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E.O. BEDAWI ET AL.

ERS/ESTS statement on the management of pleural infection

in adults

Eihab O. Bedawi 1,2,3,4, Sara Ricciardi 5,6, Maged Hassan 7, Michael R. Gooseman8, Rachelle Asciak9,10,
Olalla Castro-Añón 11,12, Karin Armbruster13, Martina Bonifazi14,15, Sarah Poole16, Elinor K. Harris17,
Stefano Elia 18,19, Rafal Krenke 20, Alessandro Mariani 21, Nick A. Maskell 22, Eva Polverino 23,
Jose M. Porcel 24, Lonny Yarmus25, Elizabeth P. Belcher 26, Isabelle Opitz 27 and
Najib M. Rahman 1,2,3,28

1
Oxford Pleural Unit, Oxford Centre for Respiratory Medicine, Oxford University Hospitals NHS Foundation Trust, Oxford, UK. 2Oxford
Respiratory Trials Unit, University of Oxford, Oxford, UK. 3NIHR Oxford Biomedical Research Centre, University of Oxford, Oxford, UK.
4
Department of Infection, Immunity and Cardiovascular Disease, University of Sheffield, Sheffield, UK. 5Unit of Thoracic Surgery, San
Camillo Forlanini Hospital, Rome, Italy. 6PhD Program Alma Mater Studiorum, University of Bologna, Bologna, Italy. 7Chest Diseases
Department, Faculty of Medicine, Alexandria University, Alexandria, Egypt. 8Department of Thoracic Surgery, Hull University Teaching
Hospitals NHS Trust, Hull York Medical School, University of Hull, Hull, UK. 9Department of Respiratory Medicine, Queen Alexandra
Hospital, Portsmouth, UK. 10Department of Respiratory Medicine, Mater Dei Hospital, Msida, Malta. 11Department of Respiratory
Medicine, Lucus Augusti University Hospital, EOXI Lugo, Cervo y Monforte de Lemos, Lugo, Spain. 12C039 Biodiscovery Research Group
HULA-USC, Health Research Institute of Santiago de Compostela (IDIS), Santiago de Compostela, Spain. 13Department of Medicine,
Section of Pulmonary Medicine, Herlev-Gentofte Hospital, University of Copenhagen, Copenhagen, Denmark. 14Department of
Biomedical Sciences and Public Health, Marche Polytechnic University, Ancona, Italy. 15Respiratory Diseases Unit, Azienda
Ospedaliero-Universitaria “Ospedali Riuniti”, Ancona, Italy. 16Department of Pharmacy and Medicines Management, Oxford University
Hospitals NHS Foundation Trust, Oxford, UK. 17Bodleian Health Care Libraries, University of Oxford, Oxford, UK. 18Department of
Medicine and Health Sciences “V. Tiberio”, University of Molise, Campobasso, Italy. 19Thoracic Surgical Oncology Programme,
Policlinico Tor Vergata, Rome, Italy. 20Department of Internal Medicine, Pulmonary Diseases and Allergy, Medical University of Warsaw,
Warsaw, Poland. 21Thoracic Surgery Department, Heart Institute (InCor) do Hospital das Clnicas da Faculdade de Medicina da
Universidade de São Paulo, São Paulo, Brazil. 22Academic Respiratory Unit, University of Bristol, Bristol, UK. 23Pneumology
Department, Hospital Universitari Vall d’Hebron, Institut de Recerca Vall d’Hebron, Barcelona, Spain. 24Pleural Medicine Unit,
Department of Internal Medicine, Arnau de Vilanova University Hospital, IRBLleida, Lleida, Spain. 25Division of Pulmonary and Critical
Care, Johns Hopkins University School of Medicine, Baltimore, MD, USA. 26Department of Thoracic Surgery, Oxford University
Hospitals NHS Foundation Trust, Oxford, UK. 27Department of Thoracic Surgery, University Hospital Zurich, Zurich, Switzerland.
28
Chinese Academy of Medical Health Sciences, University of Oxford, Oxford, UK.

Corresponding author: Eihab O. Bedawi ([email protected])

Shareable abstract (@ERSpublications)

Intrapleural fibrinolytic-based therapy has revolutionised pleural infection management, but
surgical intervention remains vital in select patients. Studies into early and targeted escalation of
treatment based on risk stratification are now required. https://bit.ly/3y6rZ8a

Cite this article as: Bedawi EO, Ricciardi S, Hassan M, et al. ERS/ESTS statement on the management
of pleural infection in adults. Eur Respir J 2023; 61: 2201062 [DOI: 10.1183/13993003.01062-2022].

Abstract
Copyright ©The authors 2023. Pleural infection is a common condition encountered by respiratory physicians and thoracic surgeons alike.
For reproduction rights and The European Respiratory Society (ERS) and European Society of Thoracic Surgeons (ESTS) established a
permissions contact
[email protected]
multidisciplinary collaboration of clinicians with expertise in managing pleural infection with the aim of
producing a comprehensive review of the scientific literature. Six areas of interest were identified:
Received: 14 June 2022 1) epidemiology of pleural infection, 2) optimal antibiotic strategy, 3) diagnostic parameters for chest tube
Accepted: 22 Aug 2022 drainage, 4) status of intrapleural therapies, 5) role of surgery and 6) current place of outcome prediction in
management. The literature revealed that recently updated epidemiological data continue to show an overall
upwards trend in incidence, but there is an urgent need for a more comprehensive characterisation of the
burden of pleural infection in specific populations such as immunocompromised hosts. There is a sparsity
of regular analyses and documentation of microbiological patterns at a local level to inform geographical
variation, and ongoing research efforts are needed to improve antibiotic stewardship. The evidence remains
in favour of a small-bore chest tube optimally placed under image guidance as an appropriate initial

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EUROPEAN RESPIRATORY JOURNAL ERS/ESTS STATEMENT | E.O. BEDAWI ET AL.

intervention for most cases of pleural infection. With a growing body of data suggesting delays to
treatment are key contributors to poor outcomes, this suggests that earlier consideration of combination
intrapleural enzyme therapy (IET) with concurrent surgical consultation should remain a priority. Since
publication of the MIST-2 study, there has been considerable data supporting safety and efficacy of IET,
but further studies are needed to optimise dosing using individualised biomarkers of treatment failure.
Pending further prospective evaluation, the MIST-2 regimen remains the most evidence based. Several
studies have externally validated the RAPID score, but it requires incorporating into prospective
intervention studies prior to adopting into clinical practice.

Introduction
It is estimated that 2.5 million people globally died due to pneumonia in 2019, approximately 250 000 in
Europe [1]. Up to 50% of pneumonia cases develop a pleural effusion, an occurrence which in itself is
associated with a 3–6-fold increase in mortality [2]. While the majority of these “simple” parapneumonic
effusions resolve with antibiotics and optimal medical therapy, approximately 15% progress to bacterial
invasion of the pleural space and become true “pleural infection”, defined as a pleural collection in the
context of infective symptoms with a pH <7.2, or a low glucose (<2.2 mmol·L−1, in the presence of
normal serum blood glucose), a pleural collection that is culture positive or an “empyema” when frank pus
accumulates in the pleural space.

Presentation is often delayed due to a subacute onset, and the reported median hospital length of stay
(LOS) of 14–19 days [3–8] is associated with significant healthcare resource utilisation with the potential
requirement for prolonged antibiotics, chest tube drainage, intrapleural therapy and/or surgery. This
culminates in this condition being linked to the overall highest average cost per case (approximately EUR
21 822 per admission in Europe [4]) among pleural disease and other acute lung conditions. Most
worryingly, patient outcomes have not significantly improved, with average 30-day and 3-month
mortalities at approximately 10% [9, 10] and 1-year mortality at 20% rising up to 35% in the elderly and
immunocompromised [11]. New treatment strategies are urgently needed.

Existing pleural infection guidelines are outdated [12, 13] and there are significant variations in practice
across the world with regard to standard care, use of intrapleural therapy and surgery. Despite the sparsity
of large multicentre randomised controlled trials (RCTs), several important additions to the literature in
recent years have informed our understanding of the underlying pathology, microbiology and advances in
intrapleural treatment. One example is the recent finding that a significant subgroup of patients (up to a
third) present with “primary pleural infection” without radiological evidence of pneumonia [14] and appear
to have a microbial profile similar to the oral cavity, supporting spread to the pleural space via alternative
routes, potentially haematogenously [15, 16]. Innovations in surgery with experience using less invasive
techniques such as video-assisted thoracoscopic surgery (VATS) have made this modality safer and more
accessible in later stage disease and to an older, frailer population.

This statement aims to form a narrative review of the current evidence with regard to adult pleural
infection management. It does not make clinical practice recommendations; however, in specific areas
where the evidence is scarce or mixed, these limitations are described and the practice of the Task Force
members is mentioned for information (as denoted by the italic text), but not with the aim of guiding
clinical practice.

Methods
A Task Force was assembled with the goal of producing a statement that represented a comprehensive,
scientific review of the literature, identified by systematic searches with conclusions supported by
accompanying references. Membership of the Task Force was based on recommendations of the European
Respiratory Society (ERS) Scientific Committee in collaboration with the European Society of Thoracic
Surgeons (ESTS) Board, and included representation from seven European countries, the USA, South
America and North Africa. The Task Force was comprised of nine respiratory physicians (with
subspecialist expertise in pleural disease, respiratory infection and interventional pulmonology), three
thoracic surgeons, a clinical epidemiologist and a clinical pharmacist, with the support of four early career
ERS members and two early career ESTS members.

Prior to the conception of this statement, informal meetings were held with an established pleural infection
Patient Focus Group (led by the Oxford Respiratory Trials Unit (E.O.B. and N.M.R.)) to identify patient
priorities to ensure these were incorporated into the scope of the statement. Specifically, issues such as the
inconvenience of prolonged antibiotics, earlier diagnosis, optimal intervention and inability of clinicians to
provide an individualised prognosis were highlighted.

