Therapy of parapneumonic empyema in children: a protocol for a scoping review of the literature

Background Empyema (the presence of pus in the pleural space) is a severe complication of community-acquired pneumonia and significant cause of morbidity, but, fortunately, not mortality in children. Between 0.6 and 2% of pneumonias are complicated by empyema and the three main pathogens involved are Streptococcus pneumoniae, Staphylococcus aureus and group A Streptococcus 1,2,3,4. Optimal management in children, especially the choice of antibiotics, method of administration and duration of therapy, pleural dranage or surgery, are still a matter of debate and currently, lack of strong specific recommendations. This paper displays the study protocol for a scoping review that aims to summarize the available literature on the microbiological epidemiology, the medical and surgical treatment options, and the outcomes of pleural empyema in pediatric population. Methods Comprehensive research combining the terms pediatric (children aged 0 to 18 years) and pleural empyema will be performed on PubMed and SCOPUS to identify all eligible studies. At first, two reviewers will screen the abstract and then their full text to determine the articles that meet the inclusion criteria. This work will be carried out independently, everyone on a different Excel spreadsheet and each researcher will be blinded to the decision of the other researcher. When the process is completed, in case of discordance, any disagreement will be identified and resolved through discussion or with help of a third author. Dissemination The findings of this review will be published in a peer-reviewed journal.


Introduction
2][3][4][5] It has been estimated that parapneumonic effusions develop in about 1 in 100-150 children with CAP 6,7 but they could be discovered in as many as 40% of hospitalised children with CAP. 8 CAP, are caused mainly by Streptococcus pneumoniae 9 and their incidence has shown fluctuations over time.In particular, a significant global reduction in pneumococcal disease and mortality rates has been reported after the introduction of heptavalent pneumococcal conjugate vaccine (PCV7), which covers serotypes 4, 6B, 9V, 14, 18C, 19F and 23F, into the standard childhood immunisation schedule. 10In the following years, however, in the USA an increase in pneumococcal empyema, related to serotypes not covered by PCV7, has been reported. 11After the replacement of the PCV7 with the PCV13, which covers also serotypes 1, 3, 5, 6A, 7F and 19 A, there has been a significant reduction in incidence and rate of hospitalisation for empyema. 12The introduction of PCV13 is particularly important in consideration of the strong correlation between parapneumonic empyema and serotype 1 of pneumococcus. 13her bacteria seem to be less frequently pathogens of CAP.However, other possible bacterial pathogens of parapneumonic empyema are represented by group A Streptococcus and Staphylococcus aureus. 13inical presentation of parapneumonic empyema is similar to that of uncomplicated CAP. In physical examination, typically, parapneumonic empyema is characterized by decreased air entry breath and dullness to percussion. 9A clinical suspect of parapneumonic empyema should be confirmed performing a chest X-ray and/or pulmonary ultrasound.Ultrasound technique has a higher sensitivity than radiograph in determining extension and nature of fluid collection and it is very useful for monitoring children with empyema, considering that it does not expose to X-rays.Thoracic CT is not considered a first line exam in order to make diagnosis of empyema, but it should be performed when it is not possible to make a clear diagnosis or when there is a suspect of malignancies (i.e.Burkitt's lymphoma).
All cases of parapneumonic empyema should be treated with empiric intravenous antibiotic therapy, covering Streptococcus pneumoniae, Streptococcus pyogenes and Staphylococcus aureus.However, in case of large effusion (> 2 cm) or compromission of respiratory function a chest drainage is essential. 5,14Chest drainage is generally performed under ultrasound guide and children should be under sedation/general anaesthesia. 14Intrapleural fibrinolytics (i.e.urokinase) are particularly useful in shortening hospitalisation in cases where drainage is slow, in consideration of thick or loculated fluid. 5,14Thoracic surgery should be taken in consideration in cases of failure of antibiotic therapy, chest drainage and fibrinolytics.However, guidelines are unclear about which surgical procedure is best and at which timing, as well duration of drainage or of antibiotic therapy, including optimal timing about oral shift and how these issues reflect on outcomes.
This scoping review aims to analyse the optimal antibiotic therapy, defining antibiotic molecule, route of administration and duration of antimicrobial therapy.

