat intervention were:
continued fever with evidence of a persisting collection on ultrasound
(15/32), nil drain output with a persisting collection on ultrasound
(8/32), a post-procedural air leak with respiratory compromise (6/32),
dislodged drain (2/32) and focal drainage of a parenchymal collection
(1/32).

The ultrasound characteristics and kappa score describing interobserver
reliability are presented in Table 3. The interobserver reliability was
substantial for the number of septations (Kappa 0.72, 95\% CI 0.6 to
0.8), moderate for the size of the largest locule (Kappa 0.55, 95\% CI
0.4 to 0.7) and fair for the level of echogenicity (Kappa 0.22, 95\%CI
0.1 to 0.3), pleural thickening (Kappa 0.28, 95\% CI 0.2 to 0.4),
maximum effusion depth (Kappa 0.37, 95\%CI 0.2 to 0.5) and radiologist's
risk for reintervention (Kappa 0.32, 95\% CI 0.2 to 0.5).

Each radiologist's observations were compared to the clinical outcome of
a repeat intervention. Hyperechoic pleural fluid was associated with a
repeat intervention, with cases nearly five times more likely than
anechoic fluid to have a reintervention (OR 4.9 95\%CI 1.7 to 14.2,
p=0.036). There was no association between a repeat intervention and the
number of septations, the size of the largest locule, a pleural rind,
the maximal depth of effusion, nor if either interventional radiologist
considered the case overall `high-risk' for a repeat procedure (all
p\textgreater{}0.05).

\textbf{Discussion} :

We report one of the largest cohorts of paediatric empyema cases managed
with primary CDF and, we believe, the first to compare ultrasound
findings with treatment failure. We report a clinically important
association with reintervention being nearly 5 times more likely to be
associated with hyperechoic than anechoic pleural fluid. This finding
may influence primary treatment decisions with VATS preferred to CDF in
higher risk cases, however, we found only a fair level of agreement
between two experienced paediatric radiologists on this variable.

Our findings do not suggest more organised pleural effusions to be at
higher risk of treatment failure with primary CDF treatment. The
sonographic features of multiple small locules or septations, and the
presence of a pleural rind were not associated with treatment failure.
Neither were cases considered `high-risk' by either interventional
radiologist associated with a repeat intervention. These results were
not what we expected, although consistent with (ref 15) which showed a
similar lack of association between septations and length of stay. There
is little consensus in other research of whether sonographic features at
intervention can predict treatment failure.

A retrospective cohort of chest drainage (without fibrinolytic
treatment) in adults of complicated parapneumonic effusion or empyema
identified loculations and larger pleural effusions on ultrasound, to be
associated with treatment failure.\textsuperscript{17} A prospective
paediatric cohort by Kalfa et al. compared ultrasound characteristics
and clinical outcomes after primary thoracoscopy, and reported no
association with: pleural fluid echogenicity, loculations or larger
effusions and adverse clinical outcomes (longer hospitalisation,
surgical difficulty, post-operative complications). However, this study
compared an alternate primary treatment with a relatively low
reintervention rate (6\%) and did not define the ultrasound criteria.
The main finding from this cohort was the association of a delay to
procedure of \textgreater{}4 days with adverse clinical
outcomes.\textsuperscript{18}

The ultrasound characteristics selected in this study were based on
criteria that have been used by other researchers to describe more
organised effusions.\textsuperscript{15-17} We refined previous
variables seeking a more quantitative and objective measures of
assessment, though this did not improve the utility of ultrasound to
predict outcome. Despite efforts to standardise these criteria there
remains a large subjective element in their description, as reflected by
the variability in the kappa statistic. Jaffe et
al\textsuperscript{15}reported better overall interobserver agreement in
describing ultrasound pleural fluid by two radiologists (kappa 0.71)
compared with our data (kappa 0.22 -- 0.72), although they employed a
simplified grading system within a smaller sample size. Further, in that
study interobserver agreement was lower when the same radiologists
reported a more comprehensive description of CT findings in empyema
(kappa 0.52).

Our study design had several limitations. Firstly, the radiologists were
asked to describe the pleural effusion from still images captured by
another sonographer. This approach denied the radiologist the dynamic
changes associated with probe positioning and respiratory movement. The
consultants may have focussed on different still images from the patient
to formulate their descriptions. This study also did not include the
duration of symptoms at the time of the ultrasound and ultrasound
changes may vary throughout the disease course.

Secondly, using retrospective data, the indications for reintervention
were not standardised but interpreted from the clinical record. Most
cases were associated with a persistent fever or a clinically
significant air leak, these features could represent more complicated
disease such as necrotising pneumonia and bronchopleural fistulae rather
than a failure of drain efficacy. In these cases, no diagnosis of
necrotising pneumonia was recorded, though in the absence of
confirmatory CT imaging this is often a clinical diagnosis. Further
research should consider this interaction as a potential confounding
factor.

\textbf{Conclusion} :

In a large cohort of children managed with chest drainage and
fibrinolytic therapy for paediatric empyema, we report hyperechoic fluid
as a being associated with treatment failure. There was no association
between pleural thickening, the number of septations, the size of the
largest locule, and the maximal depth of an effusion or the
interventional radiologist's estimated risk of reintervention. Even with
objective criteria for assessment of pleural fluid, ultrasound imaging
findings cannot predict the risk of treatment failure.

References

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2. Dorman RM, Vali K, Rothstein DH. Trends in treatment of infectious
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8. Sonnappa S, Cohen G, Owens CM, et al. Comparison of urokinase and
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15. Jaffe A, Calder AD, Owens CM, Stanojevic S, Sonnappa S. Role of
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16. McHugh ML. Interrater reliability: the kappa
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17. Huang H-C, Chang H-Y, Chen C-W, Lee C-H, Hsiue T-R. Predicting
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18. Kalfa N, Allal H, Lopez M, et al. Thoracoscopy in pediatric pleural
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