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The final scope of the statement was agreed at the initial meeting in January 2021, specifically that it
would be limited to adult pleural infection and would not include paediatric pleural infection or
tuberculous pleuritis as it was agreed that these were distinct clinical entities. Six clinically relevant,
patient-centred areas of pleural infection research were chosen by consensus with specific research
questions built around these.

The literature search was undertaken by subgroups allocated to each clinical question with access to an
ERS methodologist and a librarian (E.K.H.). MEDLINE, Embase and Scopus databases were searched
using a combination of appropriate MeSH (Medical Subject Headings) terms and key words. Search results
were limited to the last 15 years (with older studies for reference only). The full search strategy for each
clinical question is shown in supplementary material S8. Once the search had been run, further potentially
eligible articles were identified by reviewing the reference lists of identified papers. The search was
repeated in February 2022 to identify recently published papers.

Abstracts were screened independently for inclusion by subgroup members and were included based on
pre-specified eligibility criteria (supplementary material S8). Any queries or disagreements were resolved
through discussion at Task Force virtual meetings, with final word to the Task Force chairs (E.O.B., I.O.
and N.M.R.).

Subgroups prepared drafts summarising the relevant literature for their clinical question, which underwent
review by the full Task Force before being revised and submitted to the chairs. The Task Force chairs
collated the drafts into a complete statement and the final draft was approved by all members prior to
submission to the ERS and ESTS, and hence represents a statement of the entire Task Force. Future
research recommendations reflecting some of the gaps in the literature from each focus area have been
summarised in supplementary material S7.

Results
Question 1: What is the current burden of pleural infection?
Despite a lack of reliable characterisation of trends globally, recent epidemiological data [3–5] have
demonstrated trends in rising incidence similar to those observed at the turn of the last decade (figure 1.1 and
table 1.1) Summary of epidemiological studies of pleural infection [17–20]. In England, there was an increase
from 6.44 to 8.38 per 100 000 hospital admissions between 2008 and 2017 [3]. In France, BOBBIO et al. [4]
observed a similar incidence, increasing from 7.15 to 7.75 per 100 000 in the short period between 2013 and
2017. In the USA, MUMMADI et al. [5] reported a 37.5% relative increase in pleural infection-related
hospitalisation between 2007 and 2016. This represents a worrying upwards trend compared to the increase
from 3.04 to 5.98 cases per 100 000 between 1996 and 2008 reported by GRIJALVA et al. [18] in the USA in
2011 or the 36% relative increase in Denmark between 1997 and 2011 [9].

12 11.8
11.1

10
per 100 000 adult population

9.6
8.7
Hospitalisation rate

8.4 8.4
8 8.1
7.6 7.75
7.2 7.15
6.4
6 6.0 5.98
5.2 5.4
5.0
4 4.1

3.04
2

0
1987
1988
1989
1990
1991
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1995
1996
1997
1998
1999
2000
2001
2002
2003
2004
2005
2006
2007
2008
2009
2010
2011
2012
2013
2014
2015
2016
2017

Year
France [4] UK [3] Denmark [9] USA [5]
USA [20] USA [18] USA [19] Taiwan [10]

FIGURE 1.1 Trends in incidence of pleural infection in different countries from the world literature.

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TABLE 1.1 Summary of epidemiological studies of pleural infection

First author [ref.], Country Years Population, n Age, years Male, % Mortality, % Hospital length of stay,
year days

BOBBIO [4], 2021 France 2013–2017 25 512 62.4±15.6 71.7 17.1 19 (IQR 11–35)
ARNOLD [3], 2021 UK 2008–2018 51 057 64 (IQR 51–75) 68.5 In-hospital: 14.9 15 (IQR 6–28)
SØGAARD [9], 2014 Denmark 1997–2011 6878 Nonaggregated data 65.8 30-day: 10.5 in 1997 22 (IQR 12–43) in 1997
versus 9 in 2011 versus
17 (IQR 10–28) in 2011
MUMMADI [5], 2021 USA 2007–2016 2735 Nonaggregated data 68.0 In-hospital: 7.1 13.8 (95% CI 13.3–14.2)
GUPTA [20], 2021 USA 2005–2014 150 496 58.3±0.1 67.9 In-hospital: 4.4; 12.3±0.1
2.6 in 2014
GRIJALVA [18], 2011 USA 1996–2008 157 094 48.4 (95% CI 47.4–49.4) 64.2 In-hospital: 7.2 15.2
(26 125 ⩽18 years (>16.1
old) in ⩾65 years old)
FARJAH [19], 2007 USA 1987–2004 4424 57.0±18.6 66.8 30-day: 10.8 14.1±11.8
FINLEY [17], 2008 Canada 1995–2003 11 294 <1– >90 69 ND 21.8±33.9
(children included)
SHEN [10], 2012 Taiwan 1997–2008 26 385 60 (45–72) in 1997/8 76.6 In-hospital: 21 (13–34) in 1997/8
versus 17.6 (1997/8) versus
65 (49–77) in 2007/8 versus 16.0 (2007/8) 19 (12–31) in 2007/8
IQR: interquartile range; ND: no data.

These rising trends are likely the result of variable interplay between an ageing population living longer
with chronic comorbidities (such as the increased prevalence of diabetes mellitus [8, 21]) acting as risk
factors, the increased prescribing of immunosuppressive agents, the natural evolution of bacterial pathogens,
as well as improved access to sensitive imaging (computed tomography (CT) and bedside ultrasound).

Age and gender distribution

Similar to previous reports [19], the increases were highest among those aged >60 years with almost a
doubling across the decade studied (2008–2017) [3]. However, it is important to note that at least 40% of
adult pleural infection hospitalisations in the UK and Europe are still represented in the 18–64 years age
group, rising to 60% in the USA [3–5]. The marked male predominance remains consistent at
approximately 2.3:1 (70%) [3–6, 19, 22]. Interestingly, this appears to begin after adolescence (equal gender
distribution in children), rises gradually and peaks in the >60 years age group. The reasons for this are not
fully understood but plausible hypotheses include gender differences in health-seeking behaviours (delayed
presentation in males), worse dental hygiene trends and male predominance of pre-existing comorbidities.

Comorbidities
A recent systematic review reporting data from over 225 000 patients found that the prevalence of
pre-existing comorbidity in pleural infection is high (up to 72%) [8, 23], with chronic respiratory and
cardiovascular conditions having the highest contribution (table 1.2) Prevalence of pre-existing
comorbidities in patients with pleural empyema. The French national database study found a median
Charlson Comorbidity Index (CCI) of 5 in patients with pleural infection (compared with a CCI of 3 in
those without cancer or recent surgery) [4].

Independent of other risk factors, patients with diabetes mellitus were twice as likely to develop pleural
infection and within pleural infection cohorts, the prevalence of diabetes mellitus was 5 times higher than
the general population [21]. Malnutrition and alcohol abuse are also important risk factors [24], stressing
the significance of dietary supplementation during therapy. Concurrent malignancy rates as high as 30%
have been reported [4] (average 12–13% [8, 25]), emphasising the importance of avoiding diagnostic
anchoring, particularly during a protracted clinical course.

While a decreased risk of pleural infection in COPD has been hypothesised to be related to the use of
inhaled corticosteroids, resulting in a dampened pleural inflammatory response [24, 26], other studies have
reported conflicting findings [27]. It is plausible that hyperexpanded lungs and a higher intrinsic pressure
results in smaller effusions. It is noteworthy that patients with COPD often have other comorbidities that
increase their risk of developing pleural infection. A recent nationwide cohort study in Taiwan with

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TABLE 1.2 Prevalence of pre-existing comorbidities in patients with pleural empyema

Pre-existing comorbidities Prevalence, % (interquartile range)

Any comorbidity 72 (58–83)

Specific disease
Hypertension 23 (17–38)
Diabetes 17 (11–27)
Stroke 13 (5–20)
Ischaemic heart disease 11 (5–16)
COPD 11 (6–20)
Chronic kidney disease 7 (5–13)
Adapted with permission from CARGILL et al. [8].

propensity-matched controls found schizophrenia to be a risk factor for developing pleural infection [28],
although a relationship between mental health illness and increased risk of infections generally has been
reported and is complex [29, 30].

Immunosuppressive states acquired through diseases such as HIV infection or iatrogenically induced by
treatments (steroids, immunomodulatory and chemotherapeutic agents) have been reported to be associated
with pleural infection [31, 32], but data on these are poorly collected in recent epidemiological studies [8].
Future studies should focus on routine collection of these data to allow a better understanding of the course
and outcomes of pleural infection in these specific groups where the microbiology and immune response
are likely to differ from immunocompetent states.

Coronavirus disease 2019, seasonal variation and the role of viruses

With reference to the coronavirus disease 2019 (COVID-19) pandemic, a recent meta-analysis found that
approximately 10% of patients developed pleural effusions [33]. Although the severe acute respiratory
syndrome coronavirus 2 virus has been isolated in pleural fluid [34], in most cases effusions are expression
of comorbidities such as heart failure, and have been shown to be associated with increased risk of
COVID-19 severity and mortality. To date there is no convincing evidence of “viral empyema” as a direct
complication of severe COVID-19 pneumonia.

Viruses are rarely considered as a potential aetiological factor of pleural infection. A spike in cases of
secondary bacterial pneumonia with empyema was well documented following the 1918 Spanish influenza
epidemic and more recently in Utah in the USA following the 2009 influenza A pandemic [35]. The
potential role of viruses in the epidemiology of pleural infection was recently explored by ARNOLD et al.
[3]. Overall, pleural infection diagnoses increased by 25% in the winter months and in nine of the 10 years
studied, the highest annual point incidence of influenza coincided with the highest admission rate for
empyema (with a 2-week lag), with an approximately 1.8 times increase in admissions noted. These data
suggest that there may be a seasonal variation in pleural infection incidence and a temporal association
with influenza. However, a direct causative role of viruses in the pathogenesis of pleural infections has yet
to be clearly established and we conclude that shared risk factors for both diseases may, at least in part,
explain their concomitant onset.

