The humanistic and economic burden of chronic wounds: A protocol for a systematic review

Abstract

Background:
Chronic non-healing wounds present a substantial economic burden to healthcare system; significant reductions in quality of life for those affected, and precede often serious events such as limp amputations or even premature deaths. This burden is also likely to increase with a larger proportion of elderly and increasing prevalence of life-style diseases such as obesity and diabetes. Reviews of the evidence on the burden of illness associated with chronic wounds have not been comprehensive in scope and have not provided an assessment of the distribution of the health care costs across categories of resource use.

Methods/design:
This study is a systematic review of multiple databases for studies on adult patients with chronic wounds and with the primary objective to assess the impact on health-related quality of life by category of ulcers, and associated direct and indirect costs. Eligible studies will primary be empirical studies evaluating, describing or comparing measurement of quality of life and economic impact. Two reviewers will independently screen titles and abstracts and select studies involving adults with chronic wounds. These investigators will also independently extract data using a pre-designed data extraction form. Differences in applied methodologies and uncertainties will clearly be accounted for. Conservative valuations of costs and impact on health-related quality of life will be prioritised. Variations that may depend on age distribution, the categorisation of ulcer, healthcare system etc. will be described clearly.

Discussion:
The proposed systematic review will yield a comprehensive assessment of the humanistic and economic burden of chronic wounds in an adult population. A better understanding of the humanistic and economic burden of chronic wounds is essential for policy and planning purposes, to monitor trends in disease burden and not at least in order to estimate the real-world cost-effectiveness of new treatments and therapies.

Systematic review registration:
PROSPERO CRD42016037496.

Full text

P R O T O C O L Open Access
The humanistic and economic burden of
chronic wounds: a protocol for a systematic
review
Krister Järbrink
1
, Gao Ni
1
, Henrik Sönnergren
2
, Artur Schmidtchen
3
, Caroline Pang
4
, Ram Bajpai
1
and Josip Car
1,5*
Abstract
Background: Chronic non-healing wounds present a substantial economic burden to healthcare system;
significant reductions in quality of life for those affected, and precede often serious events such as limp
amputations or even premature deaths. This burden is also likely to increase with a larger proportion of
elderly and increasing prevalence of life-style diseases such as obesity and diabetes. Reviews of the evidence
on the burden of illness associated with chronic wounds have not been comprehensive in scope and have
not provided an assessment of the distribution of the health care costs across categories of resource use.
Methods/design: This study is a systematic review of multiple databases for studies on adult patients with
chronic wounds and with the primary objective to assess the impact on health-related quality of life by
category of ulcers, and associated direct and indirect costs. Eligible studies will primary be empirical studies
evaluating, describing or comparing measurement of quality of life and economic impact. Two reviewers will
independently screen titles and abstracts and select studies involving adults with chronic wounds. These
investigators will also independently extract data using a pre-designed data extraction form. Differences in
applied methodologies and uncertainties will clearly be accounted for. Conservative valuations of costs and
impact on health-related quality of life will be prioritised. Variations that may depend on age distribution, the
categorisation of ulcer, healthcare system etc. will be described clearly.
Discussion: The proposed systematic review will yield a comprehensive assessment of the humanistic and
economic burden of chronic wounds in an adult population. A better understanding of the humanistic and
economic burden of chronic wounds is essential for policy and planning purposes, to monitor trends in
disease burden and not at least in order to estimate the real-world cost-effectiveness of new treatments and
therapies.
Systematic review registration: PROSPERO CRD42016037496
Keywords: Chronic wounds, Hard-to-heal ulcers, Quality of life, Health-related quality of life, Quality-adjusted
life years, Cost of illness, Costs and cost analysis, Economics
* Correspondence: josip.car@imperial.ac.uk;josip.car@ntu.edu.sg
1
Centre for Population Health Sciences (CePHaS), Lee Kong Chian School of
Medicine, Nanyang Technological University, 59 Nanyang Drive, Experimental
Medicine Building, Singapore 636921, Singapore
5
Global eHealth Unit, Department of Primary Care and Public Health, School
of Public Health, Imperial College London, 3rd Floor Reynolds Building, St
Dunstan’s Road, London W6 8RP, UK
Full list of author information is available at the end of the article
© The Author(s). 2017 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0
International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and
reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to
the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver
(http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
Järbrink et al. Systematic Reviews (2017) 6:15
DOI 10.1186/s13643-016-0400-8
Content courtesy of Springer Nature, terms of use apply. Rights reserved.

