Optimal management after the resolution of a first episode of pneumothorax

Optimal imaging modality for diagnosing pleural malignancy

Table 1

Table 2

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Table 5

Table 6

This guideline aims to provide evidence-based guidance on the
investigation and management of:

i. Spontaneous pneumothorax (SP)
ii. Undiagnosed unilateral pleural effusion
iii. Pleural infection
iv. Pleural malignancy

Pleural disease is common and represents a major and rapidly
developing subspecialty that presents to many different hospital
services. Since the last British Thoracic Society (BTS) Guideline for pleural disease published in 2010,3–9 many high-quality and practice changing studies, using patient-centred outcomes,  have been published. The paradigms for the investigation and management of pleural disease have therefore shifted. For example, ambulatory treatments have become much more prominent in the management of pleural disease. 

This guideline aims to capture this evidence and use it to answer the most important questions relevant to today’s practice.

The guideline will be of interest to UK-based clinicians caring for adults with pleural disease, including chest physicians, respiratory trainees, specialist respiratory nurses, specialist lung cancer nurses, specialist pleural disease nurses, pathologists, thoracic surgeons, thoracic surgeon trainees, acute physicians, oncologists, emergency physicians, hospital practitioners, intensive care physicians, palliative care physicians, radiologists, other allied health professional and patients and carers.

Guideline group members were selected to offer a broad geographical coverage of the UK and to include specialists with backgrounds in respiratory medicine, thoracic surgery, oncology, palliative care, nursing and pathology. The group included specialists from tertiary centres as well as district general hospitals.

The guideline is specifically designed to answer important questions in the investigation and management of pleural disease in adults.

Questions have been agreed by the whole guideline group. While as many important questions as possible have been included, there are areas that have not been covered. As this guideline covers four broad areas of pleural disease, the number of questions is limited by the practicalities of writing a guideline with a large scope that remains relevant and up to date at the point of publication and a workload manageable by the guideline group.

This guideline covers adult patients in both inpatient and ambulatory settings, and questions from investigation to management in the inpatient and outpatient settings and by specialists of all disciplines involved in the care of patients with pleural disease.

Mesothelioma has been excluded from this guideline as this is already covered in the BTS Guideline for the investigation and management of pleural mesothelioma. (10) Benign (non-infectious, non-pneumothorax) pleural disease and rare pleural diseases are also excluded. Guidance on pleural interventions are covered in the BTS Clinical Statement on Pleural Procedures.(1)

Healthcare providers need to use clinical judgement, knowledge and expertise when deciding whether it is appropriate to apply recommendations for the management of patients. The recommendations cited here are a guide and may not be appropriate for use in all situations. The guidance provided does not override the responsibility of healthcare professionals to make decisions appropriate to the circumstances of each patient, in consultation with the patient and/or their guardian or carer.

The Guideline Development Group (GDG) was chaired by three respiratory consultants—Professor Nick Maskell, Professor Najib Rahman and Dr Mark Roberts. The GDG had a wide membership and included colleagues from respiratory medicine, oncology, radiology, pathology and palliative medicine. Two patient representatives were recruited to the group, but due to personal circumstances both had to withdraw before completion of the guideline (August 2019 and July 2021). However, two further patient representatives were recruited at the end of the guideline process to review the final guideline and provide the patients’ perspective.

Those on the group were not required to be BTS members and a full list of members can be seen in Appendix 2

The guideline is specifically designed to answer important questions in the investigation and management of pleural disease in adults. Questions have been agreed by the whole guideline group. While as many important questions as possible have been included, there are areas that have not been covered. As this guideline covers four broad areas of pleural disease, the number of questions is limited by the practicalities of writing a guideline with a large scope that remains relevant and up to date at the point of publication and a workload manageable by the guideline group.

This guideline covers adult patients in both inpatient and ambulatory settings, and questions from investigation to management in the inpatient and outpatient settings and by specialists of all disciplines involved in the care of patients with pleural disease.

The GDG was convened in July 2018, with the first meeting taking place in November 2018. The full GDG met 10 times during the development of the guideline and kept in close contact by teleconference and email throughout the process.

This BTS Guideline uses Grading of Recommendations, Assessment, Development and Evaluation (GRADE) methodology in the guideline development process. Full details are provided in the BTS Guideline production manual.

Clinical questions were defined from the scope of the guideline and formulated into systematic review type questions (diagnostic accuracy, intervention or prognostic) according to the nature of the question. A full list of clinical questions for each section of the guideline is provided below. 

Patient-centred outcomes were agreed by the group for each question.

The Population, Intervention, Comparator and Outcome (PICO) framework, or equivalent for the diagnostic accuracy and prognostic review questions, formed the basis of the literature search. The initial searches were completed by the University of York (and latterly by BTS Head Office). Systematic electronic database searches were conducted to identify all papers that may be relevant to the guideline. For each question, the following databases were searched: Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials, MEDLINE and EMBASE. The search strategy is available for review below.

Two literature searches were conducted for the guideline, with the number of resulting abstracts from each search shown in Table 1.

Table 1: Literature searches were conducted for each section of the guideline as follows:

Letters, conference papers and news articles were removed and criteria for initial screening of the abstracts were:

• Does the study type match the study type criteria in the clinical question protocols?

• Does the population match the clinical question population(s)?

• Is the abstract in English?

The remaining abstracts were screened by Professor Maskell, Professor Rahman and Dr Roberts and potentially relevant abstracts allocated to the relevant clinical questions. Abstracts were not rejected on the basis of the journal of publication, authorship or country of origin.

GDG members were allocated to work on individual questions in small groups. Each abstract was read and at least two members agreed whether the abstract was ‘potentially relevant’ or ‘not relevant’ to the clinical question of interest. Abstracts were excluded if they were deemed ‘not relevant’ to the clinical question.

Full papers were obtained for all abstracts assigned as ‘potentially relevant’. Each full paper was reviewed to assess if it addressed:

1. The clinical question population;

2. The index test and reference standard (for diagnostic accuracy questions), the intervention and comparator (for intervention questions) or the exposure and referent (for prognostic questions);

3. The study type(s) defined in the clinical question protocol;

4. The clinical question outcome(s).

Each full paper fulfilling the above criteria, and agreed by at least two members of the GDG, was ‘accepted’ for meta-analysis and subsequent critical appraisal.

In circumstances where there was little, or no supporting evidence that fulfilled the above criteria, the full paper inclusion strategy was widened to include evidence that partially addressed the clinical question.

The second literature search (Search 2, Table 1) was undertaken in May 2021 to capture additional published evidence while the guideline was in development prior to finalising the draft document. The additional abstracts were reviewed and allocated to the clinical questions as above.

The full list of abstracts has been retained and is kept in an archive.

Each ‘accepted’ full paper underwent a systematic review. Data were extracted and meta-analyses were performed for each clinical question on an outcome-by-outcome basis for intervention reviews, or an index test basis for diagnostic accuracy reviews. If meta-analysis was not possible, for example, if there was insufficient evidence to perform a meta-analysis, if data could not be extracted to input into a meta-analysis, or data across studies had been published in different formats, all relevant supporting data were tabulated where possible.

All full papers contributing towards a meta-analysis underwent critical appraisal. For all non-meta-analysed data included in an evidence review, contributing papers also underwent critical appraisal where possible.

Meta-analyses and risk of bias assessments (critical appraisal) were performed in Review Manager V.5.3 and agreed by at least two members of the GDG. Diagnostic accuracy meta-analyses involved an additional step which was performed by BTS Head Office using the MetaDTA app.(11) Papers no longer deemed relevant were removed from the systematic review, with the decision to ‘exclude’ a paper solely based on it not fulfilling the clinical question criteria.