Question 2: In adults with pleural infection, what is the optimal antibiotic strategy?
Extensive and inappropriate use of antibiotics has been associated with increased mortality and duration of
hospitalisation [36], resulting in the emergence of antibiotic-resistant pathogens, a severe public health
threat [37]. Focused and narrower spectrum antibiotics are difficult to achieve in pleural infection due to
the poor yield of pleural fluid cultures using the current “gold standard” (culture-based pathogen detection
methods). In a recent systematic review of over 10 000 patients, the yield from standard culture was only
56% [38]. This is likely due to a combination of prior receipt of antimicrobials, low bacterial concentration
in pleural fluid and nutritionally fastidious microorganisms that are difficult to isolate due to stringent
requirements [39, 40].

An overview of the bacteriology and methods of optimising the microbiological yield in pleural infection
are presented in supplementary material S2.

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Antibiotics and the pleura

In pharmacokinetic studies the penetration of antibiotics into the pleura is expressed by calculating the ratio
between the area under the curve (AUC) for the concentration of a given antibiotic in the pleural fluid to
that in the serum (AUCPF/S) [41]. In a rabbit model of empyema, penicillin had the highest AUCPF/S (2.31)
followed by metronidazole (0.98), ceftriaxone and clindamycin. Gentamicin had the lowest AUCPF/S in
this study [41]; therefore, due to low pleural penetration and the tendency of aminoglycosides to be
inactivated in the acidic medium of the infected pleural space [42], this group is not recommended for
managing pleural infections [12].

In a study of humans with parapneumonic effusions, ceftriaxone concentration remained above the
minimum inhibitory concentration for most susceptible organisms for 53 h after a single parenteral dose
[43]. In patients with methicillin-resistant Staphylococcus aureus (MRSA) mediastinitis receiving linezolid,
the drug had an AUCPF/S of 1.64 [44], suggesting it is likely to be a suitable option in resistant pleural
infection. One study evaluating the pharmacokinetics of carbapenems in pleural fluid demonstrated the
most favourable results for the use of meropenem [45]. In both rabbit [46] and human [47] studies,
moxifloxacin has also demonstrated favourable pleural penetration as an oral treatment option [46].

In patients with fungal pleural infection, nonliposomal formulations of antifungal therapy are preferred to
liposomal formulations due to their superior pleural penetration [48, 49].

Antibiotic regimens for pleural infection

The initial antibiotic regimen for pleural infection is almost always empirical because of the importance of
prompt initiation of antimicrobial therapy. In usual practice, complete microbiological workup is carried
out at the earliest opportunity to ensure the treatment is appropriate and to allow narrowing of the spectrum
once the culture results and antibiogram become available. It is noteworthy that even in situations where an
anaerobic organism is not identified on microbiological tests, it is still recommended to continue anaerobic
coverage given the difficulty in culturing these organisms that commonly infect the pleural space [50].

The choice of regimen is usually based on whether the infection is community or hospital acquired,
together with the local prevalence of microorganisms and antibiotic resistance patterns [12]. Individual
factors to be taken in consideration include age, comorbidities, previous hospitalisation and/or antibiotic
treatments. Pleural infection by antibiotic-resistant pathogens is relatively common and, in one study, 37%
of isolates in community-acquired infections and 77% of isolates in hospital-acquired infections were
resistant to at least one of the antibiotics commonly prescribed for respiratory infections [51].

An example antibiotic protocol is presented in supplementary material S3.

Difficult to treat infections/special situations

Factors associated with bacterial resistance include the presence of chronic kidney disease, diabetes
mellitus, malignancy and recent antibiotic therapy [52]. In a systematic review of 134 studies of unselected
cohorts of adults with pleural infection, the incidence of immune compromising conditions was relatively
low, with median prevalence of diabetes mellitus 17%, malignancy 12%, chronic kidney disease 7%,
long-term steroid use 4% and chemotherapy 4% [8]. However, patients with immune compromise
( particularly with HIV disease) are at increased risk of developing parapneumonic effusions as a
complication of pneumonia [53] and are prone to infections by unusual organisms. For example, patients
with HIV have been reported to suffer from pleural infections by organisms such as Pneumocystis jirovecii
[54], Nocardia spp. [55] and Toxoplasma gondii [56].

Fungal aetiology of pleural infection is uncommon, with an incidence ranging between 1.75% in
community-acquired infections and 2.68% in hospital-acquired infections [11, 52, 57–60]. In up to 40% of
instances where a fungus is isolated from pleural fluid, it represents contamination rather than true
infection [61, 62]. However, in 708 pleural fluid positive cultures from patients with cancer, 18% grew
fungi [63]; hence, this is not an insignificant clinical issue.

The most common species are Candida spp. followed by Aspergillus spp. [61, 63]. In series of patients
with fungal empyema, 60–79% had immune compromising conditions [61, 64]. Other risk factors for
fungal empyema include recent thoracic or abdominal invasive procedures [63, 64]. Besides the challenges
with treating these infections that require long courses of toxic antimicrobials, the 6-week mortality of
fungal empyema in patients with cancer was as high as 34% [63]. Some infections that are endemic in
certain geographic areas (e.g. parasitic infections [65] and melioidosis [66]) can cause pleural infections

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that are challenging to diagnose or treat, but detailed description of these conditions is outside the scope of
this document.

The evidence from tuberculosis and recurrent bacterial pneumonia can be extrapolated, and HIV
screening is routinely performed in pleural infection. In current practice, pleural fluid fungal cultures are
used in patients with known malignancy and immunocompromising conditions.

Antibiotic duration and strategy

The duration of antibiotic treatment in pleural infection has not been specifically assessed in adequately
powered RCTs. The complexity is due to a heterogeneity of factors potentially influencing a favourable
outcome, including drug penetration into the pleural space, host immune response, infection setting and
microbial sensitivity to antibiotics. Treatment strategies are generally extrapolated from lung abscess, with
a general consensus of at least 3 weeks, based on clinical, biochemical and radiological response [12, 67].

One recent study, the ODAPE trial, was a noninferiority double-blind RCT assessing a 2-week versus
3-week antibiotic strategy [68]. The study was underpowered as it had to terminate early due to
under-recruitment but showed excellent success rates in the small group (n=25) treated with a 2-week course,
provided successful drainage and clinical stability had been achieved. These preliminary data are encouraging
and set the scene for further large prospective studies specifically targeting a pleural infection population.

An initial intravenous course of antibiotics of 5–7 days is usually administered to dampen the initial
systemic inflammatory response and while no studies have specifically addressed this in pleural infection,
extending the initial intravenous component would not appear to confer additional benefit extrapolating
from evidence in other deep-seated infections [69, 70].

Patients who have been surgically treated for pleural infection may require shorter post-operative courses
but antibiotic resistance remains an important consideration [51]. Even within this cohort specifically,
some potentially multidrug-resistant pathogens such as Enterobacteriaceae or MRSA have been associated
with increased risk of mortality and prolonged LOS [71]. Conversely, some pleural infection
microorganisms such as Streptococcus pneumoniae do not tend to partake in pleural “co-infection”;
therefore, where these are isolated, they are likely to be the dominant pathogen and it may be reasonable to
narrow the antibiotic spectrum, e.g. by stopping metronidazole, potentially also improving tolerance and
compliance. In practice, longer antibiotic courses are used for nosocomial infections or infections
occurring post-surgical interventions, although we would emphasise that there are specific situations, such
as a post-pneumonectomy infected space, where the data suggest that these should not be treated as
standard empyema and where earlier thoracic surgery intervention may be required [72, 73].

Monitoring treatment response

The American Thoracic Society/Infectious Diseases Society of America 2007 criteria for clinical stability
of community-acquired pneumonia have demonstrated good performance in guiding clinical decision
making around switching to oral therapy, discharge or re-evaluation of patients at risk of treatment failure
[74]. A substantial proportion of pleural infections are parapneumonic in aetiology; hence these criteria,
despite not being specifically validated for pleural infection, can be extrapolated from pneumonia. It is
important to note that many cases of pleural infection present subacutely without “sepsis” features and in
up to a third, without evidence of parenchymal infection [14]. In such cases, assessing treatment response
can be more complicated, placing greater weight on radiological assessment of pleural drainage and
biochemical response.

Based on the evidence to date, C-reactive protein (CRP) appears to be sufficient as a biochemical marker
of treatment response, particularly due to its low cost and availability [75]. The use of procalcitonin (PCT)
in monitoring treatment response has been addressed in a small comparative surgical study (n=22) to
evaluate the post-operative course in pleural infection [76] and in another small single-centre medical study
(n=53), both demonstrating favourable performance compared to CRP [77]. However, further prospective
trials with larger study groups are required to clarify a role for PCT in monitoring pleural infection
progress. Although radiological improvement is often considered to evaluate response to treatment,
complete resolution of pleural abnormalities on imaging (chest radiography/CT) is often delayed compared
to clinical response.

In current practice, inpatient treatment and early response are guided predominantly by clinical and
biochemical parameters with suggested follow-up time-points at 2–4 weeks to detect early treatment failure
and 8–12 weeks to ensure complete resolution of the radiology.