Background
A chronic wound can be defined as one that has failed
to proceed through an orderly and timely reparative
process to produce anatomic and functional integrity
within a period of 3 months or that has proceeded
through the repair process without establishing a sus-
tained and anatomic and functional result [1, 2]. The no-
menclature is far from agreed upon, and these wounds
are sometimes referred to as hard-to-heal or difficult to
heal wounds/ulcers, and the time span required for
chronicity has been defined in the range from 4 weeks
up to more than 3 months [2–4]. Based on the causative
aetiologies, the Wound Healing Society classifies chronic
wounds into four categories: pressure ulcers, diabetic ul-
cers, venous ulcers and arterial insufficiency ulcers [5].
Older people are the highest risk group for chronic
wounds given that wound repair slows down as the body
ages [6, 7] and incidences of cardiovascular disease and
diabetes (which increase the incidence of chronic
wounds) also increase with age [8]. The basic biology
and the influence of age-associated changes on wound
healing are poorly understood, and there are numerous
research questions still to be answered [7].
Wounds are typically managed as a co-morbidity of
other conditions, limiting the impact of efforts to over-
come the growing challenge they represent. Clinicians
often lack specialised training in the diagnosis and treat-
ment of wounds because it is not a defined specialisation
and different specialists such as dermatologists, podia-
trists, endocrinologists, vascular surgeons and geriatri-
cians, maybe involved in the care to a different extent in
different healthcare systems. From a policy perspective,
this fragmented responsibility has led to a lack of priori-
tisation of resources and capabilities around wound care,
and in a clinical sense has produced inconsistent treat-
ments, prolonged healing and an uncoordinated ap-
proach to prevention [9]. It is a ‘silent epidemic’[10],
and this has often resulted in inadequate planning and
poor implementation of prevention, treatment and man-
agement strategies. Consequently, wound research is an
important but neglected field. The lack of research has
compromised innovation in new therapies, diagnostics,
clinical practices and procedures. For example, the sci-
entific literature highlights the lack of knowledge on the
biological processes associated with wound healing and
limited evidence for effective pathways of clinical care
and therapies for prevention and healing [11].
Although wound care is a multibillion-dollar world-
wide problem, that only in the USA affect 5.7 million
people (~2% of population) at an annual cost of US$20
billion [12]. A UK report suggested that treatment and
care of chronic wounds accounts for 3% of total health-
care expenditure in developed countries [13], but this is
probably somewhat low because a more recent study
from Wales using estimates of prevalence and cost
from routine NHS data concludes that chronic
woundshaveaprevalenceof6%andconsumeatleast
5.5% of NHS expenditure [14].Chronic non-healing
wounds would thereby impose an immense financial
burden to the society, not only through an economic
burden on the health care system but also through a
reductioninproductivity[15].
Chronic wounds may require several years to heal, and
some remain unhealed for decades. During this time, pa-
tients can experience severe pain, significant emotional
and physical distress, reduced mobility and social isola-
tion [16]. Studies have also shown that chronic wounds
not only cause severe emotional and physical trauma to
the patient but also to their families [17]. Chronic
wounds may also result in disabilities after all available
therapeutic interventions have been exhausted, and an
amputation is necessary. Ulcers precede 85% of all am-
putations [18] while diabetic ulcer is the reason for 70%
of all lower limb amputations. Globally, there is an am-
putation every 30 s due to a non-healing diabetic ulcer
[19]. The 5-year mortality rate following amputation is
reported to be between 40 and 70% [20] and is higher
among patients with major amputation [21]. Unfortu-
nately, events such as infections, amputations and death
as a consequence of a wound are all too common and
may be avoidable with accurate diagnosis and early ap-
propriate treatment.
The ageing populations in many parts of the world
and the increasing incidence of chronic diseases make
the requirement for improved wound care urgent and
critical. However, to enable effective implementation,
there needs to be greater awareness about the increasing
clinical challenge that wounds present, and methodology
needs to be developed to ascertain and ensure that cost-
effective clinical practices are employed. Currently, there
is a lack of research on the humanistic and economic
burden of chronic wounds and there is consequently a
need to comprehensively quantify the burden of chronic
wounds to the individual and healthcare system.
An improved knowledge would equip decision makers
with a tool for evaluating therapies and an increased un-
derstanding of what drives a cost-effective wound care.
Accurate and robust measurement of disease burden is
therefore imperative for the future planning of health-
care services and optimisation of clinical pathways. The
development of new knowledge and innovative tech-
nologies, and the widespread adoption of these develop-
ments into best practice clinical pathways is also
required if a more effective wound care is to be
achieved. There are great challenges ahead. A systematic
review published in 2014 has shown that few cost-
effectiveness studies exist to guide decision makers re-
garding guideline-based or strategic interventions for
Järbrink et al. Systematic Reviews (2017) 6:15 Page 2 of 7
Content courtesy of Springer Nature, terms of use apply. Rights reserved.