Having generated evidence profiles for each of the clinical question, GDG question groups assessed the quality of the evidence using the GRADE methodology.(12) Where meta-analysis was not possible, but studies had used comparable methodologies and data reporting methods to allow an assessment of the quality of the data, a prognostic review GRADE analysis approach was used.(13-14)

Where GRADE analysis was not possible, but GDG members felt the evidence was important to be included in the evidence statements, these have been listed as (Ungraded). Definitions of the evidence statement (GRADE) scores are shown in Table 2.

Table 2: Evidence statement (GRADE) score definitions

Each clinical question review was reviewed by the full GDG during the regular meetings and consensus was reached in relation to the evidence summary.

The GDG proceeded to decide on the direction and strength of recommendations considering the quality of the evidence, the balance of desirable and undesirable outcomes and the values and preferences of patients and others. GRADE specifies two categories of strength for a recommendation, as shown in Table 3.

Table 3: Explanation of the terminology used in BTS recommendations

From the outset, it was acknowledged that there would be little high-quality evidence for some of the clinical questions identified. In this instance, low-grade evidence was considered, along with the expert opinion of the GDG via informal consensus at the meetings.

Good practice points (GPPs) were developed by informal consensus in areas where there was no quality evidence, but the GDG felt that some guidance, based on the clinical experience of the GDG, might be helpful to the reader. These are indicated as shown below.

• Advised best practice based on the clinical experience of the GDG.

In some instances where evidence was limited, but GDG members felt that it was important to include a recommendation rather than a GPP, recommendations were agreed by informal consensus and categorised as (Strong—by consensus) or (Conditional—by consensus), based on the same criteria detailed in Table 3.

Cost-effectiveness was not considered in detail as in-depth economic analysis of recommendations falls outside of the scope of the BTS Guideline production process. However, the GDG were asked to be mindful of any potential economic barriers to the implementation of recommendations and GPPs.

Research recommendations were also identified and are detailed in online supplemental appendix 2.

The guideline group corresponded regularly by email and meetings of the full group were also held in the period between November 2018 and late 2020. A revised draft guideline document was circulated to all the relevant stakeholders for consultation in May 2022 followed by a period of online consultation.

The BTS Standards of Care Committee reviewed the ‘Investigation of the undiagnosed unilateral pleural effusion’ and ‘Pleural malignancy’ sections of the draft guideline in March 2020 and the full guideline in March 2022.

The Guideline and Summary can also be accessed via the Thorax journal here: Full Guideline and Summary.

The term pneumothorax describes air in the pleural space and is characterised as spontaneous in the absence of trauma or causative medical intervention. It is an increasing problem, with annual hospital admission rates rising from 9.1 to 14.1 per 100 000 population in the last 50 years, leading to substantial symptom burden and healthcare utilisation.(15 16) Since the last version of the BTS pneumothorax guideline, published in 2010 (5) there have been several large high-quality clinical trials examining the management of SP.(17–20)

This guideline seeks to consolidate and update the pneumothorax guidelines in the light of this subsequent research using GRADE methodology and addresses the following clinical questions addressing adults with pneumothorax:

• What is the best acute management for SP? (Question A1)

• What is the optimal management of patients after resolution of first episode of pneumothorax? (Question A2)

• What is the optimal management of patients with ongoing air leak? (Question A3)

• What is the optimal surgical approach when performing surgery? (Question A4)

• What is the optimal operation when performing surgery? (Question A5)

Other areas of clinical importance that are not covered by the guideline questions are discussed in the ‘Other areas of clinical importance not covered by the clinical questions’ section, including traumatic and iatrogenic pneumothorax which are not specifically covered in the evidence review.

Spontaneous pneumothoraces can be subclassified into primary spontaneous pneumothorax (PSP) in the absence of suspected lung disease or secondary spontaneous pneumothorax (SSP) in patients with established underlying lung disease. This distinction does not imply that patients with PSP have normal underlying lung parenchyma, with the majority demonstrating emphysema-like pulmonary changes on CT imaging, but instead reflects that current management and outcomes differ between the two patient groups. Patients can also be characterised as SSP if they are older than 50 years of age and have a smoking history. This categorisation reflects case series data that this cohort may respond differently to needle aspiration (NA) than younger patients or non-smokers.

There have been substantial changes in recommendations in this BTS Guideline compared with the 2010 Guidelines. Size of pneumothorax is no longer an indication for invasive management (although does dictate the safety of conducting an intervention) and the use of chest drains is mainly centred around patients with high-risk characteristics (Appendix 1, Pneumothorax pathway). The expanded evidence base now allows for a more personalised approach and greater patient choice. For details of interventions and how these are best conducted, please refer to the BTS Clinical Statement on Pleural Procedures for further details.(1)

Drainage of symptomatic pneumothorax, either with NA or intercostal chest drain (ICD) attached to an underwater seal is the current standard of care for PSP. There is ongoing debate over the respective benefits of NA over ICD, with multiple recent randomised trials comparing NA with ICD. Conservative management (ie, no active intervention) is often undertaken in patients with small or incidental PSP, but could be an alternative to NA or chest drain in patients with larger pneumothoraces.

Ambulatory treatment using a purpose-made device containing a one-way valve, or Heimlich valve attached to chest drain has the potential to allow outpatient management of pneumothorax. A proportion of pneumothoraces will recur and both chemical pleurodesis via chest tube and thoracic surgery have the potential to reduce this risk. Thoracic surgery is often the treatment of choice for ongoing air leak, or for those with recurrent pneumothorax. However due to the risk of recurrence, trials have been performed to establish whether thoracic surgery could be offered at first presentation of pneumothorax. Conservative management, in which no intervention is undertaken and the patient is observed or reviewed repeatedly, is also a further alternate initial potential treatment strategy. Hence, the first clinical question was:

A1 For adults with spontaneous pneumothorax, is conservative management, needle aspiration, ambulatory management, chemical pleurodesis or thoracic surgery better than intercostal drainage at improving clinical outcomes?

A summary of the evidence review is shown in table 4 and the evidence statements (conclusions from the evidence review), recommendations and GPPs are presented below.

The full evidence review is available in online supplemental appendix A1.

Table 4 Evidence Review Summary for 'What is the best acute management for spontaneous pneumothorax?

*Meta-analysis not possible, data reported in different formats.

†Meta-analysis results reported as per 1000 patients.

ICD, intercostal drainage; LOS, length of stay; NA, needle aspiration; PSP, primary spontaneous pneumothorax; SSP, secondary spontaneous pneumothorax.

Evidence statements

Conservative Management

• Length of hospital stay appears to be shorter following conservative management for the treatment of PSP in adults when compared with ICD. (Ungraded)

• Risk of pneumothorax recurrence appears to be greater following ICD when compared with conservative management for the treatment of PSP in adults. (Very low)

• There may be more complications experienced following ICD when compared with conservative management for the treatment of PSP in adults. (Ungraded)

Needle aspiration

• Length of hospital stay appears to be shorter following NA for the treatment of PSP in adults when compared with ICD. (Low)

• There appears to be no difference in the rate of recurrence between NA or ICD for the treatment of PSP in adults. (Very low)

• There appears to be a greater need for further pleural procedures following NA when compared with ICD for the treatment of PSP in adults. (Very low)

• The risk of overall complications following NA or ICD appear to be the same for the treatment of PSP in adults (Very low), but there may an increased risk of subcutaneous emphysema following ICD. (Low)

Ambulatory management

• There appears to be a reduction in the length of hospital stay following ambulatory management when compared with standard care for the treatment of PSP in adults. (Moderate)

• There appears to be no difference in the rate of pneumothorax recurrence, the rate of hospital re-admission, the need for pleural procedures or complications following ambulatory management or standard care for the treatment of PSP in adults. (Very low)

Chemical pleurodesis

• There appears to be no difference in the length of hospital stay following chemical pleurodesis or ICD alone for the treatment of PSP in adults. (Low)

• The risk of pneumothorax recurrence appears to be lower following chemical pleurodesis when compared with ICD alone for the treatment of PSP or SSP in adults. (Very low)

