Itch in Chronic Wounds: Pathophysiology, Impact, and Management

Background: The aims of this review are to analyze the current literature regarding the characteristics and pathophysiological mechanisms of itch in chronic wounds, to assess the impact on quality of life and delayed-healing, to focus on the best strategies of prevention and treatment, to highlight the importance of on-going research in order to fully understand the pathophysiology, and to improve the management of target therapies. Methods: A systematic literature review was performed using MEDLINE, PubMed, Embase, Scopus, ScienceDirect, and the Cochrane Library. We included a total of 11 articles written in English with relevant information on the pathophysiology of itch in chronic wounds and on management strategies. Results: Itch in chronic wounds was found to be correlated with xerosis, larger wound areas, necrotic tissue and amount of exudate, peripheral tissue edema, sclerosis, granulation tissue, contact dermatitis, and bacterial burden, as well as with lower quality of life. Conclusions: Although there are several aspecific pharmacological and non-pharmacological approaches, there appears to be no validated prevention or management strategy for itch in chronic wounds. Further studies are needed to clarify the association and pathophysiology of itch in chronic wounds, to evaluate the safety and efficacy of topical treatments on perilesional skin to reduce itch, to characterize multidimensional sensations of itch in chronic wounds, to identify specific cytokine and chemokine expressions that are correlated to a tailored-based approach, and to develop practical guidelines.


Introduction
Itch is a chief symptom in many dermatological diseases, which significantly impacts patients' quality of life (QoL) [1]. Few studies, however, have analyzed the clinical itch characteristics and pathophysiological mechanisms of itch in chronic wounds [2][3][4][5][6][7][8][9][10][11][12]. Thus, the aim of this review is to analyze the current literature on the characteristics and pathophysiological mechanisms of itch in chronic wounds, to assess the impact on QoL and delayed wound healing, and to focus on prevention and treatment strategies for pruritus associated with chronic wounds.

Literature Search
A systematic literature search was performed to identify major findings on itch in chronic wounds in adults. We used the following databases: MEDLINE, PubMed, Embase, Scopus, ScienceDirect, disease, wound pruritus, chronic wound itch, and itch management. We included only articles in English, with relevant information on the pathophysiology of wound-related itch and on management strategies. We excluded case reports, pediatric articles, and articles on acute wounds such as post-burn wounds.
We included a total of 11 articles. The PRISMA 2019 flow diagram shown in Figure 1 explains the search methodology used in the study.

Impact on QoL
We selected four articles regarding the impact on QoL. The key data are summarized in Table 1 [2-4,7].

Characteristics and Pathophysiological Mechanisms of Itch
We selected nine articles focused on the characteristics and pathophysiological mechanisms of itch. Table 1 summarizes the main key data-authors, year of publication, country, type of article, purpose of the study, and findings [4][5][6][7][8][9][10][11][12]. Overview of the physiological mechanisms of itch and comorbidities in acute and chronic wounds The itch causes a range of physical and psychological problems, reducing QoL and delaying healing. There are no specific guidelines on itch management in chronic wounds and further studies are needed.

Upton D. et al. [8]
2013 Australia Literature review Overview on psychological itch treatment in wounds Unconventional treatments such as habit reversal training, relaxation, massage, and itch coping programs showed a potential role in reducing itch in association with standard treatments, but current literature evidence is limited.

D'Erme A.M. et al. [9]
2016 Italy Literature review Overview on contact allergy and polysensitization in patients with chronic wounds Advanced dressings can cause allergic contact dermatitis. The most frequent was hydrogel, followed by hydrocolloid and by silver wound dressings. Primary prevention is required, avoiding sensitizers and irritant products, along with secondary prevention using patch tests in all patients with non-healing wounds.

Impact on QoL
We selected four articles regarding the impact on QoL. The key data are summarized in Table 1 [2][3][4]7].

Prevention of Itch in Chronic Wounds
We found no articles on how to prevent itch in chronic wounds, so we decided to correlate data on the pathophysiological mechanisms of itch with current wound care management strategies.