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Question 3: In adults with pleural infection, what are the optimal diagnostic parameters predicting
need for chest tube drainage?
Can we refine the diagnostic approach to pleural infection?
Pleural fluid analysis is vital to achieving the correct diagnosis and guiding the appropriate subsequent
intervention. In the presence of a clinical history or biochemical picture compatible with infection, current
guidelines [12, 13] recommend using a pleural fluid pH <7.2 (or in the absence of pH, a combination of
glucose concentration <40 mg·dL−1 (2.2 mmol·L−1) with lactate dehydrogenase (LDH) >1000 IU·L−1)
[78] as the most important predictors of chest tube drainage. The same groups agree that the presence of
pus and/or microorganisms on Gram stain or culture should necessitate chest tube drainage [12, 13].

Several factors can affect both biochemical and cytological features of pleural fluid. The residual syringe
volume of lidocaine or heparin can falsely lower the pH, while the presence of air in the syringe or pleural
fluid protease-producing organisms can lead to a false elevation in pH [79]. While most cytological
examinations of pleural infection fluid will show “acute inflammation” with neutrophilic predominance, it
should be noted that early antibiotic administration can convert pleural fluid characteristics into a
lymphocyte predominant picture [80].

A binary “pH” biomarker in a condition that represents a progression along a spectrum lends itself to
flaws. To this end, other markers have been assessed in terms of their ability to discriminate a complicated
parapneumonic pleural effusion (CPPE) requiring urgent tube drainage from an uncomplicated (simple)
parapneumonic pleural effusion (UPPE) often responding to antimicrobial treatment alone.

Serum CRP (sCRP) >200 mg·L−1 had low sensitivity (58%) and specificity (81%); however, the
combination of sCRP with pleural fluid analysis increased the diagnostic yield, resulting in a specificity as
high as 98% for sCRP >200 mg·L−1 and pleural fluid glucose <60 mg·dL−1 (<3.3 mmol·L−1) [81]. A
recent narrative review of serum PCT (sPCT) in pleural infection found sPCT sensitivity and specificity for
diagnosing pleural infection ranged from 69% to 83% and from 80% to 94%, respectively. The Task Force
members concluded that the current evidence does not support the routine use of serum PCT for the
diagnosis or as a predicting factor for drainage in pleural infection [82].

With regard to additional pleural fluid testing, pleural fluid CRP level >100 mg·L−1 was found to have the
same performance characteristics (AUC 0.81) in differentiation between a CPPE and UPPE as the widely
accepted biochemical parameters, including pH and glucose [83]. Combinations of pleural fluid CRP with
pH or glucose resulted in a further increase in discriminative value, with 75–80% sensitivity and 97%
specificity for CPPEs. Pleural fluid PCT has not been shown to have a significant diagnostic role in
differentiation between infectious versus noninfectious pleural effusion and to date, there have been no
studies on the role of pleural fluid PCT in discrimination between CPPE and UPPE [82].

Based on the evidence, in a clinical context suggestive of infection, the authors would perform urgent
pleural fluid sampling of a unilateral effusion to confirm/exclude a diagnosis of pleural infection. Pleural
fluid pH remains the most accurate predictor for chest tube drainage. The current evidence does not show
utility for the routine use of sPCT.

Imaging
Pleural ultrasound is a widely available and easy-to-use diagnostic method. Important features include the
presence of echogenic swirling (often signifying strong exudate or pus) and fibrin strands seen as
septations or fully enclosed loculations [84]. Robust prospective comparative studies were not identified in
the literature, but a recent study comparing chest radiography, CT and ultrasound appeared to demonstrate
the latter to outperform the discriminative yield of CT in ruling in CPPE. Ultrasound had a sensitivity and
specificity of 69.2% and 90%, respectively, compared to chest CT sensitivity of 76.9% and specificity of
65% [85]. The positive likelihood ratio of ultrasound to diagnose CPPE was significantly higher than those
for CT and chest radiography (6.92, 2.20 and 1.54, respectively; p<0.05) [85]. It should be noted that the
presence of septations should warn about possible differences in pH between different fluid locules which
may affect management decisions.

The classic CT signs regarded to be typical for CPPE/empyema include thickening and enhancement of
the parietal pleura, increase in the thickness and attenuation of the adjacent extrapleural fat, and
enhancement of both the visceral and parietal pleura (“split pleura” sign), presence of multiple bubbles in
the effusion (signifying anaerobic “gas-producing” bacteria), and pleural septations. These signs have good
sensitivity, but low specificity [86]. A CT scoring model designed to distinguish CPPE and UPPE was
generated and validated in a retrospective series, with a sum score of ⩾4 yielding 84% sensitivity, 75%

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specificity, 81% diagnostic accuracy and AUC 0.83 for labelling CPPE [87]. An easier method to
differentiate between CPPE and UPPE based on the presence of the “split pleura” sign combined with a
distance between both pleural layers (occupied by pleural fluid) ⩾30 mm has been proposed and was
characterised by a reasonable diagnostic accuracy (AUC 0.80) [88].

To date, the literature does not define a role for magnetic resonance imaging (MRI) in adult pleural
infection, although its role as a radiation-free noninvasive imaging modality is being explored in paediatric
pleural infection, where further cross-sectional imaging is specifically required [89, 90]. Of note, most of
the aforementioned CT features have MRI correlates, such as the increased extrapleural fat attenuation
which may be seen as increased signal on fat-suppressed T2-weighted images. Infectious pleural effusions
have a typical fluid appearance of low signal on T1-weighted and high signal on T2-weighted images.
MRI outperforms CT in visualisation of septations [91].

The authors conclude that ultrasound is adequate for initial assessment, clinical decision making and
guiding diagnostic sampling. Based on the current evidence, the Task Force members would adopt a
lower threshold for pleural drainage in the presence of septations, echogenicity and larger pleural
collections. In current practice, where pleural sepsis persists beyond the initial 48 h of drainage,
evaluation with a contrast-enhanced CT scan (in the venous “pleural” phase) can be helpful in revealing
malpositioned chest tubes, lung abscesses, adjacent subdiaphragmatic abscesses and bronchopleural
fistulas.

Distinguishing pleural infection from an inflammatory malignant pleural effusion

Pleural infection in patients with malignant pleural effusion (MPE) is of particular importance since a
significant proportion of these patients are immunocompromised (due to malignant disease, chemo- and/or
radiation therapy) and are exposed to repeated pleural interventions. The diagnosis of pleural infection in
MPE patients may be challenging due to the nonspecific results of pleural fluid analysis (e.g. low pH and
low glucose can be attributed to both pleural malignancy and pleural infection). Data on pleural infection
superimposed on MPE are scarce and somewhat ambiguous, largely due to the low yield of pleural fluid
culture, the pre-test probability of pleural infection at the time of sampling patients with MPE and the size
of the effect of iterative thoracenteses in increasing the risk of pleural infection [92].

The inflammation associated with MPE can raise commonly used biomarkers including LDH, CRP and
adenosine deaminase, but to date, no biomarker has been studied for the specific application of diagnosing
infected MPE. In one study, PCT was found to be a relatively specific marker distinguishing between
pleural infection and noninfective pleural effusions matched for systemic inflammation as measured by
CRP. In contrast to CRP, PCT remained stable even in the presence of intense noninfective inflammation
caused by talc pleurodesis [93].

Diagnosis of pleural infection in patients with MPE can be complex. In practice, a lower threshold for
antimicrobial initiation is used followed by close observation. In this specific scenario, the authors feel
sPCT may have some utility but acknowledge that this is based on a low level of evidence.

Chest tube size

“Small-bore” chest drains are usually defined as <14 F [94, 95] or <16 F [96], albeit the definition varies
across studies and is therefore somewhat equivocal. In this document, small-bore drains are defined as
⩽14 F and large-bore chest drains are defined as ⩾18 F. Traditionally, large-bore chest drains have been
used to drain pus or viscous fluid. A retrospective analysis of the MIST-1 RCT (n=405) [22] is the only
direct comparison study of chest tube size in pleural infection [97]. Patients treated with a range of chest
drain sizes (from <10 F to >20 F) showed no difference in primary and secondary outcomes (death, need
for thoracic surgery, LOS, chest radiograph appearance and lung function at 3 months) according to chest
drain size. Moreover, large-bore chest drains were associated with more pain [97]. These data therefore
show that small-bore chest drains are sufficient as a first-line intervention for pleural infection. There is
concern that smaller bore chest drains tend to become occluded with fibrin or pus. In the MIST-1 trial
[22], chest tube patency was maintained with 3-times-daily 30 mL saline flushes. One retrospective study
reported that only one out of 58 drains flushed with 20 mL sterile saline every 6 h became blocked (versus
six out of 19 nonflushed drains) [94]. Care is usually taken to ensure that all the fenestrations on the chest
drain are located intrapleurally to work effectively and minimise the risk of infected fluid leakage into
subcutaneous tissue.

There is sufficient evidence that 12–14 F chest tubes are efficient as a first-line intervention in pleural
infection, with regular saline flushes. In their practice, the Task Force members prioritise correct

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placement using radiological guidance (ultrasound or CT) targeting the largest locule where these are
present with securement/fixation sutures and bespoke dressings. Chest drains <12 F are usually avoided to
minimise risk of blockage and dislodgement.

Do all cases need draining? The evidence for a conservative approach and alternative/less invasive
strategies
Small parapneumonic effusions that are <5 cm on an erect lateral chest radiograph [98] or <2.5 cm on CT
scan [99] can be managed without thoracentesis, although where diagnostic sampling is feasible this may
be helpful to confirm diagnosis and microbiology. A recent retrospective study confirmed that some
patients with small pleural collections can be managed successfully with antibiotics alone with a slightly
higher but statistically insignificant infection-related mortality rate [100]. This suggests that for very small
or difficult to access pleural infection collections, it may be possible in selected patients to treat with
antibiotics treatment alone without drainage of fluid, although we recommend caution with regular review.