• There appears to be a greater need for opioid pain relief following chemical pleurodesis when compared with ICD alone for the treatment of PSP in adults. (Moderate)

• Although there appears to be no difference in mortality rate at time of treatment (Very low), tetracycline chemical pleurodesis may cause greater post-treatment mortality when compared with ICD alone for the treatment of pneumothorax in adults. (Very low)

Thoracic surgery

• Length of hospital stay appears to be shorter following thoracic surgery, when compared with ICD, for the treatment of PSP in adults. (Very low)

• The rate of pneumothorax recurrence appears to be reduced following thoracic surgery, when compared with ICD, for the treatment of PSP in adults. (Very low)

• Pneumonia and persistent air leak complications appear to be greater following video-assisted thoracic surgery (VATS), when compared with ICD, for the treatment of PSP in adults. (Very low)

• There appears to be no difference in the rate of mortality following thoracic surgery or ICD, for the treatment of pneumothorax in adults, with the mortality rate being very low for both treatments. (Very low)

Recommendations

• Conservative management can be considered for the treatment of minimally symptomatic (ie, no significant pain or breathlessness and no physiological compromise) or asymptomatic PSP in adults regardless of size. (Conditional—by consensus)

• Ambulatory management should be considered for the initial treatment of PSP in adults with good support, and in centres with available expertise and follow-up facilities. (Conditional)

• In patients not deemed suitable for conservative or ambulatory management, NA or tube drainage should be considered for the initial treatment of PSP in adults. (Conditional)

• Chemical pleurodesis can be considered for the prevention of recurrent SSP in adults (eg, patients with severe chronic obstructive pulmonary disease who significantly decompensated in the presence of a pneumothorax, even during/after the first episode). (Conditional)

• Thoracic surgery can be considered for the treatment of pneumothorax in adults at initial presentation if recurrence prevention is deemed important (eg, patients presenting with tension pneumothorax, or those in high-risk occupations). (Conditional)

Good practice points

• When establishing local ambulatory treatment pathways, planning and coordination between with the emergency department, general medicine and respiratory medicine is vital.

• When performing chemical pleurodesis for the treatment of pneumothorax in adults, adequate analgesia should be provided before and after treatment.

• All treatment options should be discussed with the patient to determine their main priority, with consideration for the least invasive option.

Recurrence following SP is a frequent concern and overall occurs in 32% of patients after a single episode of PSP(21) and 13%–39% after a first episode of SSP.(16) Current usual practice in the UK is to consider surgical intervention after the second episode of an SP to reduce subsequent further recurrences. The aim of the next question was to assess if there was evidence to support the use of surgical intervention (surgical pleurodesis or bullectomy) at an earlier stage in an elective context, prior to the first recurrence, comparing against non-surgical techniques (non-surgical talc or conservative management):

A2 What is the optimal management of patients after resolution of a first episode of pneumothorax?

The evidence statement and GPPs are presented below; and the full evidence review is presented in online supplemental appendix A2.

Most spontaneous pneumothoraces will resolve once the air leak has ceased. However, some patients will have persistent/prolonged air leak and/or failure of the lung to re-expand on CXR. There are several treatment options available including application of thoracic suction, converting to larger-bore chest drain, blood patch or chemical pleurodesis, endobronchial valves or thoracic surgery and the next clinical question asked if any of these treatment options give better clinical outcomes than ongoing chest tube drainage alone:

A3 In adults with spontaneous pneumothorax and ongoing air leak (excluding postsurgical patients), which treatments are better than ongoing chest tube drainage alone at improving clinical outcomes?

Due to a lack of evidence, not all treatment strategies were reviewed, but the evidence statements and GPPs are presented below and the full evidence review is available in online supplemental appendix A3.

Pneumothorax can be treated surgically, either acutely to treat a persistent air leak or prevent recurrence in patients whose initial pneumothorax has resolved. Surgery can be via thoracotomy, that is, an open incision into the pleural cavity, or via VATS, whereby instruments are introduced into the pleural cavity via ports in the chest wall. Within these two categories, there is significant variation, particularly in the size of incision and number of ports. Both approaches allow access to the pleural space to perform bullectomy, pleurodesis or pleurectomy as required, but there may be significant differences in key outcomes. Hence, the aim of this review was to compare these two main surgical approaches for the treatment of adults with pneumothorax:

A4 For adults with pneumothorax, what is the optimal surgical approach when performing surgery?

A summary of the evidence review is shown in table 5 and the evidence statements and recommendations are presented below. The full evidence review is presented in online supplemental appendix A4.

Table 5: Evidence Review summary for ‘What is the optimal surgical approach when performing surgery?’

Thoracic surgery for pneumothorax can be broadly divided into two different types:

1. Resection of lung parenchyma (often visible blebs which are usually <1–2 cm and subpleural, or bullae which are usually >1–2 cm, although the terms are used interchangeably) to remove the suspected source of the current air leak and prevent future potential sources of air leaks; and

2. Surgical pleurodesis to obliterate the pleural space via an inflammatory symphysis of the visceral and parietal pleura to prevent the accumulation of air within that space and prevent any future episodes of pneumothorax.

The former requires a ‘bullectomy’, a form of wedge resection using stapler equipment, and can also include the use of a ‘sealant’ (such as glue and a mesh) to further fortify the site of lung resection. The latter can be achieved through a number of different methods intra-operatively including pleural abrasion, partial pleurectomy and talc poudrage. The next question compared these two main types of pneumothorax surgery for the treatment of SP in adults:

A5 In adults with spontaneous pneumothorax what is the optimal operation for improving clinical outcomes?

A summary of the evidence review is shown in table 6 and the evidence statements and recommendation are presented below. The full evidence review is presented in online supplemental appendix A5. 

Table 6: Evidence Review summary for ‘What is the optimal operation when performing surgery?’

Some areas of clinical importance which have not been covered by the guideline clinical questions are included below as a guide for clinicians.

Pleural effusions are a common medical problem with >60 recognised causes including disease local to the pleura or underlying lung, systemic conditions, organ dysfunction and drugs.

Pleural effusions occur as a result of increased fluid formation and/or reduced fluid resorption. The precise pathophysiology of fluid accumulation varies according to underlying aetiologies. As the differential diagnosis for a unilateral pleural effusion is wide, a systematic approach to investigation is necessary. The aim is to establish a diagnosis swiftly, while minimising unnecessary invasive investigations, in order to facilitate treatment (for common causes of pleural effusion please refer to Tables 2, 4 and 6 of Appendix 1, Unilateral pleural effusion diagnostic pathway).

A careful history and physical examination of the patient remains the most important first step when evaluating someone with an undiagnosed pleural effusion. The likely cause can often be elucidated by careful history taking, which will then allow directed further investigations. The patient’s drug history should always be recorded, as a number of medications have been reported to cause exudative pleural effusions. A useful resource can be found by downloading the Pneumotox app, which contains comprehensive data in this regard (available from the Apple App Store and Google Play). Interestingly, since the management of a malignant pleural effusion (MPE): British Thoracic Society Pleural Disease Guideline 2010,(6) the frequency of causative drugs has changed with the most common drug implicated as causing exudative pleural effusions being tyrosine kinase inhibitors. A detailed occupational history, including any previous asbestos exposure is also vital information when investigating all pleural effusions.

Thoracic ultrasound (TUS) is now an extension of the physician’s arm and has never been as important, both as a diagnostic tool and to improve the safety of invasive procedures. TUS should be performed on every patient at their initial presentation and again whenever a pleural procedure is being performed. The initial TUS evaluation will help to answer the question ‘Is it safe to perform a diagnostic aspiration?’ However, it will also provide information on the size and character of the effusion. Signs of malignancy with nodularity of the diaphragm and parietal pleural are highly suggestive of malignancy and assist in optimising the patient pathway and streamlining investigations.

