A scoping review protocol to identify clinical signs, symptoms and biomarkers indicative of biofilm presence in chronic wounds

Introduction

Wound healing occurs via a complex sequence of events which, under normal circumstances, proceed in an orderly fashion through haemostatic, inflammatory, proliferative and remodelling/maturation phases to restore cutaneous integrity and barrier function. However, in the presence of complicating factors such as diabetes or chronic venous insufficiency, the healing process can break down and the wound becomes chronic, failing to heal in a timely manner.^1,2 There is a lack of consensus regarding the definition of chronic wounds and they have for example, been described as ‘wounds that have not proceeded through an orderly and timely reparation to produce anatomic and functional integrity after 3 months’, ‘wounds that lack a 20–40% reduction in size after 2–4 weeks of optimal treatment or when there is not complete healing after 6 weeks’, or simply as ‘wounds that fail to proceed through the normal phases of wound healing in an orderly and timely manner’^2,3. Typically, these wounds include but are not limited to venous, diabetic and pressure aetiologies⁴. Chronic wounds of mixed aetiologies were estimated to have a pooled prevalence of 2.21 per 1000 population in a 2019 meta-analysis of three studies, while a second meta-analysis from the same year including nine studies estimated the pooled prevalence of chronic leg ulcers to be 1.5 per 1000 population⁵. Chronic wounds are burdensome to the individual in terms of finances and quality of life, and to healthcare systems. Unhealed diabetic foot ulcers (DFU), venous leg ulcers (VLU) and pressure ulcers (PU) cost the United Kingdom National Health Service (NHS) approximately £4 billion in 2017–2018, or an average of £6305 per patient.^6,7

Infection commonly affects chronic wounds and is associated with poor clinical outcomes⁸. The risk of hospitalisation for patients with a DFU is increased by a factor of 50 while the risk of lower-extremity amputation is 150 times higher if their wounds become infected. Development of infection in chronic wounds is a complex process. Multiple factors including virulence of colonising organisms, synergy between multiple microbial species, bioburden and host resistance interact with each other and determine whether a wound will progress from a non-threatening, contaminated/colonized state through to critically colonized or infected states.⁹

Bacteria can manifest in wounds as a free-floating planktonic phenotype or as a sessile biofilm phenotype¹⁰. Biofilms occur when microbial cells organise themselves into aggregates or communities encased in a self-produced polymeric matrix which typically attach to surfaces. Biofilms exhibit high levels of tolerance to antimicrobial agents and host defences¹¹. When they form in critically colonized chronic wounds, healing stalls and the wound remains stuck in the inflammatory phase^12–16.

In 2017, a panel of specialists, chosen for their expertise in chronic wounds and biofilms, for their scholarly activity and publication record, issued a consensus document¹⁷. The document aimed to clarify the role of biofilms in clinical practice, help clinicians to recognize biofilms in chronic non healing wounds and optimise patient management. A modified Delphi process was used to achieve consensus on a series of statements formulated to address issues in ten areas relevant to management of non-healing chronic wounds. Five-point likert scales of agreement (1 = disagree strongly – 5 = agree strongly) and ranking (1 = not important – 5 = most important) were used to score the statements. There was strong agreement (mean 4.0, standard deviation [SD] 0.82) that specific clinical signs and symptoms should be used to confirm presence of biofilm in the absence of diagnostic bedside tests. Clinical features, such as a recurring gelatinous material on the wound edge, have been proposed as surrogate markers of wound biofilm but there was weak agreement (mean 3.6, SD 1.5) that the clinical signs and symptoms that could indicate the presence of biofilm. Little is known about presentation and diagnosis of wound biofilms and knowledge of their characteristics is limited¹⁸. Generally, biofilms are difficult to diagnose and currently no guidelines exist to help clinicians and microbiologists in diagnosis and treatment¹⁹.

In addition, little quantitative work has been done with respect to clinical signs and symptoms of biofilm in chronic wounds, especially in human patients, and existing published research is mainly observational rather than incorporating more rigorous study designs^{12,17,18,20,21}.

For these reasons we suspect that a rigorous systematic review with a focused research question and strict criteria with respect to eligible study design may be too exclusive and fail to answer the research question.

A scoping review methodology will therefore be employed to identify any associated clinical signs and symptoms thought to determine the presence of biofilm in chronic wounds.

The research question for the study is: what clinical signs, symptoms and biomarkers are proposed within the literature to determine the presence of biofilm in chronic wounds?

Methods

The Preferred Reporting Items for Systematic Review and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR) statement, the Joanna Briggs Institute Manual for Evidence Synthesis will guide this work^22,23.

Discussion

Little work regarding biofilms’ impact on chronic wounds involving human subjects has been done and much of our clinical understanding is based on in vitro work. Clinician’s knowledge of research data and of the importance of biofilms in the management of non-healing chronic wounds is inconsistent¹⁷. This review will for the first time, consolidate those signs, symptoms and biomarkers of biofilm in chronic wounds reported in the literature into one document which may serve to open an avenue for future clinical research in this area.

Dissemination

The findings of this scoping review will be published in a peer-reviewed medical journal.

The research team will also regularly update and disseminate project findings to key stakeholders, research colleagues, patient representatives and knowledge users.

Study status

The review has not yet initiated.

Data availability

No data are associated with this article.