REVISED Amendments from Version 1
We have performed the requested changes.
In particular we have: -Clarified further some inclusion and exclusion criteria.
-Clarified analyses according to microbiological results.
-Expanded outcomes and literature research.
-Improved grammar structure as suggested by reviewer 1.
Any further responses from the reviewers can be found at the end of the article

Review questions
Considering the importance of a mutual consensus in the clinical management of parapneumonic empyema in children, as documented in the available literature, 15 the main review question will be: what is the available literature about the most appropriate antibiotic treatment for paediatric PE in terms of first-line agents choice, dose, route of administration and duration?This review will also assess the following sub-questions: 1. Which are the most frequently reported pathogens and what is their antibiotic susceptibility profile? 2. Which outcomes and complication rates of PE are the most frequently reported in literature?Which are the most frequently reported treatments, both conservative or invasive, and which leads to improved outcomes and shorter length of stay?
Inclusion criteria Participants This review will include studies performed on children and adolescents (younger than 18 years) with a confirmed diagnosis of empyema, defined as the presence of pus within the pleural cavity.The diagnosis of empyema is established by the presence of pus, positive Gram's stain, or culture, or nucleic-acid amplification tests, in the pleural fluid.We will only include studies that have documented at leaast one of the following: the microbiological aetiologies, performed antimicrobial and surgical therapies, as well outcomes (at least at time of discharge).Only studies in English will be included.Empyema due to tuberculosis will be excluded.

Concept
The main concept of this review will be empyema in all its aspects, with a particular focus on treatment options.

Context
Considering the severity of the disease, we will not expect to find articles involving patients not hospitalized so we will include only inpatients.

Type of sources
This review will include both randomized controlled trials and non-randomized controlled trials.All the types of observational studies, prospective and retrospective (including case-control, cohort and cross-sectional studies, small case series or single case reports) will be included.

Search strategy
The search will be performed by one reviewer.We started our research in April 2023 in the following bibliographic databases: PubMed and SCOPUS.There will be date restrictions: we will search from the 1st of January 2000 to 31st of March 2023.Only articles written in English will be included.The search strategy will include a combination of the following word and their synonymous: "pediatric", "empyema", "pleural effusion" and "treatment".The search strategy for PubMed is available in the extended data section of this protocol; the terms used for this search will be adapted for use with other bibliographic database.

Study selection
After the search, the studies will be exported to Rayyan.A first screen to exclude duplicates will be performed by one author.
Titles and/or abstracts of studies retrieved using the search strategy will be screened independently by two reviewers to identify studies that could be inserted reviewed.Full texts of potentially eligible studies will be retrieved and independently assessed for eligibility by two reviewers.Each researcher will be blinded to the decision of the other researcher.Any disagreement between them over the eligibility of studies will be resolved through discussion and, in case of further disagreement, by discussion with a third reviewer.
All the studies that will not meet the inclusion criteria will be excluded and a table with the reason why those studies were excluded will be inserted in the final manuscript.
The results of the search will be reported in the PRISMA flow diagram.

Data extraction
Two review authors will extract data independently, both on a different Excel spreadsheet.Each researcher will be blinded to the decision of the other researcher.When the process will be completed, in case of discordance, any disagreement will be identified and resolved through discussion (with a third author if necessary).
An Excel file will be used to store data.When available, extracted information will include: 1. study general features: title, author, year of publication, type of study, number of patients included in the study, geographical area where the study has been performed 2. participant general features: sample size of each group, nationality, age, socio-economic status, comorbidities 3. clinical manifestation of the condition: fever (including days), cough with mucus, dyspnoea, chest pain and others.
4. main imaging findings: type of lung involvement at chest X-Ray and/or CT scan, type of CNS involvement at CT scan or MRI, type of skin involvement evaluated by ultrasound or CT scan or MRI, heart (US or CT or MRI) 5. characteristics of eventual antimicrobial treatments performed during the empyema (length of therapy, when this has been started and which antibiotic was used) 6. adjunctive treatments performed and length of therapy during the empyema (e.g., steroids or other immunomodulatory medications) 7. surgical treatments performed and length of therapy during the empyema (e.g., drainage or thoracoscopy or surgical resection) 8. outcomes (admission to intensive care, death, survival; survival with sequelae; type of sequelae)

Data analysis and presentation
To report our findings, we will follow Preferred Reporting Items for Systematic reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR) Checklist.
We will produce a narrative synthesis of the findings from the studies included in the review describing the results we have obtained and providing our opinion on their interpretation.A particular focus with a narrative synthesis will be performed for antimicrobial and surgical therapy characteristics in terms of frequency of antibiotic choice, efficacy, and duration of therapy.
We will also use tables and charts to summarize both study characteristics and the most important clinical, diagnostics, treatments, and outcomes data.
More specifically, we will summarize our findings using different tables.The first one will include the characteristics of included studies (number of studies, study design, year of publication, characteristics of the study populations and countries where studies were conducted) and the participant general features.Then we will provide different tables or figures summarizing main data about clinical presentation, imaging characteristics, treatments performed, outcomes and predictors of empyema.We will also evaluate outcomes and treatment approaches according to the different aetiologies.
This way we hope we will be able to provide a useful document containing what is currently known of pediatric empyema with the aim of informing clinicians about the general characteristics of these conditions, focusing on risk factors and early clinical features, and guide future research projects to fill current gaps.