If it is not safe to proceed with a pleural aspiration, a CT scan should be obtained as the next step. If malignancy is suspected, the CT scan should include the chest, abdomen and pelvis; if malignancy is not likely, then a CT of the thorax with pleural contrast (venous phase) should be performed.

When a firm diagnosis cannot be made, it is sensible to reconsider diagnoses with a specific treatment (eg, tuberculosis (TB), pulmonary embolism, lymphoma, IgG4 disease and chronic heart failure) (refer to box 1 in Appendix 1, Unilateral pleural effusion diagnostic pathway). Watchful waiting with interval CT scans is often an appropriate management strategy in this setting and also in those with a persistent pleural effusion that is too small to sample.

What is the diagnostic accuracy of radiology?

Radiological tests form a key role in the detection and diagnostic pathway of a unilateral pleural effusion in adults and may include CXR, CT, TUS, positron emission tomography-CT (PET-CT) and MRI. The first clinical question in the ‘Investigation of the undiagnosed unilateral pleural effusion’ section reviewed the diagnostic accuracy of radiology when investigating unilateral pleural effusions of benign aetiology:

• B1 What is the diagnostic accuracy of radiology when diagnosing benign pleural disease as a cause of unilateral pleural effusion in adults?

Please note that the diagnostic accuracy of radiological tests for distinguishing benign from malignant disease is addressed in the ‘Pleural malignancy’ subsection ‘Which imaging modality is best for diagnosing adults with suspected pleural malignancy?’.

An overview of the evidence review is shown in the ‘Pleural infection’ and ‘Non-infective causes of unilateral pleural effusions’ subsections below, followed by the evidence statements and GPPs. The full evidence review is available in online supplemental appendix B1.

Pleural infection

The absence of malignant radiological features (circumferential pleural thickening with nodularity involving the mediastinal surface) is suggestive of a benign pleural effusion, but there is overlap in the imaging features of malignancy and infection. On CT, features that are more common in pleural infection (parapneumonic, empyema and TB) than malignancy are (34 35):

1. Lentiform configuration of pleural fluid;

2. Visceral pleural thickening (‘split pleura sign’);

3. Hypertrophy of extrapleural fat (>2 mm);

4. Increased density of the extrapleural fat;

5. Presence of pulmonary consolidation.

However, poor sensitivity of these features (0.20–0.48) highlights the need for diagnostic thoracentesis in unexplained pleural effusions to allow pleural fluid characterisation.

Thoracentesis (pleural aspiration) is a key intervention for both diagnostic and therapeutic purposes in the investigation and management of the patient with a unilateral pleural effusion. The use of TUS immediately prior to pleural intervention for suspected fluid has been strongly advocated as a means of improving patient safety by reducing the frequency of iatrogenic complications and improving diagnostic yield. This is different to the temporally and geographically remote use of TUS prior to pleural intervention, also known as the ‘X marks the spot’ technique. The next clinical question therefore assessed whether image-guided (ie, ultrasound-assisted techniques where the anatomy is confirmed on ultrasound and an intervention is immediately conducted and ‘real time’ or ultrasound guided where needles are watched under ultrasound into the pleural space) intervention has better clinical outcomes when compared with non-image-guided intervention in adult patients with suspected unilateral pleural effusion:

• B2 For adults with suspected unilateral pleural effusion, is image-guided intervention better than non-image-guided intervention at improving clinical outcomes?

A summary of the evidence is shown in Table 8 and the evidence statements and recommendation are presented below. The full evidence review is available in online supplemental appendix B2.

Table 8: Evidence Review summary for ‘Is image guided intervention better than non-image guided intervention?’

Increasing the volume of pleural fluid in a pleural aspiration sample may aid in the cytological diagnosis of malignancy and understanding the optimal volume and container should allow optimisation of clinical pathways for the diagnosis of pleural malignancy and infection. Hence, the next clinical question was:

• B3 What is the optimal volume and container for a pleural aspiration sample when diagnosing unilateral pleural effusion in adults?

The evidence statements, recommendations and GPPs are presented below, and the full evidence review is available in online supplemental appendix B3.

Unilateral pleural effusion may result from a variety of diseases, including malignant, inflammatory, infectious and cardiovascular illnesses. Pleural fluid aspiration facilitates measurement of various disease biomarkers. If accurate, pleural fluid tests may obviate the need for pleural biopsy or other investigations and facilitate early treatment initiation, including early ICD in patients with complex PPE or empyema, so the next question asked:

• B4 What is the diagnostic accuracy of pleural fluid tests when diagnosing adult patients with unilateral pleural effusion?

To address this question, it was first necessary to define the disease states that are of clinical interest in adults presenting with unilateral effusion, and to define a relevant gold standard for each (Table 9). The index tests reviewed vary with the target disease resulting in five subquestions, each containing relevant index test gold standard pairs.

Table 9: Reviewed disease state subgroups and associated gold standards

AAFB – acid alcohol fast bacilli; LVEF – left ventricular ejection fraction

A summary of the evidence review for each disease state (Table 9) is shown in subsections below, followed by the evidence statements, recommendation and GPPs. The full evidence review is available in online supplemental appendix B4.

Secondary pleural malignancy

A summary of the diagnostic accuracies of cytology and pleural biomarkers carcinoembryonic antigen (CEA), fragment of cytokeratin 19 (CYFRA21-1), carbohydrate antigen 19-9 (CA19-9), cancer antigen 15-3 (CA15-3) and cancer antigen 72-4 (CA72-4) for diagnosing secondary pleural malignancy are shown in Table 10.

Table 10: Summary of the diagnostic accuracies of secondary pleural malignancy pleural biomarkers

CA15-3 – cancer antigen 15-3; CA19-9 – carbohydrate antigen 19-9; CA72-4 – cancer antigen 72-4; CEA – carcinoembryonic antigen; CYFRA 21-1 – fragment of cytokeratin 19

Tuberculous pleural effusion

The point estimate diagnostic accuracies of pleural biomarkers adenosine deaminase (ADA) and interferon gamma (IFN-gamma) for diagnosing tuberculous pleural effusion are shown in Table 11.

Table 11: Summary of the diagnostic accuracies of tuberculous pleural effusion pleural biomarkers

ADA – adenosine deaminase; CI – confidence intervals; IFN-gamma – interferon gamma

Heart failure

The point estimate diagnostic accuracy of pleural fluid N-terminal prohormone brain natriuretic peptide (NT-proBNP) for diagnosing heart failure pleural effusion is shown in Table 12.

Table 12: Summary of the diagnostic accuracy of heart failure pleural effusion pleural biomarkers

Unilateral pleural effusion may result from a variety of conditions, including malignant, inflammatory, infectious and cardiovascular illnesses. Serum biomarkers that directly reflect underlying pathophysiology have the potential to shorten diagnostic pathways, either by obviating the need for invasive pleural investigations or by directing interventions such as tissue biopsy or fluid drainage. As for the review on pleural fluid tests (‘What is the diagnostic accuracy of pleural fluid tests (biomarkers)?’ section above), it was again necessary to define the disease states that are of clinical interest in adults presenting with unilateral effusion and to define a relevant gold standard for each (please see table 9 for details), as the index tests reviewed varied with target disease. The next clinical question was:

• B5 What is the diagnostic accuracy of serum biomarkers when diagnosing adult patients with unilateral pleural effusion?

A summary of the evidence review for each disease state (table 9) is shown in the ‘Secondary pleural malignancy’, ‘Tuberculous pleural effusion’, ‘Heart failure’ and ‘Pleural infection (CPPE or empyema) and autoimmune pleuritis’ subsections below. This is followed by evidence statements, recommendation and GPPs and the full evidence review is available in online supplemental appendix B5.

Secondary pleural malignancy

The sensitivity and specificity of serum CA15-3, CEA, C reactive protein (CRP) and CYFRA21-1 for diagnosing secondary pleural malignancy is shown in table 14. Please note that all presented data are based on data from single studies.