Ambulatory management/iterative thoracenteses

In some centres, iterative or repeated therapeutic thoracenteses are used as standard first-line treatment
[100]. Four case series of patients with CPPE or empyema who underwent iterative thoracocenteses were
summatively analysed (n=250) [101–104] in a review of minimally invasive management of pleural
infection and a 76% successful treatment rate was reported with repeated thoracocentesis [105]. The
advantages proposed by advocates of this technique are that the patients are more mobile than they would
be with a chest drain in situ, different locules may be targeted at each aspiration procedure, and that there
is a possibility of outpatient management reducing LOS and cost [103]. One recently published
retrospective comparative study of two successive cohorts of patients with CPPE or pleural empyema in
whom repeated thoracentesis with intrapleural urokinase (n=52) versus intrapleural urokinase plus DNase
(n=81) was applied as the first-line treatment showed a failure rate of 17% and 19%, respectively [106]. It
would seem a reasonable option for lower risk patients without evidence of systemic sepsis and small/
moderate volume effusions; however, to date, there is no RCT data to support this as a first-line option and
it is currently not recommended by any guidelines [12, 13]. Importantly, the associated healthcare resource
utilisation and the potential increased risk of repeated procedure-related complications have not been
adequately studied.

Indwelling pleural catheters and pleural infection

In the context of pleural infection, indwelling pleural catheters (IPCs) are relevant in two ways:
1) catheter-related pleural infection as a complication of IPC insertion and 2) IPCs as a therapeutic option
for the outpatient management of chronic pleural infection, especially with trapped lung.

In a recent modified Delphi consensus statement on the management of IPCs, two types of infectious
complications were defined: local IPC-related infections (including catheter-associated cellulitis, exit site
infection and tunnel tract infection) and IPC-related pleural space infection [107, 108].

In a large multicentre retrospective review of 1021 patients treated with IPC, pleural space infections
specifically developed in 50 (4.9%) patients with an overall mortality risk of 0.3% [109], significantly
lower than standard pleural infection. In another large multicentre series (n=1318), WILSHIRE et al. [110]
recently found a similar infection rate (6–7%) but importantly also showed that the risk of IPC-related
infection did not appear to be increased by antineoplastic therapy use or an immunocompromised state. In
multivariable competing risk analyses they found longer IPC in situ duration to be associated with a higher
risk of infection [110].

IPC-related infections generally tend to occur around 6 weeks post-insertion [109, 110], which goes against
them being directly procedure related; however, studies investigating the mechanisms leading to pleural
space infections in this group are lacking [111]. They are most frequently reported in association with
S. aureus organisms followed by Pseudomonas aeruginosa; however, to date, there are no studies
specifically evaluating the bacteriology and significance of bacterial colonisation in this cohort [8].

Most patients can be successfully treated with oral antibiotics (3–4 weeks) and attaching the catheter to an
underwater seal drainage bottle for continuous drainage, without the need for IPC removal or replacement
[107, 109]. Although this condition rarely requires surgical intervention [112], early discussion with
thoracic surgical teams is usually conducted if the patient is receiving systemic chemotherapy. An
additional chest drain and surgical intervention is sometimes considered, especially if there is evidence of
undrained collections contributing to systemic sepsis [54]. Longer antibiotic courses are frequently required

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and intrapleural enzyme therapy (IET) via the IPC is another therapeutic option for patients who are not
surgical candidates [107, 108].

Recurrent or chronic pleural infection creates difficult management issues, especially in those with trapped
lung and where there is no surgical option. Small studies and case series have shown IPCs to be a
potentially useful treatment strategy for achieving longer term sepsis control in those candidates who are
not fit for surgery or those who decline surgery [113, 114].

Question 4: In adults with pleural infection, what is the role of intrapleural therapy?
Is there a role for fibrinolytic monotherapy?
Prior to 2011, there was no alternative to fibrinolytic monotherapy as medical treatment for nondraining
empyema. The MIST-1 study, to date the largest multicentre RCT in pleural infection, showed that
streptokinase resulted in no improvement in outcomes for patients who fail standard care [22]. Looking at
other trials of monotherapy, a recent prospective RCT by ALEMÁN et al. [115] comparing tissue
plasminogen activator (tPA; alteplase) versus urokinase found no difference in the mortality rate, surgical
referral rate or a composite of both.

In 2019, a Cochrane review of RCTs of fibrinolytic monotherapy concluded that monotherapy may be
associated with a reduction in the requirement for surgical intervention and overall treatment failure, but
importantly there was considerable heterogeneity between the studies reviewed and only MIST-1 had an
overall low risk of bias [116]. The meta-analysis confirmed no evidence of change in mortality compared
with placebo (OR 1.24 (95% CI 0.74–2.07)).

There is no evidence-based role for fibrinolytic or DNase monotherapy in adult pleural infection.

Effect of fibrinolytics on clinical outcomes?

The landmark MIST-2 RCT demonstrated that the combination of tPA with DNase (henceforth referred to
as IET) led to improvements in radiographic clearance ( primary outcome) and statistically significant
reductions in surgical referral (77%) and LOS (6.7 days) compared to placebo (secondary outcome) [6].

We examined 10 studies following MIST-2 (between 2011 and 2020) that also evaluated the role of IET
on surgery and LOS (table 4.1). We could not identify other directly comparative RCTs of IET versus
placebo, but the two largest series by POPOWICZ et al. [117] and PICCOLO et al. [118] reported a requirement
for surgical intervention of, respectively, 7.7% and 4.9% with combination therapy, in contrast to 15% of
patients from the placebo groups in the MIST-1 and MIST-2 trials. No studies to date have shown a
mortality benefit.

What is the optimal IET strategy?

In the MIST-2 study, patients were randomly assigned to IET (or one of the other arms) immediately after
chest tube insertion. The relatively small number of patients in the IET arm of MIST-2 meant that aspects
such as safety and adverse events were not adequately evaluated; hence, overall, IET was not justified in
being immediately incorporated into “standard care” for all patients based on MIST-2 data alone. However,
since then multiple noncomparative studies have confirmed IET to be safe and effective (supplementary
material S4).

Based on the placebo controlled randomised study and subsequent case series, IET is considered by most
Task Force members as “rescue” therapy, i.e. after failing to respond to a period of initial antibiotics and
chest tube drainage, as judged by clinical (ongoing fever and tachycardia), biochemical (failure of CRP to
fall by >50%) and radiological ( persistent effusion on chest radiography or ultrasound) parameters.

There is good evidence that treatment delays are associated with worse outcomes. On this basis, most Task
Force members would initiate IET within 48 h of standard care (chest tube drainage and antibiotics), as a
potentially surgery-sparing modality if there is ongoing evidence of treatment failure. In the absence of
head-to-head superiority data, a surgical referral is usually considered in parallel to IET commencement

IET dosing and schedule

In most studies of IET (table 4.2), the dosing that has been used is tPA 10 mg and DNase 5 mg, based on
the MIST-2 trial. It should be noted that this was chosen empirically by the MIST-2 investigators and was
not the result of dose-finding studies. Lower dosing regimens of tPA (5 and 2.5 mg) have been investigated
in small observational series (without comparator data) with similar safety and efficacy [117, 119],

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TABLE 4.1 Effects of intrapleural enzyme therapy on surgery and hospital length of stay (LOS)

First author Country Study type Population, Dosage Surgery, n/N (%) Cause of surgical referral Comments LOS, days
[ref.], n/N or n or n (%)
year

RAHMAN [6], UK RCT 48/210 10 mg tPA; 2/48 (4.2) versus Clinical evidence of worsening Surgical referral at 3 months in 11.8±9.4 (mean±SD)
2011 5 mg DNase placebo 8/51 (16.0) infection tPA/DNase group lower than in
placebo group; 6.7 days
reduction in LOS observed
PICCOLO Australia, UK Prospective 107 10 mg tPA; 8 (7.7) Failure to respond to treatment Median time from first 10 (IQR 6–17) from
[118], and New observational 5 mg DNase with persistent clinical and fibrinolytic dose to surgery 3 first intrapleural
2014 Zealand laboratory evidence of active (IQR 3–4.75) days treatment
infection
POPOWICZ Australia, UK Prospective 61 5 mg tPA; 3 (4.9) Persistent infection in two One underwent VATS, another a 7 (IQR 5–10)
[117], and New observational 5 mg DNase patients; an open decortication mini-thoracotomy and the third
2017 Zealand of thick residual visceral pleural the thoracotomy
rind and resultant trapped lung
BÉDAT [199], Switzerland Prospective 41/93 10 mg tPA; 4 (10) Absence of clinical response to Multiple pleural collections and 18 (IQR 11–32)
2019 observational 5 mg DNase initial fibrinolysis large-bore drain could predict
need for additional chest tube or
surgery
KHEIR [123], USA and Prospective 38 10 mg tPA; 4 (22) for sequential; Sequential: two persistently Surgery performed after median 13 (IQR 10–15) for
2018 Chile observational (20 sequential; 5 mg DNase 5 (25) for concurrent loculated effusion, one 1.5 days (IQR 1–5) following last sequential versus
18 concurrent) (concurrent persistent sepsis and one lung dose and after 3 days (IQR 12 (IQR 5–16) for
versus entrapment; concurrent: two no 1.5–3.5) in sequential and concurrent
sequential) clinical improvement; three concurrent groups
persistent loculation
JIANG [200], USA Retrospective 56 10 mg tPA; 2 (3.6) Treatment failure; VATS carried Two patients with refractory 15 (IQR 11–28)
2020 5 mg DNase out with success septic shock considered not
(concurrent) candidates for VATS
KHEMASUWAN USA Retrospective 84 10 mg tPA; 27 (32.1) Worsening sepsis regardless of No 9 (IQR 6–12), from
[196], 5 mg DNase radiographic abnormality in six; drain insertion
2018 (concurrent) ongoing infection and worsening
follow-up chest CT scan in 19;
haemothorax in two

ERS/ESTS STATEMENT | E.O. BEDAWI ET AL.