Study status
Protocol has been submitted and researched launched on the different datasets.Abstract screening will start after protocol submission.

Patient and public involvement
There was no direct patient and public involvement in this review.However, the key questions that led us implementing this research project were inspired by public discussions started by family associations in the media, highlighting the importance of better comprehension of how empyema can be recognized earlier in the disease course (before clinical conditions deteriorates and cannot be controlled anymore), or empyema may also be prevented if this complication is a consequence of a previous unrecognized and untreated lung infection.

Strengths and limitations of this study
• A scoping review can represent the best way to report on the types of evidence that are published in a certain field and our paper will provide an overview of empyema, focusing on predictors of positive outcomes.
• A scoping review can represent the best way to examine this field to guide future research on this topic.
• To report our findings, we will follow the Preferred Reporting Items for Systematic reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR) Checklist to ensure methodological strength to our paper.
• Only two databases were screened, and only English paper will be considered limiting the number of papers that will be included.
• No critical appraisal neither risk of bias of the included studies will be performed, considering the exploratory role of this paper.

Open Peer Review
Current Peer Review Status:

Catherine A Byrnes
Auckland District Health Board, Starship Children's Health, Auckland, New Zealand Thanks -I think the changes are appropriate.
I think it looks good for indexing.
I have a couple of minor English edits to make to read correctly (but if you make those changes it can go straight to indexing ) Intro para 5 'a suspicion of malignancies' Intro para 6 ''or compromising respiratory function' intro para 6 'including optimal timing about shifting to oral antibiotics and' intro para 7 'defining antibiotic of choice' participants 'as well as outcomes' study selection 'could be reviewed' (delete 'inserted') data extraction 'when the process is completed' that's it -thanks Competing Interests: No competing interests were disclosed.
Reviewer Expertise: Paediatric Respiratory disease I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard.
Reviewer Report 27 June 2024 https://doi.org/10.5256/f1000research.167272.r285923 1.In the method part, I am not aware of how the bacterial results is analyzed or included.Please consider elaborating it.
2. The severity of outcomes including intensive care unit stay can be included as analysis.
3. Some of the pleural empyema can be caused by tuberculosis, which the antimicrobial use would be different.Please consider to address this in the protocol.
Is the rationale for, and objectives of, the study clearly described?Yes Is the study design appropriate for the research question?

Are sufficient details of the methods provided to allow replication by others? Yes
Are the datasets clearly presented in a useable and accessible format?

Not applicable
Competing Interests: No competing interests were disclosed.
Reviewer Expertise: Respiratory Medicine, Respiratory infection, Epidemiology I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above.

Catherine A Byrnes
Auckland District Health Board, Starship Children's Health, Auckland, New Zealand Generally this is a good proposal -responding to queries and questions generated from patients and using Prism as the backbone which is good.Not much is mentioned regarding chest drains -nil in abstract, not till the 2 nd to last paragraph in the introduction and as part of the Qs -mentioned in passing.The authors need to clarify this a bit more.Is chest drainage and/or video assisted thoroscopic surgery going to be included? 1.
Articles only in English or other languages.The authors should define the languages of the articles they are searching in.

2.
Only including patients that have an identified organism -many patients are difficult to get 3. a positive culture from -and often the published articles have some with identified organisms and some without -yet the authors here are only including those where bacteria have been isolated -can they clarify this?
If greater than 100 articles -will then restrict to last 5 years -better if stuck to the whole.Either do all articles or restrict to 5 years -wouldn't go with the number being a restriction.

4.
Note that although this is being presented as a protocol, the review has already started.5.
In the selected word options for search -no "pleural effusion".The authors have given the search words they have used but have not included "pleural effusion".

6.
The manuscript could do with some English editing -I appreciate that the authors are likely writing this in a second language.Some editing is needed to put some of the phrasing into correct grammatical English.

Is the study design appropriate for the research question? Partly
Are sufficient details of the methods provided to allow replication by others?
The benefits of publishing with F1000Research: Your article is published within days, with no editorial bias • You can publish traditional articles, null/negative results, case reports, data notes and more • The peer review process is transparent and collaborative • Your article is indexed in PubMed after passing peer review • Dedicated customer support at every stage • For pre-submission enquiries, contact research@f1000.com

Version 2 Reviewer
Report 01 August 2024 https://doi.org/10.5256/f1000research.167272.r285922© 2024 Byrnes C.This is an open access peer review report distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.