Table 14: Summary of the diagnostic accuracies of secondary pleural malignancy serum biomarkers

CA15-3-cancer antigen 15-3; CEA - carcinoembryonic antigen; CRP - C-reactive protein; CYDRA 21-1 - fragment of cytokeratin 19

Tuberculous pleural effusion

The diagnostic accuracies of serum biomarkers T-spot and TB antibody for diagnosing tuberculous pleural effusion are shown in table 15. Please note again that the presented data come from single studies.

Table 15: Summary of the diagnostic accuracies of tuberculous pleural effusion serum biomarkers

Heart failure

The diagnostic accuracy of NT-proBNP as a diagnostic serum biomarker for diagnosing heart failure in patients with unilateral pleural effusion is shown in table 16.

Table 16: Summary of the diagnostic accuracy of heart failure pleural effusion serum biomarkers

Obtaining pleural tissue is often necessary to achieve definitive diagnosis in patients presenting with pleural effusion and/or thickening. There are a variety of pleural biopsy techniques (see the BTS Clinical Statement on Pleural Procedures for further details (1) and the aim of the final clinical question in this section was to assess which biopsy method(s) is/are best for achieving accurate histological diagnosis:

• B6 What is the diagnostic accuracy of pleural biopsy in adults with suspected pleural disease?

Large heterogeneity in study methodology and result reporting made meta-analysis impossible, so a pragmatic approach was adopted to achieve a structured stepwise narrative approach, focusing on studies where direct comparative data were available. Confirming a diagnosis of malignant pleural disease or pleural infection, specifically tuberculous pleuritis, were both considered. Making a histological diagnosis of non-specific pleuritis (also referred to as other terms such as fibrinous pleurisy and pleural fibrosis) was also considered a genuine and clinically relevant finding when followed-up for at least 12 months.

A summary of the evidence review is shown in table 17 using the definitions shown in box 1.

Table 17: Evidence Review summary of ‘What is the diagnostic accuracy of pleural biopsy?’

The evidence statements and recommendations are shown below and the full evidence review is available in online supplemental appendix B6.

Pleural infection remains a common medical problem with significant mortality and morbidity despite a better understanding of the aetiology, pathophysiology and recent advances in management approaches. With a combined incidence of over 80 000 cases per annum in the USA and the UK, and an incidence of 11.2 cases per 100 000 population per year in the UK, pleural infection continues to cause a considerable burden to health systems.(40)

A number of studies have been published demonstrating that the incidence of pleural infection is increasing across the Western world,(41–43) including recent data from the UK,(44) and the precise cause of the increase in infection rate, especially in the elderly population, is as yet unclear.

This guideline is intended to address key areas of new evidence since publication of the last BTS Guideline in 2010,(7) which included the specific following questions addressing adults with pleural infection:

• What is the best predictor of clinical outcomes? (Question C1)

• Do pleural fluid or radiology parameters accurately determine which patients should be treated with ICD? (Question C2)

• What initial drainage strategy provides the best clinical outcomes? (Question C3)

• Does intrapleural therapy improve outcomes compared with other treatment options (eg, drainage alone or surgical intervention)? (Question C4)

• Which surgical approach provides the best clinical outcomes? (Question C5)

• Which method of surgery provides the best clinical outcomes? (Question C6)

Areas of clinical importance not covered by the guideline questions are discussed in the ‘Pleural infection, Other areas of clinical importance not covered by the clinical questions’ section.

Other specific areas that have not been covered in this guideline can be referenced from the Management of pleural infection in adults: British Thoracic Society Pleural Disease Guideline 2010, including pathophysiology and the developmental stages of pleural infection.(7)

Pleural infection is defined as bacterial entry and replication in the pleural space (45)—the terms ‘complicated’ and ‘uncomplicated’ PPE have been used, but these terms suggest that an associated pneumonia is always a requirement to establish pleural infection which is not the case. The term ‘empyema’ refers to the macroscopic detection of purulent pleural fluid and represents one end of a spectrum of pleural infection.(46) Here, the term ‘pleural infection’ is used to include both empyema and CPPE.

The cornerstones of management of pleural infection are unchanged since the last guideline. These include early identification of cases and accurate diagnosis (covered in the section on approach to the undiagnosed effusion), prompt and suitable antibiotic therapy, nutrition management and deep vein thrombosis prophylaxis and efficient drainage of infected collections (covered in this guideline) via chest tube and adjunctive therapies including intrapleural agents and ultimately surgical management.(7)

Clinical outcomes in pleural infection remain poor, with up to 20% of patients dying after an episode of pleural infection over 12 months, and the requirement for surgery in around 15%.(47,48) Understanding which patients are at greater risk of adverse outcomes may allow clinicians to identify means by which their care can be improved to reduce mortality and morbidity, and potentially target invasive treatment to those at highest risk. Hence, the first clinical question in this section asked whether there are baseline clinicoradiological markers that predict clinically important outcomes from pleural infection:

• C1 For adults with pleural infection, what is the best predictor of clinical outcomes?

The evidence statements and recommendation are presented below; and the full evidence review is presented in online supplemental appendix C1.

Evidence statements

Clinical parameters

• Higher RAPID scores (Table 18) appear to indicate an increased risk of mortality (Low) (figure 1) and may indicate an increased length of hospital stay. (Ungraded)

• The Charlson Comorbidity Index Score (CCIS) is associated with an increased risk of mortality with increased CCIS score. (Ungraded)

Table 18: RAPID score*

Parameter	Measure		Score
Renal	Urea (mmol/L)	< 5.0 5.0 – 8.0 > 8.0	0 1 2
Age	< 50 years 50-70 years > 70 years		0 1 2
Purulence of pleural fluid	Purulent Non-purulent		0 1
Infection Source	Community acquired Hospital acquired		0 1
Dietary factor	Albumin (g/L)	> 27.0 < 27.0	0 1
Risk category	Score 0-2 Score 3-4 Score 5-7		Low risk Medium risk High risk

*The RAPID score takes into account serum urea level, age, pleural fluid purulence, infection source and serum albumin levels to risk stratify patients into low-risk, medium-risk or high-risk groups.(68)

 

Figure 1

Comparison of the risk of mortality with low, medium and high RAPID scores (based on the meta-analysis results from online supplemental appendix C1, table C1d and figures C1a–C1f).

Where bacteria have translocated into the pleural space, ICD is likely to be required to resolve infection, and here this is termed ‘pleural infection’. The presence of macroscopically purulent pleural fluid is termed empyema and diagnostic of pleural infection, and such cases require ICD. In the absence of purulent pleural fluid, there are challenges in determining when best to treat patients with PPE by ICD. Various parameters are available at the point of considering a diagnosis of pleural infection to inform initial decision-making regarding ICD and classification as CPPE which requires drainage, or uncomplicated parapneumonic effusion which will resolve without recourse to drainage. Such parameters include pleural fluid biochemistry (pH, lactate dehydrogenase (LDH), glucose) and radiological features (TUS and CT). Prompt identification of patients with pleural infection who require drainage is necessary to improve patient outcomes by potentially preventing progression to more advanced stages of empyema, so the next clinical question asked:

• C2 For adults with pleural infection, do pleural fluid or radiology parameters accurately determine which patients should be treated with intercostal drainage?

The evidence statements, recommendations and GPPs are presented below; and the full evidence review is presented in online supplemental appendix C2.

