View metadata, citation and similar papers at core.ac.ukARTICLE IN PRESS brought to you by CORE provided by Sussex Research Online Journal of Psychosomatic Research xx (2009) xxx–xxx Psychological stress and wound healing in humans: A systematic review and meta-analysis☆ ⁎ Jessica Walburna, , Kavita Vedharab, Matthew Hankinsa, Lorna Rixona, John Weinmana aInstitute of Psychiatry, Department of Psychology, King's College London, London, UK bInstitute of Work, Health, and Organizations, University of Nottingham, Nottingham, UK Received 18 October 2008; received in revised form 3 March 2009; accepted 7 April 2009 Abstract Objective: The current review aims to synthesize existing chronic clinical wounds, experimentally created punch biopsy knowledge about the relationship between psychological stress and blister wounds, and minor damage to the skin caused by and wound healing. Methods: A systematic search strategy was tape stripping. Seventeen studies in the systematic review conducted using electronic databases to search for published reported that stress was associated with impaired healing or articles up to the end of October 2007. The reference lists of dysregulation of a biomarker related to wound healing. The retrieved articles were inspected for further studies and citation relationship between stress and wound healing estimated by the searches were conducted. In addition, a meta-analysis of a meta-analysis was r=−0.42 (95% CI=−0.51 to −0.32) (Pb.01). subset of studies was conducted to provide a quantitative Conclusion: Attention now needs to be directed towards estimation of the influence of stress on wound healing. Results: investigating potential moderators of the relationship, mediating Twenty-two papers met the inclusion criteria of the systematic mechanisms underpinning the association, as well as the dem- review and a subsample of 11 was included in a meta-analysis. onstration of a causal link by the development of experimental The studies assessed the impact of stress on the healing of a interventions in healthy populations. variety of wound types in different contexts, including acute and © 2009 Elsevier Inc. All rights reserved. Keywords: Psychoneuroimmunology; Punch biopsy; Stress; Suction blister; Transepidermal water loss; Wound healing Introduction enables researchers to bridge this gap and investigate the impact of stress on an objective, concrete, and clinically Numerous studies show that stress is associated with relevant outcome, where the immune system plays a increased mortality and morbidity across a range of conditions significant role [7]. Research investigating the determinants [1–3] and many studies highlight the impact of stress upon of wound healing has traditionally focused on clinical and specific markers of immune functioning [4], but few have biomedical factors (i.e., size of wound, dressing type, extent been able to connect the “micro” immune changes with of pathology) associated with speed of healing [8–10]. “macro” changes in disease outcomes [4–6]. The recent However, recently the potential impact of psychosocial utilization of wound healing as a primary outcome measure factors, including psychological stress, has been investigated. The objective of this review was therefore to systematically identify and synthesize existing knowledge about the relation- ☆ This study is funded by the Medical Research Council, Health ship between psychological stress and wound healing. Services Research Collaboration. “ ⁎ A wound may be defined as a disruption of normal tissue Corresponding author. Institute of Psychiatry, Department of ” Psychology, 5th Floor Bermondsey Wing, Guy's Campus, SE1 9RT structure and function [11] and can be categorized by its London, UK. Tel.: +44 0207 848 6065; fax: +44 0207 188 0184. etiology, location, or duration. There are a variety of causes E-mail address: [email protected] (J. Walburn). which give rise to many different types of wounds including 0022-3999/09/$ – see front matter © 2009 Elsevier Inc. All rights reserved. doi:10.1016/j.jpsychores.2009.04.002 ARTICLE IN PRESS 2 J. Walburn et al. / Journal of Psychosomatic Research xx (2009) xxx–xxx surgery (planned intervention), trauma (i.e., burns or lacer- of water in and out of the body known as its barrier function ations), pathological changes in the body (i.e., circulatory [21]. Recovery of the barrier can be measured by the level of vessels associated with leg ulcers), as well as wounds related transepidermal water loss (TEWL) [22]. This review aimed to to pressure (i.e., pressure ulcers) [12]. Wounds frequently investigate whether a common relationship with stress occur in the skin (cutaneous), although they can also occur in existed across different wound types and experimental the mucosa (i.e., in the mouth, nose, digestive tract) [13]. models. There are a number of reviews in existence Wounds are classified as “acute” if they progress through the examining the relationship between stress and wound healing stages of healing in the appropriate time. Alternatively, they [23–26]; however, none is systematic in their methodology are “chronic” if progression through the expected phases does nor has attempted to quantify the relationship. The aims of not occur and healing is delayed [14]. this review are twofold: (i) to summarize existing research Cutaneous wound healing is a complex process composed looking at the nature of the relationship between stress and of interdependent and overlapping stages, namely, clot wound healing in a systematic review and (ii) to quantify the formation, inflammation, proliferation,andremodeling size of the relationship in a meta-analysis of a subset of [15,16]. The initial postinjury phase is characterized by the included studies. formation of a fibrin clot followed by the inflammatory stage (within 1–3 days after injury) which is dominated by immune cells (i.e., neutrophils and macrophages) that destroy bacteria Method and debride the wound. These cells also release substances called cytokines which communicate between cells [17], Procedure specifically interleukin-1 (IL-1α, IL-1β), IL-6, IL-8, and tumor necrosis factor (TNF), and matrix metalloproteinases The systematic review involved searching a range of (MMPs) which are regulated by cytokines and digest factors computerized databases including AMED (Allied and during the healing process [18]. These substances are crucial Complementary Medicine), BNI (British Nursing Index), if normal tissue repair is to progress. By Day 4, the CINAHL (Cumulative Index to Nursing and Allied Health proliferation phase begins whereby cells important in tissue Literature), Cochrane Database of Systematic Reviews, regeneration (collagen-rich fibroblasts and epithelial cells) EMBASE, MEDLINE, MEDLINE In-process and other and vascularization (capillaries) migrate and replicate. Non-Indexed Citations, PsycINFO, and Web of Science Remodeling is the final phase of healing where cell numbers (WOS). The databases were searched from their earliest date decrease and collagen fibers are remodeled to increase the up to the end of October 2007. The review used a subject strength of the wound. The repaired or scar tissue is not and text word strategy with (DISTRESS, STRESS, ANXI- identical to the intact skin, but it is structurally and ETY, DEPRESSION) AND (WOUND HEALING, ULCER, functionally adequate [19].CytokinesandMMPsare TRANSEPIDERMAL WATER LOSS) as the primary search important in this phase which may persist for weeks and terms. The search strategy was tailored for each database to months [7,16]. Healing in other tissue types follows a similar ensure that it was comprehensive. The abstracts of the articles trajectory, although there are tissue specific differences, such identified by the electronic search were examined to identify as oral mucosal wounds healing more quickly with less relevant articles which were retrieved for further inspection to scarring [20]. ascertain whether they met the inclusion criteria. The As can be seen from the above description, successful reference sections of all retrieved articles were searched to healing is dependent in part on a fully functioning immune identify further articles. A citation search was carried out on system thus making it vulnerable to the myriad of factors all included articles using the Social Science Citation Index. which can impair immune performance. Since both acute and The methodology of the review attempted where applicable chronic psychological stress can modulate immune function to adhere to the QUOROM statement regarding best practice [4], it becomes reasonable to consider that psychological for systematic and meta-analytic reviews [27]. stress might have an adverse effect on wound healing. As well as the variety of different clinical wounds described Inclusion/exclusion criteria previously there are currently two experimental paradigms used by researchers to investigate wound healing in the Studies were included in the systematic review if they laboratory. Specifically, inflicting a standardized wound to fulfilled the following criteria. the skin or oral mucosa using a punch biopsy or alternatively creating suction blisters [16]. A third less invasive approach The measurement or condition of psychological stress involves causing minor injury to the stratum corneum or outer Studies were included if they contained original data in- layer of the skin by repeated application of cellophane tape. vestigating the impact of any form of negative psychological This damages the ability of the