MAJID [124], USA, UK and Retrospective 73 10 mg tPA; 7 (9.6) No radiographic response No 7 (IQR 5–11)
2016 Chile 5 mg DNase
(concurrent)
MCCLUNE USA Retrospective 101 10 mg tPA; 3 (15) versus 13 (16) ND No 17 (IQR 9–25)
[122], 5 mg DNase versus
2016 (6 doses 13 (IQR 9–19)
(>6 days versus
standard use#))
MEHTA [121], USA Retrospective 55 10 mg tPA; 4 (7.3) Persistent fluid collection and/or One of the four patients who 13 (IQR 11–18)
2016 5 mg DNase treatment failure with persistent underwent surgery died within
(once daily sepsis in two; inability of the 30 days of intrapleural
(3 doses)) lung to fully re-expand in two tPA/DNase instillation
RCT: randomised controlled trial; tPA: tissue plasminogen activator; IQR: interquartile range; VATS: video-assisted thoracoscopic surgery; CT: computed tomography; ND: no data. #: standard use
defined as ⩽6 days.
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TABLE 4.2 Summary of dosing and administration regimens used in intrapleural enzyme therapy studies

First author [ref.], year Study type Comparative or Patients treated Agents used (dosing) Total Concurrent or
noncomparative with active number of sequential?
combination, n/N doses

RAHMAN [6], 2011 RCT Comparative 52/210 5 mg DNase; 6 doses of Sequential

10 mg tPA each agent
(twice daily)
PICCOLO [118], 2014 Prospective Noncomparative 107/107 5 mg DNase; Maximum 6 Sequential
observational 10 mg tPA doses of
(twice daily) each agent
MAJID [124], 2016 Retrospective Noncomparative 73/73 5 mg DNase; Maximum 6 Concurrent
10 mg tPA doses of
(twice daily) each agent
MCCLUNE [122], 2016 Retrospective Noncomparative 101/101 5 mg DNase; 6 doses of Sequential
10 mg tPA each agent
(twice daily for
3 days)
MEHTA [121], 2016 Retrospective Noncomparative 55/55 5 mg DNase; Maximum 3 Concurrent
10 mg tPA doses of
(once daily) each agent
POPOWICZ [117], 2017 Prospective Noncomparative 61/61 5 mg DNase; Median 6 Concurrent
observational 5 mg tPA doses of
(twice daily) each agent
KHEIR [123], 2018 Prospective Comparative 38/38 5 mg DNase; Maximum 6 Sequential
observational 10 mg tPA doses of (n=18);
(twice daily) each agent concurrent
(n=20)
KHEMASUWAN [196], 2018 Retrospective Noncomparative 84/84 5 mg DNase; Maximum 6 Concurrent
analysis 10 mg tPA doses of
(twice daily) each agent
JIANG [200], 2020 Retrospective Noncomparative 56/56 5 mg DNase; Median 3 Concurrent
cohort 10 mg tPA doses of
(once daily) each agent
RCT: randomised controlled trial; tPA: tissue plasminogen activator.

with 12% (tPA 5 mg) and 24% (tPA 2.5 mg) of these study populations ultimately requiring dose
escalation [117].

It is noteworthy that any cost benefit of lower dosing is dependent on vial size manufacturer supply (varies
by country) as the tPA Summary of Product Characteristics (www.medicines.org.uk/emc/product/898/
smpc) suggests that the reconstituted solution is for single use only and from an infection control
perspective, should be used immediately after reconstitution.

Most studies using IET administer agents twice daily [6, 118] for a maximum of 3 days (total of six doses
of both medications) as per the MIST-2 regime. Case series data have shown that once-daily administration
and extended dosing regimens may be suitable alternatives in terms of efficacy and safety, respectively,
although comparative trials are needed [120–122].

The authors conclude that optimal IET dosing and schedule have not yet been rigorously studied. Until
dose-ranging studies occur, being the only dose and schedule tested in a double-blinded RCT setting, the
regimen with the highest level evidence for efficacy is tPA 10 mg and DNase 5 mg intrapleurally twice a
day for six doses [6].

Preparation and administration regimen

Sequential administration of IET was used in the MIST-2 study based on the tPA Summary of Product
Characteristics suggesting that mixing of this solution with other drugs (such as DNase) could lead to
adverse structural and/or functional changes in tPA or the admixed compound. This suggests that
sequential administration of tPA and DNase is safer pharmacologically than concurrently. However, it is
unknown whether concurrent intrapleural administration of tPA and DNase affects the pharmacokinetics of

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either drug. There are data showing that concurrent and sequential administration may be equally safe and
effective [123]. In practice, concurrent dosing also decreases the amount of cumulative time that the chest
tube remains clamped and reduces the frequency needed to access the chest tube. These changes may
result in improved provider compliance and reduced risk of iatrogenic infection.

In current practice, concurrent administration is preferred due to convenience and decreased risk of
iatrogenic infection, but the evidence does not favour one over the other.

A suggested protocol for IET preparation, administration and monitoring is included in supplementary
material S4.1.

IET safety and adverse events

The MIST-2 study recruited 52 participants in the tPA/DNase combination arm and reported two bleeding
events (3.8%) [6]. Subsequently, a number of smaller studies have reported rates of pleural bleeding with
intrapleural administration of tPA (with or without DNase) in the context of pleural infection of between
1.8% and 12% [115, 118, 121–125]. Other than the heterogeneity between these studies, the key limitation
was the small study populations and therefore low event rates.

Bleeding risk and complications were specifically evaluated recently in the largest series of IET in pleural
infection (over 1800 patients) [126]. The overall bleeding rate was 4.1% and in the 172 patients who
received a lower dose tPA regimen (median 5 mg), the bleeding rate was not significantly reduced.
Moreover, in a multivariate regression analysis, the data showed that the use of concurrent systemic
anticoagulation, increasing RAPID score, elevated urea and platelets <100×109 L−1 were associated with a
significant increase in bleeding risk [126]. Hold systemic treatment-dose anticoagulation prior to
commencing IET for up to 48 h (or maintaining international normalised ratio <2 in case of warfarin) was
shown to mitigate the additional bleeding risk.

In patients with a perceived higher than average risk of bleeding (for whom surgical intervention for
pleural infection is not an option), most Task Force members would commence with a reduced dose of tPA
(5 mg) and escalate according to response. In cases where it may be unsafe to withhold anticoagulation
(e.g. recent pulmonary embolism), Task Force members may opt to use split-dose low-molecular-weight
heparin alongside IET but appreciate that these cases are complex and require careful, multidisciplinary
consideration.

The commonest side-effect with IET is pain requiring escalation of analgesia, in up to 36%
(supplementary table S4.1), particularly following the first dose; hence, most Task Force members ensure
pre-medication with analgesia to improve compliance.

A summary of other studies reporting data on IET-related side-effects, complications and mortality is
provided in supplementary table S4.2a. Suggested contraindications to IET use are presented in
supplementary table S4.2b.

Intrapleural saline irrigation

If fibrinolytics are contraindicated, pleural saline irrigation has been shown to be a potentially useful
therapeutic option. In 2015, HOOPER et al. [127] conducted the first RCT of pleural irrigation with normal
saline versus standard care alone in patients with pleural infection. The administration regimen consisted of
a 250 mL bottle of 0.9% sodium chloride on a drip stand and run through a giving set connected to the
chest tube, into the pleural space. The tube was then clamped for 1 h before being open to free drainage.
This was repeated 3 times a day for a total of nine irrigations and demonstrated a superior resolution of CT
pleural fluid volume ( primary outcome) over the course of the treatment compared to standard care alone,
as well as a reduction in surgical referrals (secondary outcome) [127]. It is noteworthy that the 50%
surgical requirement in the control group was very high compared to other RCTs and this was an
unblinded study. Two retrospective studies [128, 129] have also demonstrated that intrapleural saline
irrigation may be useful in the management of pleural infection, but further studies are required in larger
multicentre RCT settings.

Until larger multicentre RCTs consolidate the evidence base, currently most Task Force members would
consider saline irrigation in pleural infection on a case-by-case basis where there are strong
contraindications to IET (e.g. therapeutic anticoagulation which cannot be stopped) and where surgery is
not a viable option.

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Intrapleural antibiotics
Direct administration of antibiotics may have the theoretical advantage of reducing systemic side-effects
and antibiotic resistance. However, the efficacy of intrapleural treatment may be hampered by nonuniform
distribution across often septated or multiloculated pleural spaces (in comparison with parenteral
administration). Existing guidelines therefore either take an equivocal position [130] or recommend against
[12, 13] the use of intrapleural antibiotics in acute pleural infection due to the lack of evidence for their
efficacy.

In current practice, intrapleural antibiotics are reserved for managing post-lung resection pleural infections
which often require prolonged courses of parenteral antibiotics [131–133]. An antibiotic-eluting chest tube
has been trialled in a rabbit model and was shown to allow steady release of antibiotics for up to 14 days
[134, 135]. Safety and efficacy of such technology are yet to be proven in human studies.

There is currently no evidence for the role for intrapleural antibiotics in the routine management of
pleural infection outside specific surgical scenarios.

Question 5: In adults with pleural infection, what is the role of surgery and other interventions?
Role of surgery and choice of approach
Improvements in medical therapy have reduced the requirement for surgical management of pleural infection;
however, a significant minority (15–20%) of patients continue to require surgical intervention where sepsis
and residual collection persist [6, 7] or the patient presents with late-stage disease [6, 130]. In the absence of
prospective, comparative studies directly addressing the question, the role of empyema stage (supplementary
table S5) in predicting success or failure of image-guided drain placement remains unclear [13]. An
additional complicating factor, and the cause of some heterogeneity in the reported literature, is that in
clinical practice, empyema staging is continuum of pathology with patients rarely presenting with “pure”
stage II pleural infection, but rather a “mixed stage” with areas of fibrin organisation on the pleural surface.

