F1000Research F1000Research 2046-1402 F1000 Research Limited London, UK 10.12688/f1000research.131669.1 Study Protocol Articles Presepsin and procalcitonin as markers of infectious respiratory diseases in children: a protocol for a scoping review of the literature

[version 1; peer review: 1 approved with reservations]

 Sodero Giorgio Writing – Original Draft Preparation Writing – Review & Editing https://orcid.org/0000-0003-3711-4928 1 Mariani Francesco Methodology Writing – Original Draft Preparation Writing – Review & Editing https://orcid.org/0000-0002-1142-6678 a 1 Pulcinelli Valentina Writing – Original Draft Preparation 1 Gentili Carolina Writing – Original Draft Preparation 1 Valentini Piero Supervision 2 Buonsenso Danilo Conceptualization 2 Universita Cattolica del Sacro Cuore, Rome, Italy Department of Woman and Child Health and Public Health, Fondazione Policlinico Universitario Agostino Gemelli, Rome, Italy francesco.mariani.100292@gmail.com

No competing interests were disclosed.

 9 3 2023 2023 12 253 1 3 2023 Copyright: © 2023 Sodero G et al. 2023 This is an open access article distributed under the terms of the Creative Commons Attribution Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Background: Presepsin is a new inflammatory marker used in clinical practice for the diagnosis of severe bacterial infections, which might be used in combination or substitution of other classical indexes such as procalcitonin. Presepsin has been studied mainly in specific categories of patients (generally adults, critically ill patients or neutropenic children) to identify severe bacterial infections and to predict the mortality risk, while the role of this marker in discriminating bacterial from viral infections in otherwise healthy children of different age groups is less examined. This scoping review aims to better explore available evidence around the potential role of presepsin in pediatric respiratory infectious diseases, analyzing its ability to distinguish the severity and type of respiratory pathology and comparing it with a classic inflammation index such as procalcitonin.

Methods: We started our research in February 2023 in the following bibliographic databases: PubMed, EMBASE, Cochrane and SCOPUS. The main review question will be “What is known about the diagnostic role of presepsin and/or procalcitonin in the differential diagnosis of respiratory tract infection’s severity and etiology?” We will include randomized and non-randomized controlled trials, prospective and retrospective observational studies, performed on children and adolescents (younger than 18 years), hospitalized or not, with a confirmed diagnosis of upper and/or lower respiratory infectious disease. We will include children diagnosed with pneumonia, bronchiolitis, bronchitis, croup, and other types of infectious respiratory diseases. To report our findings, we will follow Preferred Reporting Items for Systematic reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR) Checklist.

Dissemination: The findings of this review will be published in a peer-reviewed journal and presented in national and international conferences.

 Presepsin infectious disease bronchiolitis The author(s) declared that no grants were involved in supporting this work. Introduction

Presepsin is a new marker of inflammation formed by cleavage of N-terminal of soluble CD14, a member of the Toll-like receptors group; this protein is present in macrophage and other granulocyte cells on their cell membranes, and it is responsible for intracellular transduction of endotoxin signals. 1 In the last years, presepsin has been increasingly used in clinical practice as an indicator of presence and severity of serious infections like sepsis, as it is released by immune system cells involved in the response to pathogenic bacteria, although its utility in patients’ prognosis is not yet fully understood, particularly in children. 2

In pediatrics, it has been particularly studied for the early diagnosis of neonatal sepsis, in combination with other classic inflammation markers such as procalcitonin, 3 while the role of presepsin in discriminating bacterial from viral infections in other clinical scenarios is less studied. For example, respiratory diseases still represent a major cause of mortality, morbidity and antibiotic use, and in this context presepsin could be used as a useful discriminator of bacterial pneumonia or severity, 4 and it could be also related to the mortality risk of critical patients.

Although its use in neonates is well characterized, 3 the evidence for the use of this marker in children aged > 6 months is not clear because it is not a test routinely used in clinical practice and it has been studied mainly in critically ill patients or with important comorbidities such as neutropenia, 5 , 6 with excellent results.

This scoping review aims to analyze the use of presepsin and procalcitonin in pediatric respiratory infectious diseases, analyzing the ability to distinguish the severity and type of respiratory pathology. In addition, we will also focus on comparing presepsin with procalcitonin, a better studied marker of severe bacterial infections in children.

 Review questions

The main review question will be “What is known about the diagnostic role of presepsin and/or procalcitonin in the differential diagnosis of respiratory tract infection’s severity and etiology?”

This review will also assess the following sub-questions:

Does the adjunction of presepsin to the use of procalcitonin improves the accuracy in identifying bacterial infectious diseases?

What is the role of presepsin and procalcitonin in the subgroup of children with bronchiolitis?

What is the role of presepsin and procalcitonin in the subgroup of children with respiratory syncytial virus bronchiolitis?

Inclusion criteria Participants

This review will include studies performed on children and adolescents (younger than 18 years) with a confirmed diagnosis of upper and/or lower respiratory infectious disease (clinical, microbiological or radiological diagnosis). We will include children diagnosed with pneumonia, bronchiolitis, bronchitis, croup, and other types of infectious respiratory diseases.

 Concept

The main concept of this review will be the use of presepsin and procalcitonin in pediatric respiratory infectious diseases.

 Context

Considering the large spectrum of severity of the disease, we expect to find articles involving patients both hospitalized or not for respiratory infections.