Discussion
Cutaneous chronic wounds are classified as vascular (arterial, venous, mixed arterial-venous), diabetic foot ulcers, pressure ulcers, and atypical wounds (such as inflammatory, neoplastic, vasculitis, and exogenous). Wound itch is a frequent problem in clinical practice, but is poorly described in the literature. There are currently no exact data on the incidence and/or prevalence of itch in cutaneous wounds. The only data available report the characteristics of wounds and their relationship with itch. Our results from the systematic review show a linear correlation between wound area and itch through the release of itch triggers such as histamine and growth factors on the wound bed [6].
Remaining on wound characteristics analysis, the amount of necrotic wound bed tissue is another important finding; dead tissue blocks healing and leads to scratching, with further damage and enlargement of wounds [6].
A high amount of exudate is another wound characteristic that causes maceration and is an itch trigger factor. The collection of fluids in tissue can also causes mechanical stress that may exacerbate itch and promote mast cell invasion into nerve fibers, which can trigger or aggravate itch [6].
The induration in the periwound area, i.e., sclerosis, is another potential cause of wound itch; tissue damage activates inflammatory processes with mast cell degranulation promoting the release of pruritogen mediators [7].
The final findings of our review are about the granulation tissue. This tissue occurs in the proliferative phase of the wound healing process and contains fibroblasts and different types of inflammatory cells and may also release neoangiogenesis factors, connective proteins, nerve growth factors, and pruritogen mediators, which partially explain the phrase "it's itching, it must be healing", commonly used by healthcare providers [6]. However in some conditions, such as in infected wounds, granulation tissue can be hypertrophic and friable, and can cause excessive itch. Infected wounds may also itch because bacterial biofilm can interact through proadrenomedullin N-terminal 20 peptide (PAMP) with Toll-like 2 receptors (TLR-2, and activate protein cascades with the release of itch mediators [13]. Regarding management, the tissue debridement, inflammation/infection, moisture imbalance, epithelial edge advancement (TIME) principles of wound bed preparation are particularly effective in the management of these pathophysiologic factors in order to reduce the itch sensation [14].
By correlating the level of itch with wound management, our literature review has shown that, in selected patients, moderate compression bandaging can be used to manage itch by increasing the venous tone and normalizing circulation by removing edema [15].
Another important itch management strategy is the proper care of perilesional skin by two steps: proper selection of the wound dressings in line with the level of exudate and the size of the wound and the utilization of barrier products (principally zinc oxide paste, silicone-based ointments, polymer barrier preparations) and moisturizers [16].
If causative treatment fails, a stepwise therapeutic approach based on the European S2k Guideline on Chronic Pruritus is recommended.

Conclusions
Itch in wounds is a very frequent symptom and should never be underestimated. A better characterization of itch in chronic wounds and the identification of best strategies of prevention and treatment would improve the daily functions, the psychological state, and the social interactions of patients affected by chronic wounds.
The pathophysiology is particularly complex and multifactorial, and it is not fully understood. Numerous factors influence itch such as wound area, necrotic tissue amount, exudate amount, peripheral tissue edema, sclerosis, granulation tissue, bacterial biofilm, chronic venous insufficiency (CVI), perilesional skin characteristics, neuropathic changes, and dressing sensitization, as well as by psychological and emotional components. An itch-scratch cycle can lead to secondary infections, changes in pigmentation, thickening of the skin, and delayed healing.
The subjective and multidimensional nature of itch makes it a real challenge for clinicians. Various assessment tools have been used to evaluate itch. A critical point of further research is a consensus on the development of structured questionnaires to evaluate and measure the sensory and affective dimensions of itch in chronic wounds.
Currently, there are no standards for preventing and managing itch in chronic wounds. The TIME principles of wound bed preparation, the topical management of perilesional skin, and a stepwise therapeutic approach based on European S2k Guideline on chronic itch (if causative treatment has failed) seem to be the best management strategies to date.
Our study presents some methodological limitations. First, the literature data on the physiopathology and management of itch in chronic wounds was particularly poor. Second, itch has very complex underlying mechanisms of a subjective and multidimensional nature, which made our investigation complicated. Third, our literature review was limited to data available on online databases.
Further studies are needed to clarify the association and pathophysiology of itch in chronic wounds, and to evaluate the safety and efficacy of topical treatments on perilesional skin and of moderate compression to reduce itch. Further research on correlations among severity of itch and cytokines, chemokines, and inflammatory marker levels in exudates, perilesional, and lesional skin in different healing phases would help in developing targeted therapies for itch in chronic wounds.
Such studies should adopt a tailored-based approach and draw up practical guidelines. The take-home messages of this review are summarized in Table 2. Table 2. Take-home messages.

Take-Home Messages
Itch in wounds is a very frequent symptom and should never be underestimated. The underlying mechanisms are very complex, including those of a subjective and multidimensional nature, which make investigations a real challenge for clinicians.
The application of the tissue debridement, inflammation/infection, moisture imbalance, epithelial edge advancement (TIME) principles of wound bed preparation, the topical management of perilesional skin, and a stepwise therapeutic approach based on European S2k Guideline on chronic itch (if causative treatment fails) seem to be the best management strategies to date.
Further studies are needed to better characterize and develop targeted therapies for itch in chronic wounds, adopting a tailored-based approach and drawing up practical guidelines.
Author Contributions: M.I. wrote the paper; T.O., M.R. and V.D. proofread the manuscript; A.J. and G.T. helped select and review the articles.
Funding: This research received no external funding.

Conflicts of Interest:
The authors declare no conflict of interest.