The principles of surgery are drainage, deloculation, debridement and obliteration of the pleural space,
ideally by decortication. In the era of VATS, surgeons have developed the required skills to achieve these
principles via minimal access surgery and its role in empyema is now well established. Two small,
randomised studies demonstrated superior outcomes when VATS was compared to chest tube with or
without fibrinolytics in organised empyema [136, 137]. Case series have shown VATS success rates of 82–
92% [138, 139]. A best evidence review demonstrated that VATS was equivalent to thoracotomy in terms
of resolution and superior in terms of reduced LOS, where most studies included mixed and late-stage
disease [140]. More recently, international guidelines have moved to supporting a more pragmatic approach
of considering VATS in most cases [12, 13, 141].

Reduction in morbidity, arguably as important to patients as disease resolution, is superior with VATS
compared to open surgery [142]. Reduced operative time [143–146], LOS [138, 143–149], pain [138, 145,
146], air leak [144, 146] and duration of tube drainage [150] are more favourable with VATS. Greater
satisfaction [12] and earlier return to work [146] have also been reported.

These studies are supported by the largest patient cohort available to date in the Society of Thoracic
Surgeons (STS) General Thoracic Surgery Database review of over 7300 patients undergoing decortication
[142]. The STS reported a statistically significant difference in mortality between open surgery (3.7%) and
VATS (2.8%), with thoracotomy also associated with increased morbidity, discharge to care other than
home and prolonged LOS [142].

In 4435 patients who underwent a VATS approach there was a 14.2% (95% CI 13.2–15.3%) conversion
rate to open thoracotomy. Conversion rates are stage related, with higher conversion rates seen in stage III
disease [142, 143, 147]. Other risk factors for conversion include delayed surgical referral over 2 weeks,
thickness of pleura and a Gram-negative causative organism [151].

Stage III empyema was previously an indication for proceeding directly to open surgery; however, it is
now regarded as a predictor of risk for conversion rather than a contraindication to VATS. Early referral to
the thoracic surgical team is therefore recommended to facilitate likelihood of proceeding to VATS without
requirement for conversion, to confer its attendant benefits [151]. Several authors have stated that the time
to referral is the commonest independent factor influencing need for conversion [71, 147]. Moreover,
improved overall outcomes have been demonstrated when surgery is undertaken within 4 weeks from onset
of symptoms, where early surgery resulted in decreased post-operative LOS, reduced operative time and
fewer prolonged air leaks [150]. In the STS database data, adverse outcomes in terms of readmission,

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major morbidity, prolonged LOS and discharge to transitional care were all higher when pre-operative
hospitalisation extended beyond 5 days [142]. In the largest randomised study of pleural infection to date
the median duration of symptoms prior to presentation was 2 weeks [22].

The evidence to date demonstrates the potential for improved outcomes with surgical referral and
discussion being initiated as early as possible, with the aim of surgery (if required) occurring within
10 days of medical presentation. In their current practice, most Task Force members would consider
surgical referral at day 3 post-initial chest tube if ongoing sepsis, radiological persistence and/or clinical
deterioration.

Among the major determinants of surgical approach is the ability to successfully perform decortication
where lung expansion is required for space obliteration. Decortication beyond space obliteration to facilitate
improved lung function is of less certain benefit. There is evidence that decortication is associated with
increased lung perfusion and spirometry, although function of the affected lung may not return to normal
[152]. In a study of the added benefit of decortication over debridement, there was no difference in
eventual cavity size [153]. Peri-operative morbidity and mortality after decortication are significant, with
reported 90-day mortality of 7.6% and post-operative morbidity of 35.7%, both significantly associated
with increasing antibiotic resistance to the infecting organism(s) [51].

Post-traumatic empyema
Post-traumatic empyema is reported to occur in up to 25% of patients with retained haemothorax [154].
The Injury Severity Score (ISS) correlates with mortality, morbidity and hospitalisation time after trauma,
and has been widely adopted to assess chest wall trauma severity, with a score of >15 being defined as
major trauma [155]. Risk factors for the development of post-traumatic empyema include the presence of
rib fractures, ISS >25, lung contusion and the requirement for additional interventions to evacuate retained
blood from the thorax [154, 156–158].

The use of prophylactic antibiotics promptly upon hospitalisation for thoracic trauma significantly
decreases the incidence of post-traumatic empyema [159]. Current trauma guidelines endorse the use of
VATS drainage for the treatment of retained haemothorax and prevention of empyema [160]. Early VATS,
within 5 days after trauma, results in complete resolution in 87% of cases (75–100%), with a conversion to
thoracotomy rate of 11% [161].

Whether medical management in the form of fibrinolytics or medical thoracoscopy has a role in retained
traumatic haemothorax is yet to be determined. In a systematic review and meta-analysis of lytic therapy
for retained traumatic haemothorax, avoidance of surgery following treatment with fibrinolytic agents was
87% (95% CI 81–92%) [162]. Of note, however, the average LOS was 14.8 (95% CI 12.8–16.8) days. In
one nonrandomised study, OĞUZKAYA et al. [163] found that VATS was associated with shorter LOS and
reduced requirement for thoracotomy compared to intrapleural streptokinase. Historical referral patterns
encourage direct surgical intervention, and whether avoidance of surgery has clinical and cost benefits in
the setting of trauma is not known.

In current practice, surgical intervention remains first-line management in patients with retained haemothorax
and post-traumatic empyema; however, medical management including intrapleural fibrinolytics may be
considered in patients at high operative risk.

Medical thoracoscopy
Medical thoracoscopy is well established in the management of pleural effusion; however, its role in
pleural infection is less clearly defined. Advocates of medical thoracoscopy have demonstrated success
rates of 79.3–97.7% in multiloculated organising empyema [164–167]. A recent meta-analysis of
nonrandomised studies reported a pooled treatment success rate of 85% when utilised as first-line therapy
or after chest tube failure, with a complication rate of 9% [143]. Higher success rates were associated with
bacteriological negative effusions and administration of adjuvant intrapleural fibrinolysis [143]. A recent
RCT of medical thoracoscopy versus intrapleural fibrinolytic therapy showed a shorter LOS
post-intervention associated with the thoracoscopy arm [168]. The small numbers within the trial and the
limitations of the primary outcome require further studies to establish the true role of medical thoracoscopy
in empyema. The SPIRIT feasibility randomised trial (ISRCTN Registry: ISRCTN98460319) demonstrated
failure of feasibility of this approach in the context of UK thoracoscopy services.

In their practice, most Task Force members occasionally consider medical thoracoscopy as a treatment
option in multiloculated pleural infection in elderly and frail patients considered to be high surgical risk,

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where there is local expertise including sufficient access to local anaesthetic thoracoscopy, thoracic
surgery and anaesthetic support.

Management of persistent pleural space and post-pneumonectomy empyema

The prognosis of empyema is generally good in young and fit patients where early treatment is instituted.
Overall surgical mortality rates, however, remain high, reported to be between 0% and 10% [136–138,
169]. It is noteworthy that where aggressive intervention cannot be undertaken, mortality rates approach
that of untreated empyema [170].

Drainage, deloculation, debridement and decortication will achieve space obliteration in most cases, a
prerequisite for achieving resolution in closed empyema surgery [171]. The combination of insufficient
diaphragmatic or mediastinal shift and incomplete lung expansion as markers of chronicity, or previous
lung resection, may contribute to a persistent space. Where a residual space is an issue, the use of muscle
or omental flaps can provide space obliteration and heal small bronchopleural fistulae. In the nowadays rare
scenario where muscle flaps are inadequate to facilitate space obliteration, or have been unsuccessful,
interventions including open window thoracostomy (OWT) or thoracoplasty are considered [172].

OWT is occasionally utilised as part of staged management, or as a definitive measure, where previous
intervention has failed or when patients are not fit for more major intervention, in the presence of chronic
empyema and where bronchopleural fistula (BPF) is present. Previous techniques have been described by
ELOESSER [173] and CLAGETT and GERACI [174]. Mortality of thoracostomy in modern series is around 6%
with success rates of up to 95% in patients with post-surgical and post-pneumonic aetiology, with and
without BPF [175, 176].

The accelerated “iterative thoracotomy” technique consists of repeated debridement and packing with
povidone-iodine dressings under general anaesthesia every 48 h [177]. BPF is closed where necessary
using techniques described above. The chest cavity is obliterated with an antibiotic solution and the
thoracotomy definitively closed when macroscopically clean. The largest series evaluating this technique
(n=75) found it to be safe and effective, reporting successful treatment in 97.3% of patients with 94.6%
having a definitively closed chest within 8 days. Median hospitalisation time was 18 days and 90-day
mortality was 4% [178].

Intrapleural vacuum-assisted closure (VAC) wound therapy, which stimulates angiogenesis and fibroblasts
to facilitate healing, is a more recent adjunct to OWT (OWT-VAC) that has the added advantage of
achieving rapid source control and suction to aid lung re-expansion. This has been associated with reduced
morbidity, LOS and total treatment times [178–180]. In their practice, the Task Force members would
consider its use in patients with residual lung in situ and in post-pneumonectomy patients, with and
without BPF. Caution is recommended in the post-pneumonectomy and BPF patients where pain,
hypotension and requirement for surgical removal of foam is described [181–183].

Mini-VAC therapy (without OWT) has been described to treat complex empyema with primary closure in
patients both with and without BPF. In a small study of patients receiving mini-VAC therapy, all six
patients [178] were discharged with a closed chest at a mean±SD of 22±11 days without further recurrence
and remaining integrity of the chest cavity [184]. The additional instillation of intrapleural antiseptic fluid
(Mini-VAC-Instill) was associated with a further reduction in treatment time and shorter LOS (15±4.8 days;
p=0.027) [182].