Evidence statements

• Pleural fluid pH appears to have a high specificity and high sensitivity for identifying patients who will undergo a complicated clinical course (complicated parapneumonic effusion (CPPE)) and thus require intercostal drainage. (Ungraded)

• In the context of clinically suspected pleural infection:

• Pleural fluid pH >7.38 appears to indicate a very low risk of CPPE. (Ungraded)

• Pleural fluid pH ≤7.15 appears to indicate a high risk of CPPE. (Ungraded)

• Pleural fluid pH between 7.16 and 7.38 appears to indicate a decreasing risk of CPPE/pleural infection with increasing pH, especially with pH >7.22. (Ungraded)

• Pleural fluid LDH or glucose measurements appear to be less accurate than pH in initial, independent prediction of which patients should be treated with intercostal drainage. (Ungraded)

• Pleural fluid pH and glucose are highly correlated, and thus where immediate or accurate pH measurement is not possible, an initial glucose of 4.0 mmol/L (in the non-diabetic patient) indicates a moderate-to-high likelihood of CPPE. (Ungraded)

• CT pleural fluid contrast enhancement may improve detection of CPPE. (Ungraded)

Recommendations

• For patients with PPE or suspected pleural infection, where diagnostic aspiration does not yield frank pus, immediate pH analysis should be performed. (Strong—by consensus)

• For patients with suspected CPPE:

  • If pleural fluid pH is ≤7.2, this implies a high risk of CPPE or pleural infection and an ICD should be inserted if the volume of accessible pleural fluid on ultrasound makes it safe to do so. (Strong—by consensus)

  • If pleural fluid pH is >7.2 and <7.4, this implies an intermediate risk of CPPE or pleural infection. Pleural fluid LDH should be measured and if >900 IU/L ICD should be considered, especially if other clinical parameters support CPPE (specifically ongoing temperature, high pleural fluid volume, low pleural fluid glucose (72 mg/dL ≤4.0 mmol/L), pleural contrast enhancement on CT or septation on ultrasound. (Strong—by consensus)

  • If pleural fluid pH is ≥7.4, this implies a low risk of CPPE or pleural infection and there is no indication for immediate drainage. (Strong—by consensus)

• In the absence of readily available immediate pleural fluid pH measurement, an initial pleural fluid glucose <3.3 mmol/L may be used as an indicator of high probability of CPPE/pleural infection and can be used to inform decision to insert ICD in the appropriate clinical context. (Strong—by consensus)

Good practice points

• Clinicians should be mindful of alternative diagnoses that can mimic PPE with a low pH and potential for loculations (eg, rheumatoid effusion, effusions due to advanced malignancy/mesothelioma).

• Pleural fluid samples taken for pH measurement should not be contaminated with local anaesthetic or heparin (eg, by extruding all heparin from an arterial blood gas syringe) as this lowers pleural fluid pH. Delays in obtaining a pleural fluid pH will also increase pleural fluid pH.

• In patients where a clinical decision is made not to insert an ICD at initial diagnostic aspiration, regular clinical reviews should be performed and repeat thoracocentesis considered to ensure that CPPE is not missed.

The data derived from this question review have been integrated into an updated decision-making algorithm for the diagnosis of patients with pleural infection which includes both pleural fluid and radiological parameters—see Appendix 1, Suspected pleural infection, non-purulent fluid—initial decision tree.

Adequate drainage of infected fluid from the pleural space in order to achieve source control is a cornerstone of pleural infection management. There are a number of means by which the infected pleural fluid may be removed, ranging from simple percutaneous aspiration or drainage via chest tube to more invasive thoracoscopic and surgical measures. The next clinical question was:

• C3 For adults with established pleural infection, what initial drainage strategy provides the best clinical outcomes and includes discussion on initial size of chest tube to be used for the treatment of pleural infection and whether initial surgical management should be considered?

A summary of the evidence review is shown in Table 19 and the evidence statements, recommendation and GPPs are presented below. The full evidence review is presented in online supplemental appendix C3.

Table 19: Evidence Review summary for ‘For adults with established pleural infection, what initial drainage strategy provides the best clinical outcomes?’

Pleural infection results in the arrangement to the usual fibrinolytic characteristics of the pleural space and it is well established that fibrin deposition and septations occur during the development of pleural infection. On this basis, intrapleural treatments have been used for many years in an attempt to reduce septations and improve drainage, thereby attempting to avoid the need for more invasive surgical management in patients with pleural infection. Intrapleural therapies include fibrinolytics, combined intrapleural enzyme therapy, saline irrigation and intrapleural antibiotics.

The next question investigated if intrapleural therapies improve clinical outcomes in adults with pleural infection (including tuberculous empyema) compared with other treatment options such as drainage alone or surgical intervention:

• C4 For adults with pleural infection, does intrapleural therapy improve outcomes compared with other treatment options (eg, drainage alone or surgical intervention)?

A summary of the evidence review is shown in Table 20 and the evidence statements, recommendations and GPPs are presented below. The full evidence review is presented in online supplemental appendix C4.

Table 20: Evidence Review summary for ‘For adults with pleural infection, does intrapleural therapy improve outcomes compared to other treatment options (e.g. drainage alone or surgical intervention)?’

Standard care—chest drainage alone or chest drainage with intrapleural placebo.

†Reported in a single study.

‡Including persistent chest pain, cough, fever, breathlessness and debilitation.

§Including chest pain, bleeding, fever and tube blockage/dislodgement.

¶Meta-analysis results reported as per 1000 patients.

TPA, tissue plasminogen activator.

Evidence statements

• Streptokinase appears to have no effect on mortality (Very low), length of hospital stay (Very low), the need for thoracic surgery (Very low) or radiographic resolution of effusion (Very low) for the treatment of pleural infection.

• Streptokinase increases post-treatment complications (Very low) when compared with chest drainage alone or placebo for the treatment of pleural infection.

• Urokinase appears to reduce the need for thoracic surgery (Low), hasten the time to resolution of fever (Very low) and reduce the length of hospital stay (Low) compared with placebo or standard care in adults with pleural infection.

• TPA plus DNAse appears to reduce the length of hospital stay (Ungraded), reduce the likelihood of persistent fevers (Ungraded) and increase improvements in CXR opacification (Ungraded), when compared with placebo in the treatment pleural infection, but TPA plus DNAse may increase the risk of post-treatment complications (serious and non-serious). (Ungraded)

• Single agent TPA or single agent DNAse do not appear to improve clinical outcomes when compared with placebo for treating pleural infection. (Ungraded)

• Saline irrigation (250 mL saline three times a day) may reduce the need for thoracic surgery (Ungraded) but appears to have no impact on mortality (Ungraded), length of hospital stay (Ungraded) or time to resolution of fever (Ungraded) when compared with saline flushes.

A significant proportion of patients with pleural infection fail to improve following optimal medical therapy, and surgical intervention is then required, accepting that not all patients are suitable to undergo surgical treatment. Precise criteria of when to refer for surgery, or what parameters constitute ‘failed medical therapy’ remain unclear.

Different surgical approaches can be used to access the infected space in pleural infection; and these are broadly classified as endoscopic techniques, termed VATS, or open techniques, termed thoracotomy. The next clinical question assessed what the optimal surgical approach is for treating patients with pleural infection:

• C5 For adults with pleural infection, which surgical approach provides the best clinical outcomes?

A summary of the evidence review is shown in Table 21 and the evidence statements, recommendation and GPP are presented below. The full evidence review is presented in online supplemental appendix C5.

Table 21: Evidence Review summary for ‘Which surgical approach provides the best clinical outcomes?’

In parallel to the surgical approaches described in the ‘Which surgical approach provides the best clinical outcomes?’ section above (and corresponding online supplemental appendix C5), at the referral point for surgery, different surgical methods can be deployed, broadly classified into drainage, debridement and visceral decortication. The final clinical question in this section therefore aimed to investigate what the best surgical method is for treating pleural infection:

• C6 For adults with pleural infection, which method of surgery provides the best clinical outcomes?

The evidence statement and GPPs are presented below; and the full evidence review is presented in online supplemental appendix C6.