 Type of sources

This review will include both randomized controlled trials and non-randomized controlled trials. All 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.

 Methods Search strategy

We started our research in February 2023 in the following bibliographic databases: PubMed, EMBASE, Cochrane and SCOPUS.

There were no date restrictions. Only articles written in English will be included.

Patients younger than 18 years of age were considered as children or pediatric patients. The search strategy for Pubmed is available as supplementary material of this protocol (Appendix 1 available at https://doi.org/10.6084/m9.figshare.22155131.v1); the terms used for this search were adapted for use with other bibliographic databases.

 Study selection

After the search, the studies have been exported to Rayyan. A first screen to exclude duplicates was 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 in the review. 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, everyone 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:

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

participant general features: sample size of each group, nationality, age, socio-economic status, comorbidities

clinical manifestations of children included in our review

main imaging findings: type of lung involvement at chest X-Ray and/or CT scan

microbiological results

results of the inflammation indices performed (procalcitonin and presepsin)

antibiotic use

hospitalization, including pediatric intensive care

outcomes (death, survival; survival with or without 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. For the narrative synthesis we will prefer articles in which etiological diagnosis was specified.

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 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 second one will include participant general features. Then we will provide different tables or figures summarizing main data about clinical presentation, type of respiratory disease analyzed, imaging characteristics, hematochemical results with procalcitonin and presepsin levels, treatments performed, outcomes and possible predictors of outcome.

Dissemination

The findings of this review will be published in a peer-reviewed journal and presented in national and international conferences.

 Study status

We performed the research and screened for duplicates.

 Patient and public involvement

There will not be direct patient and public involvement in this review.

 Data availability

No data are associated with this article.

 References Azim A : Presepsin: A Promising Biomarker for Sepsis. Indian J. Crit. Care Med. 2021 Feb;25(2):117–118. 33707884 10.5005/jp-journals-10071-23741 PMC7922456 Velissaris D Zareifopoulos N Karamouzos V : Presepsin as a Diagnostic and Prognostic Biomarker in Sepsis. Cureus. 2021 May 13;13(5):e15019. 34150378 10.7759/cureus.15019 PMC8202808 Ruan L Chen GY Liu Z : The combination of procalcitonin and C-reactive protein or presepsin alone improves the accuracy of diagnosis of neonatal sepsis: a meta-analysis and systematic review. Crit. Care. 2018 Nov 21;22(1):316. 30463590 10.1186/s13054-018-2236-1 PMC6249912 Memar MY Baghi HB : Presepsin: A promising biomarker for the detection of bacterial infections. Biomed. Pharmacother. 2019 Mar;111:649–656. Epub 2019 Jan 3. 30611989 10.1016/j.biopha.2018.12.124 El Gendy FM El-Mekkawy MS Saleh NY : Clinical study of Presepsin and Pentraxin3 in critically ill children. J. Crit. Care. 2018 Oct;47:36–40. Epub 2018 Jun 3. 29886065 10.1016/j.jcrc.2018.06.004 Özdemir ZC Düzenli-Kar Y Canik A : The predictive value of procalcitonin, C-reactive protein, presepsin, and soluble-triggering receptor expressed on myeloid cell levels in bloodstream infections in pediatric patients with febrile neutropenia. Turk. J. Pediatr. 2019;61(3):359–367. 31916713 10.24953/turkjped.2019.03.007 10.5256/f1000research.144533.r234652 Reviewer response for version 1 Blanco Noémie Boillat 1 Referee Infectious Diseases Service, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland

Competing interests: No competing interests were disclosed.

 16 2 2024 Copyright: © 2024 Blanco NB 2024 This is an open access peer review report distributed under the terms of the Creative Commons Attribution Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. recommendation approve-with-reservations

This protocol presents the background and methodology of a scoping review on prepepsin and procalcitonin as markers of infectious respiratory diseases in children.

The subject of the study is interesting and relevant because data on this specific topic is missing and prepepsin could be an interesting marker for risk stratification and antibiotic guidance.

However, the methodology of the study should be improved.

Abstract:

Background:

Type of respiratory pathology: be more precise

Methods:

Diagnostic role of prepepsin and/or procalcitonin: do you mean “prepepsin alone or in combination with procalcitonin”? We are not interested in the performance of procalcitonin alone as they are already many meta-analyses on this topic.

Confirmed diagnosis of upper/lower RTI….and other types of infectious resp disaeses: be more precise, do you plan to include ENT infections? Pharyngitis, sinusitis, otitis?

Introduction:

Why did you choose a scoping review methodology rather than a systematic review?

Analyze the use of prepepsin and/or procalcitonin: be more precise: alone or in combination with….

Type of resp pathology:: what do you mean: differentiate bacterial vs viral RTI?

Review questions:

Prepepsin alone or in combination….: please replace throughout the manuscript.

In the DD of RTI: lower RTI?

Inclusion criteria:

Please, be more precise on the inclusion age: X-18

Other types of resp ID: be more precise

Methods:

No date restriction? Is there a lower limit?

Check to be inline with the PRISMA guidelines

Is the study design appropriate for the research question?

Partly

Is the rationale for, and objectives of, the study clearly described?

Yes

Are sufficient details of the methods provided to allow replication by others?

No

Are the datasets clearly presented in a useable and accessible format?

Partly

Reviewer Expertise:

ID

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.