Thoracoplasty facilitates space obliteration by excision of the upper ribs and can be combined with muscle
flaps or omental transposition. Significant associated morbidity, including chronic pain, progressive
scoliosis and the resulting cosmetic appearance, limits first-line use of thoracoplasty in the modern era.
However, it continues to provide a useful solution in specific situations where flaps and OWT have
failed [13]. Recent series report an operative mortality of around 5% with success rates of up to 90% [185].

Pleural infection after surgical resection is a specialist area which always requires involvement of surgical
services from the point of diagnosis. Where empyema occurs following lung resection, it is usual practice
that tube drainage is instigated and bronchoscopy undertaken to confirm or refute BPF. In current
practice, re-operation with closure of the fistula and space obliteration utilising tissue flaps is preferred in
the early post-operative phase and in patients who remain fit for re-operation. In cases of late
presentation, persistent BPF or patients unfit for further operation, most Task Force members would
consider OWT±VAC as a favourable option.

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Question 6: In adults with pleural infection, what is the role of risk stratification and outcome
prediction?
Data from a large Danish cohort [72] found that delayed pleural drainage by >2 days from diagnosis was
associated with worse 30- and 90-day mortality. Delayed surgical referral has been shown to be associated
with risk of conversion and worse outcomes, with each additional pre-operative hospital day (up to 5 days)
being associated with 1.2 times increased risk of mortality per day [142]. The current practice of sequential
progression of therapies from chest tube drainage to intrapleural therapies to consideration of surgical
intervention, in a “one size fits all” approach, may be to the detriment of certain patients.

While the evidence clearly does not justify upfront intrapleural and surgical therapies for all patients with
pleural infection, one or both may eventually be necessary in at least a third of patients [6]. Despite
advances in both these treatment modalities in the last decade, the lack of improvement in outcomes may
lie in our inability to identify the patients who would benefit from them at an earlier stage in their disease.

Clinical predictors of poor outcome

The RAPID score was developed as the first prognostic risk model specifically for pleural infection [186].
Using five baseline parameters, the RAPID score could predict 3-month mortality. Since its publication,
the RAPID score has undergone prospective external validation in the PILOT study [7] and has been
assessed in a number of single-centre, retrospective studies in the USA, New Zealand and Japan, which
have all further validated its clinical applicability and association with mortality [187–190].

An overview of the RAPID score is provided in supplementary material S6.

Despite the PILOT study specifically excluding patients with an expected survival of <3 months due to
pre-existing (nonpleural infection) comorbidity, a majority of deaths occurred within the first 3 months
following diagnosis of pleural infection, as has been seen in previous studies [22, 191], suggesting that
mortality is disease specific and potentially amenable to improvement.

While the RAPID score represents a major step forward in the ability to specifically prognosticate patients
with pleural infection, it cannot yet direct clinical care or decision making. The main goal now should be
to incorporate it into future prospective studies assessing the safety and efficacy of new treatment
paradigms, perhaps using less invasive, ambulatory strategies in the low-risk RAPID population [105] and
early invasive treatment such as surgery or IET in the high-risk groups. RAPID may also be used to
inform clinicians’ discussions of the likely outcome from pleural infection at presentation and the balance
of risk or benefit from any planned medical or surgical intervention.

The CCI has been shown to be a good predictor of outcome in three pleural infection cohorts [4, 9, 25].
Other clinical factors shown to be associated with adverse outcomes in pleural infection may also be
helpful in overall prognostication and rationalisation of further intervention in individual cases. These
include multimorbidity, malignancy, alcohol excess and cardiovascular disease, the latter having also been
associated with prolonged LOS in the RAPID study. An important caveat here is that, in contrast to the
RAPID criteria, the majority of these are derived from hospital episode statistics from administrative
databases that are flawed by coding inaccuracies and thus represent a lower level of evidence.

The studies containing the largest patient cohorts and their main findings are summarised in table 6.1.

Radiological biomarkers
Radiological parameters predicting outcomes have been challenging to study in pleural infection, mostly
because studies to date have been largely small, retrospective and have demonstrated that radiology tends
to predict clinician behaviour rather than true outcome from pleural infection [192–194].

The presence of sonographic septations, or enclosed “loculations”, is often assumed to be associated with
the need for more aggressive upfront drainage therapy such as intrapleural fibrinolytics or surgical
drainage. However, the evidence linking this to worse outcomes in pleural infection is limited to small
retrospective case series [193, 195]. To date, the largest pleural infection trials [6, 22] were conducted prior
to the era of commonplace ultrasound and hence the RAPID model did not address these.

In a smaller retrospective study (n=145), aimed at developing a CT scoring system to predict

parapneumonic effusions requiring drainage, PORCEL et al. [87] identified that the presence of the “split
pleura” sign on CT or pleural fluid volume ⩾500 mL were independent predictors of surgery and

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TABLE 6.1 Summary of studies exploring outcome predictors in pleural infection

First author Country Type of study Population, Primary outcome Results

[ref.], year n

BOBBIO [4], France National healthcare 25 512 Hospital length of stay, CCI score; malnutrition or cachexia;
2021 database (2012–2017) mortality and alcohol abuse; cardiovascular disease
hospitalisation costs
BRIMS [11], Australia Western Australia public 601 Bacteriology and clinical 3-month mortality: female gender,
2019 hospitals electronic records outcomes age, CRP; 1-year mortality: age,
active cancer, renal failure
WU [201], 2018 Taiwan National database 484 Predictive scores for risk of CCI Score; CHADS2 and CHA2DS-VASc
death scores not predictive
KAHN [202], Finland Retrospective long-term follow-up, 191 (1910 Prognostic factors for Advanced age; previous malignancies;
2018 single-centre study; gender/age controls) adverse outcome institutional care; alcoholism; malignant
matched with healthy controls aetiology
from national database
PARK [60], 2016 Korea Retrospective single-centre study 164 Predictive factors/scores Scores: CURB-65 ⩾2, PSI risk class IV–V,
for 30-day mortality SOFA score >2; factors: structural lung
disease, hospital-acquired infection,
withholding intrapleural fibrinolytics
CCI: Charlson Comorbidity Index; CRP: C-reactive protein; PSI: Pneumonia Severity Index; SOFA: Sequential Organ Failure Assessment.

in-hospital mortality. BOBBIO et al. [4] additionally identified the CT evidence of a fistula ( present in 31%
of their large cohort) to be independently predictive of mortality (OR 2.09 (99% CI 1.88–2.32)).

As IET in pleural infection becomes more routine, in their retrospective study (n=84) using statistical
modelling and machine learning (not externally validated), KHEMASUWAN et al. [196] identified pleural
thickening and abscess or necrotising pneumonia as risk factors for IET failure in both models.

Microbiology
Culture-positive pleural infection has been proven to be associated with higher mortality [11], longer LOS
and worse surgical outcomes [197]. Association between bacterial pattern and 1-year survival was among
the primary outcomes of the recent largest metagenomics analysis of pleural infection bacteriology [16].
The presence of anaerobes or bacteria of the Streptococcus anginosus group (S. anginosus, S. intermedius
and S. constellatus) was associated with better patient survival. The presence or dominance of S. aureus
was linked with lower survival, while dominance of Enterobacteriaceae was associated with higher risk of
death, perhaps due to being more resistant to antibiotic therapy. Given that S. aureus was recently found to
be the most common organism isolated regardless of study or setting with increasing prevalence of
methicillin resistance [38], most Task Force members would opt for earlier escalation of therapy and
vigilant follow-up in this patient group.

Novel biomarkers
Recently, ARNOLD et al. [198] demonstrated that pleural fluid soluble urokinase plasminogen activator
receptor (suPAR) more accurately predicted the need for more invasive management compared to
conventional biomarkers, as assessed by referral for intrapleural fibrinolytic therapy or thoracic surgery.
suPAR is the soluble form of uPAR, which, once bound to endogenous urokinase, catalyses the conversion
of plasminogen to plasmin (a potent fibrinolytic). To make a firm statement about the clinical relevance of
suPAR will require an external prospective validation cohort with predetermined criteria for intrapleural
fibrinolytic therapy and/or surgery. However, this study adds credence to the role of baseline pleural fluid
biomarkers of fibrinolytic activity, perhaps through regulation of the development of pleural loculation, in
predicting clinically important outcomes.

Conclusions
Recent updated data on epidemiology of pleural infection continue to show an overall upwards trend in
incidence. There is an urgent need for a more comprehensive characterisation of the burden and trends of
pleural infection across Europe. Large microbiology studies have resulted in a clearer understanding of the
pleural microbiome and the aetiopathogenesis of pleural infection, e.g. the abundance of anaerobes found
in the oral cavity likely seeding through aspiration or haematogenously. Regular analysis and
documentation of microbiological patterns at a local level should remain a priority. Beyond the pleural

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fluid pH, ongoing efforts are needed to refine the diagnostic approach. Simple parapneumonic effusions
are poorly studied and shifting our focus downstream in the coming years is vital.

There is now a plethora of evidence, beyond the original MIST-2 study, that IET is safe and effective.
Surgery continues to hold a vital role in the management of pleural infection, outcomes from VATS are
favourable and early referral should remain a priority.

To date, the RAPID score remains the only externally validated risk stratification model that has been
shown to be predictive of outcomes in different pleural infection populations. The incorporation of this tool
in future studies is suggested to define its utility in clinical practice.

Acknowledgements: The authors would like to acknowledge the contributions of the Oxford Respiratory Trials Unit
(Oxford, UK) pleural infection Patient Focus Group for their engagement with the work of this Task Force and their
insight into patient priorities for future research.

This document was endorsed by the ERS Executive Committee on 21 September 2022 and by the ESTS on 15
September 2022.

Conflicts of interest: The authors have no conflicts of interest to disclose.

Support statement: This work was supported by the European Respiratory Society. Funding information for this
article has been deposited with the Crossref Funder Registry.

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