MPE are of increasing incidence with around a global incidence of around 70 per 100 000 per year.(52) The most common causes of secondary pleural malignancy are lung cancer and breast cancer. Other common primary sites for pleural metastasis include lymphoma, gastrointestinal malignancy and genitourinary malignancy. Malignant pleural mesothelioma (MPM) is a common cause of MPE but is not specifically addressed as part of this guideline, although principles of fluid management and pleurodesis remain similar. MPM is specifically addressed in the British Thoracic Society Guideline for the investigation and management of pleural mesothelioma 2018.(10) The management of MPE has developed hugely since the publication of the management of an MPE: British Thoracic Society Pleural Disease Guideline 2010.(6) Where previously pleural fluid cytology and chest tubes with talc pleurodesis were the mainstay of diagnosis and treatment, there are now many evidence-based options available to clinicians. Medical thoracoscopy is now more widely available and allows the combination of diagnosis and treatment (please see the ‘Medical thoracoscopy’ section in the BTS Clinical Statement on Pleural Procedures for further details(1)). Ambulatory pathways are now a realistic option for patients, and there is evidence for the relative effectiveness of each option.

Detailed radiological evaluation is commonly performed as part of the assessment for patients with clinical or X-ray findings raising the possibility of pleural malignancy. A range of imaging tools are available including TUS, CT, PET-CT and MRI. Histological confirmation is the gold standard for diagnosis of pleural malignancy, but where tissue sampling is not possible a clinical diagnosis may be made on the basis of disease behaviour over time. Hence, the first clinical question in this section evaluated the diagnostic accuracy of radiological tests to distinguish malignant from benign pleural pathology:

• D1 What is the diagnostic accuracy of radiology in adults with suspected pleural malignancy?

A summary of the diagnostic accuracies of TUS, CT and PET-CT is shown in table 22 (taken from online supplemental appendix D1, Table D1e).

Table 22: Summary of the diagnostic accuracy of thoracic ultrasound (TUS), CT and PET-CT

*Studies performed in patients with pleural effusion suspected of pleural malignancy.

The use of MRI for evaluation of the pleura is relatively uncommon, but three studies, each assessing different techniques, met the criteria for inclusion. One study assessed the morphological assessment of the pleura, using criteria by Leung et al (56) with MRI, and found it comparable to CT assessment (sensitivity 0.98, specificity 0.92).(57) However, MRI was better able to detect subtle chest wall and/or diaphragmatic infiltration than CT. Malignant pleural disease also tended to be hyperintense on T₂-weighted images and gadolinium-enhanced T₁-weighted images, unlike benign disease. A second study identified the presence of multiple hyperintense foci on the pleura on high b-value diffusion-weighted images (‘pointillism’) as a marker of malignancy (sensitivity 0.93, specificity 0.79).(58) The final study described a novel marker of pleural malignancy defined by early contrast enhancement on dynamic contrast-enhanced images which, when combined with recognised morphological features, resulted in a sensitivity and specificity of 0.92 and 0.78, respectively. However, comparison with CT evaluation in the same cohort (sensitivity 0.56, specificity 0.77) did not show a statistically significant difference.(59)

The evidence statements, recommendations and GPPs are presented below, and the full evidence review is available in online supplemental appendix D1.

Please also note that the presented data should be supplemented by reference to Section 5 of the BTS Guideline for the investigation and management of pleural mesothelioma.(10)

MPE often recur after initial aspiration.(6) Since MPE is a marker of advanced disease and is associated with a poor prognosis, treatment focuses on palliation of symptoms and maintenance of quality of life. Anecdotal reports suggest that MPEs often resolve rapidly after initiation of chemotherapy, avoiding the need for a definitive procedure, so the next clinical question aimed to determine whether SACT reduces the requirement for pleural drainage and pleurodesis, with specific focus on treatment-sensitive tumours:

• D2 For adults with malignant pleural effusion, does systemic therapy avoid the need for definitive pleural intervention?

The evidence statements, recommendation and GPPs are presented below and the full evidence review is available in online supplemental appendix D2.

Chest drain insertion with talc pleurodesis provides definitive management of MPE by creating permanent fusion of the pleural layers. This requires hospitalisation with a chest drain in situ for a number of days. Pleural aspiration with no attempt at pleurodesis is an alternative approach and has the advantage of not requiring hospital admission but fluid may recur. Understanding which of these interventions has the most benefit for important clinical outcomes would permit rational treatment choices, so the next clinical question was:

• D3 For adults with malignant pleural effusion, is pleural aspiration with no pleurodesis agent better than talc slurry at improving clinical outcomes?

The evidence statements, recommendation and GPPs are presented below, and the full evidence review is available in online supplemental appendix D3.

Chest drain insertion with talc pleurodesis and IPCs provide definitive treatment options in the management of MPE. Talc pleurodesis has long been considered the standard of care, however, understanding the role of IPCs in comparison is key to provide optimal options to patients with MPE. This led to the next clinical question:

• D4 For adults with malignant pleural effusion, is an indwelling pleural catheter better than talc slurry pleurodesis at improving clinical outcomes?

A summary of the evidence is shown in Table 23 and the evidence statements, recommendation and GPPs are presented below. The full evidence review is available in online supplemental appendix D4.

Table 23: Evidence Review summary for ‘Is an indwelling pleural catheter better than talc slurry pleurodesis?

In adults with MPE, talc pleurodesis is commonly used to provide long-term control of fluid. However, there is debate as to the best way to administer talc. This can either be talc slurry (emulsification of talc in normal saline which is then administered via a chest drain) or poudrage (administration of talc powder as an aerosol during thoracoscopy). Both techniques enable effective delivery of talc to the pleural space, but it has been theorised that talc poudrage may allow better coverage of the pleural space as the talc is directly visualised and may be associated with shorter length of stay as talc is delivered at the same procedure as fluid drainage. However, thoracoscopy is a more invasive procedure. The next clinical question assessed if thoracoscopy and talc poudrage is better than chest drain and talc slurry pleurodesis:

• D5 For adults with MPE is thoracoscopy and talc poudrage pleurodesis better than chest drain and talc slurry pleurodesis at improving clinical outcomes?

A summary of the evidence is shown in Table 24 and the evidence statements, recommendation and GPPs are presented below. The full evidence review is available in online supplemental appendix D5.

Table 24: Evidence Review summary for ‘Is thoracoscopy and talc poudrage pleurodesis better than chest drain and talc slurry pleurodesis?’

In adults with MPE, talc pleurodesis via slurry or poudrage, IPCs and aspiration are common treatment options and widely available. However, surgical intervention is a treatment option in those able to tolerate surgery, so the next clinical question reviewed if there are relative benefits of using a surgical approach in MPE compared with the above ‘physician’ approach:

• D6 For adults with malignant pleural effusion, is surgical pleurodesis or surgical decortication better than talc slurry pleurodesis at improving clinical outcomes?

The evidence statements, recommendation and GPPs are presented below, and the full evidence review is available in online supplemental appendix D6.

Management of patients with non-expandable lung can be challenging. IPCs have become the preferred management technique for these patients, so the next question reviewed the usefulness of using alternative techniques (pleural aspiration, talc slurry pleurodesis, talc poudrage pleurodesis and decortication surgery) to manage non-expandable lung in malignant pleural disease:

• D7 For adults with malignant pleural effusion and non-expandable lung, is pleural aspiration, talc slurry pleurodesis, talc poudrage pleurodesis or decortication surgery better than using an indwelling pleural catheter at improving clinical outcomes?

There is no well-defined objective definition of what constitutes ‘non-expandable lung’, but for the purposes of this guideline, non-expandable lung has been defined on expert group consensus as radiologically significant (with >25% of the lung not apposed to the chest wall) based on CXR appearances. It should be noted that there is significant interobserver variation in chest radiograph interpretation of the presence of non-expandable lung. Non-expandable lung may be associated with worse prognosis in MPE.(60) Non-expandable lung is preferred as a term to trapped or entrapped lung as it includes both visceral pleural thickening limiting re-expansion and endobronchial obstruction preventing re-expansion.

The evidence statements and GPPs are presented below, and the full evidence review is available in online supplemental appendix D7.

Patients with MPE and septated effusion are less likely to benefit from pleural fluid drainage because percutaneous drainage alone cannot effectively drain the effusion. This group of patients has been reported as having a worse prognosis than other patients with MPE.(61) Septated effusions can occur both in inpatients with chest drains and ambulant patients with IPCs. Effective drainage of the pleural space, either by decortication or by intrapleural enzymes, may improve symptoms. However, surgical intervention is invasive, and carries a significant risk of morbidity and mortality, and may not be appropriate in these patients. The next question compares the use intrapleural agents to achieve clearance of septated malignant effusion against surgical intervention or placebo.

• D8 For adults with malignant pleural effusion and septated effusion (on radiology), are intrapleural enzymes better than surgery, or no treatment at improving clinical outcomes?

No studies compared intrapleural enzymes against surgery; and furthermore, no studies were identified that looked at the role of surgery in patients with septated MPE. One reason for this may be that septated effusion is identified on ultrasound and surgeons have not historically performed ultrasound in their patients. Hence, the lack of literature supports the view that surgery is rarely used for these patients.

A summary of the intrapleural enzymes versus no treatment evidence review is shown in Table 25 and the evidence statements and GPPs are presented below. The full evidence review is available in online supplemental appendix D8.

Table 25: Evidence Review summary for ‘Are intrapleural enzymes better than surgery, or no treatment, for treating malignant pleural effusion and septated effusion (on radiology)?’

IPCs offer an ambulatory management pathway in patients with refractory MPE. The original studies (TIME2, the second Therapeutic Intervention in Malignant Effusion Trial and AMPLE, the Australasian Malignant Pleural Effusion trial) (62 63) used regimes of alternate day drainages and this has been incorporated in routine practice. There has been interest on the optimal drainage regime, whether a once-daily drainage regime would offer better clinical outcomes than the less frequent standard alternate days or whether it would be better to offer drainage when patients are symptomatic (symptom-based/conservative drainage regimes). Hence, the next question was:

• D9 For adults with malignant pleural effusion treated with indwelling pleural catheters, does symptom-based/conservative drainage have better clinical outcomes than daily drainage?

A summary of the evidence review is shown in Table 26 and the evidence statements, recommendations and GPPs are presented below. The full evidence review is available in online supplemental appendix D9.

With the increasing use of IPCs to control breathlessness in patients with MPE, there has been interest in ‘combination’ procedures, where a pleurodesis agent is inserted via a functioning IPC after a period of drainage. The next clinical question assessed the evidence for the clinical benefits of using this strategy:

• D10 For adults with malignant pleural effusion treated with indwelling pleural catheters, do intrapleural agents (talc or other pleurodesis agents) improve clinical outcomes?

The evidence statements and recommendation are presented below and the full evidence review is available in online supplemental appendix D10.

SACT provides the mainstay of active treatment for all patients with metastatic cancer, including those with disease spread to the pleura. Symptomatic malignant effusions can affect quality of life, breathing and performance status of these patients and hinder their ability to tolerate SACT, with drainage often needed prior to SACT commencing. Historically, some chemotherapy agents were delivered intrapleurally to act as sclerosants to aid pleurodesis. Recently, with the advent of medical thoracoscopy, regular insertion of IPCs and a growing number of novel anticancer treatments including immunological and biological agents, the intent of delivering intrapleural anticancer treatments has expanded beyond obtaining pleurodesis. Hence, the next question investigated if intrapleural anticancer therapies improve clinical outcomes over systemic treatments:

• D11 For adults with pleural malignancy, is intrapleural chemotherapy better than systemic treatment at improving clinical outcomes?

No studies directly compared intrapleural anticancer therapy with SACT alone, but the five studies included in the review compared:

1. Intrapleural chemotherapy versus intrapleural combination therapy (chemotherapy plus vascular endothelial growth factor (VEGF) inhibitor);

2. Intrapleural chemotherapy versus intrapleural sodium chloride;

3. Intrapleural chemotherapy versus intrapleural combination therapy (chemotherapy plus angiogenesis inhibitor);

4. Intrapleural chemotherapy;

5. Intracavitary (mixed intrapleural and intra-abdominal) chemotherapy versus intracavitary combination therapy (chemotherapy plus angiogenesis inhibitor).

The evidence statements, recommendation and GPP are presented below. The full evidence review is available in online supplemental appendix D11.

MPE are associated with short survival as, with the exception of MPM, they signify advanced or metastatic disease. Numerous other factors, including patient characteristics, pleural fluid parameters and biochemical and haematological values have been shown to be related to clinical outcomes in MPE, however these findings have often lacked validation in independent cohorts. Relating separate findings to each other, and interpreting them in the context of patients, is also often difficult. By combining prognostic factors into validated scoring systems, these may be more clinically useful, so final clinical question in this section aimed to determine if validated prognostic scores exist for MPE and, if so, their use improves clinical outcomes for adults with MPE (excluding mesothelioma):

• D12 For adults with pleural malignancy, does the use of prognostic and predictive scores improve clinical outcomes?

No studies compared clinical outcomes in patients who had treatment directed by a prognostic score at baseline compared with those who had treatment directed using standard measures. Two externally validated prognostic scoring systems have been reported for MPE, the LENT (pleural fluid LDH, Eastern Cooperative Oncology Group (ECOG) performance score, neutrophil-to-lymphocyte ratio, tumour type) and PROMISE (pleurodesis response markers in malignant pleural effusion) scores, however the impact of these scores on clinical decision-making and outcomes other than survival has not been evaluated.(64 65)

The LENT score combines pleural fluid LDH levels, ECOG performance status, serum neutrophil-to-lymphocyte ratio (NLR) and underlying tumour type to predict patients at low risk, moderate risk or high risk of mortality.(64) The PROMISE score evaluates seven clinical biomarkers and one pleural fluid biomarker (haemoglobin, CRP, white blood cell count, ECOG performance status, cancer type, pleural fluid tissue inhibitor of metalloproteinases 1 (TIMP1) concentrations and previous chemotherapy or radiotherapy) to predict absolute risk of death at 3 months.(65)

The evidence statements, recommendation and GPPs are presented below. The full evidence review is available in online supplemental appendix D12.

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The Guideline Development Group (GDG) was chaired by three respiratory consultants—Professor Nick Maskell, Professor Najib Rahman and Dr Mark Roberts. The GDG had a wide membership and included colleagues from respiratory medicine, oncology, radiology, pathology and palliative medicine. Two patient representatives were recruited to the group, but due to personal circumstances both had to withdraw before completion of the guideline (August 2019 and July 2021). However, two further patient representatives were recruited at the end of the guideline process to review the final guideline and provide the patients’ perspective. Those on the group were not required to be BTS members and a full list of members can be seen below.

BTS declarations of interest forms have been completed by all members for each year they were part of the GDG. Details of these forms can be obtained from BTS Head Office. ‘Declarations of interests’ was a standing item at each GDG meeting.

The co-chairs would like to acknowledge the huge contributions of all guideline group members both to robust discussions during the meetings and sourcing, critically reviewing papers and formulating judgements. They would also like to specifically thank Dr Kirstie Opstad at BTS Head Office who has coordinated the whole process, performed searches and initial abstract filtering, supported the evidence review process and ensured consistency of presentation of the whole guideline. 

The GDG would like to thank Mr Richard Bremner, Mr Yannick Mouchilli, Mr Chris Smith and Dr Tim Wallington (patient representatives) for their helpful contributions during development of this guideline.

Stakeholders were identified at the start of the process. All stakeholder organisations were notified when the guideline was available for public consultation and a list is published below.

• Association for Palliative Medicine of Great Britain & Ireland
• Association of Respiratory Nurse Specialists
• British Society of Thoracic Imaging
• British Thoracic Oncology Group
• Royal College of Pathologists
• Royal College of Radiologists
• Society for Cardiothoracic Surgery in Great Britain & Ireland

The guideline will be reviewed 5 years after the date of publication.

Click on the tabs to view the appendices for each section.