chronic wounds [22]. However, existing evidence point
in the direction that more specialised and intense wound
care is cost-effective and not rarely cost-saving [23].
Moreover, a Danish study has argued that by adopting a
national strategy based on best practice guidelines, it
may be possible to reduce the costs for wound manage-
ment with up to 30% [24].
A systematic review of the humanistic and economic
burden of chronic wounds is essential for policy and
planning purposes, to monitor trends in disease burden
and not at least in order to estimate the real-world cost-
effectiveness of new treatments and therapies. The in-
creasing number of elderly and the increasing prevalence
of lifestyle diseases such as obesity and diabetes will re-
sult in that the burden of chronic wounds will be con-
siderably larger if nothing is made. New treatments,
therapies and preventive interventions require cost-
effectiveness studies that would benefit hugely from
burden-of-disease estimates.
The systematic review’s outcome consists of data on
quality of life and cost consequences for pressure ulcers,
diabetic ulcers, venous ulcers and arterial insufficiency
ulcers. Quality of life or health-related quality of life
(HRQoL) is a patient-reported outcome (PRO) which
means that it is a report of the status of a patient’s health
condition that comes directly from the patient, without
interpretation of the patient’s responses by a physician
or anyone else. Common HRQoL measures include
EuroQol (EQ-5D), Short-Form 36 (SF-36), health util-
ities index (HUI) and the visual analogue scale (VAS).
The economic definition of cost is the value of oppor-
tunity forgone, strictly the best opportunity forgone, as a
result of engaging resources in an activity, in this case,
the care of chronic wounds. Costs do also arise without
the exchange of money and extends beyond those falling
on the healthcare service alone, e.g. patients themselves
and families, caregivers and communities.
The overall aim of this paper is to present a transpar-
ent process for how the information will be collected on
the humanistic and economic burden of chronic wounds
and related complications. This will include the key re-
search questions that this review will address description
of systematic literature search strategies, criteria for in-
clusion or exclusion of studies, description of coding
procedures, study quality measures and statistical proce-
dures for the quantitative analysis of data from eligible
studies.
Methods/design
Protocol
The methods for this systematic review have been de-
veloped according to the recommendations from the
Preferred Reporting Items for Systematic Review and
Meta-Analysis Protocols (PRISMA-P) 2015 statement
[25]. This systematic review protocol has been regis-
tered in the International Prospective Register of Sys-
tematic reviews (PROSPERO): CRD42016037496). A
PRISMA-P file is attached (see Additional file 1).
Research questions
The overall objective is to determine the burden of
chronic wounds and related complications. The focus is
on chronic wounds in the categories of pressure ulcers,
diabetic ulcers, venous ulcers and arterial insufficiency
ulcers.
Specific review questions are as follows:
What is the impact on the patient’s and carer’s
health-related quality of life of chronic wounds in
the categories of pressure ulcers, diabetic ulcers,
venous ulcers and arterial insufficiency ulcers?
What is the reported economic impact of chronic
wounds in the categories of pressure ulcers, diabetic
ulcers, venous ulcers and arterial insufficiency
ulcers?
Eligibility criteria
Population
The population of interest will include adult patients
18 years of age and older with pressure ulcers, diabetic
ulcers, venous ulcers and arterial ulcers. Patients with
chronic wounds resulting from non-preventable surgical
wounds and wounds from skin tumours will be
excluded.
Outcome
Impact on HRQoL for patients and carers of defined
chronic wounds and complications measured either
over different generic domains (e.g. EQ-5D, SF-36,
HUI) or by a single-index health utility measure (e.g.
time trade-off (TTO), standard gamble (SG), visual
analogue scale (VAS)).
Measured and valued cost consequences of defined
chronic wounds and specified complications thereof.
Measured and valued cost consequences could be
either incidence or prevalence based.
Study design
Studies will be restricted by design and observational
studies, cross-sectional studies, cohort studies, case-
control studies, single arm and systematic review/meta-
analyses will be included.
Non-research letters and editorials, seminar reviews
and case studies/series reporting cases will be excluded.
Studies reporting health-related quality of life will be re-
stricted to include studies that measures patient-
Järbrink et al. Systematic Reviews (2017) 6:15 Page 3 of 7
Content courtesy of Springer Nature, terms of use apply. Rights reserved.

reported generic HRQoL and studies that measures dis-
ease specific HRQoL will consequently be excluded.
Randomised controlled trials will be excluded based
on methodological inappropriateness of research design
for the type of questions to be answered. Economic
modelling studies will be excluded as they present data
for costs or cost-effectiveness related to specific inter-
ventions under investigation.
Search strategy
We will begin by developing a comprehensive database
containing empirical studies evaluating, describing or
comparing measurement of quality of life and/or the
economic impact of chronic wounds (including hard-to-
heal wound/ulcers) and complications thereof in general
populations. A systematic search of MEDLINE (Ovid),
EMBASE (Ovid), EBM Reviews and Cochrane (Ovid),
Cumulative Index to Nursing and Allied Health Litera-
ture (CINAHL) (EBSCO), PsycINFO (EBSCO) and Glo-
bal Health (EBSCO) will be undertaken. As we are
primarily interested in the contemporary literature on
this topic, we will examine publications from January
2000 through December 2015.
To construct a comprehensive set of possible search
terms, we list indexing terms (for example, subject head-
ings and subheadings, publication types) and text words
used to describe concept clusters (single words or
phrases that may appear in titles or abstracts, both in
full and in various truncations). For instance, we search
pressure ulcer with its keyword “pressure ulcer”with all
heading and subheadings, and then we search alternative
keywords “pressure sore”or “bed ulcer”or “bed sore”
appearing in the title or abstract in the form of full or
truncations. We sought further terms from clinicians
and librarians, and from published strategies from other
groups. The search strategy was developed by the re-
search team in collaboration with an experienced med-
ical research librarian at the Lee Kong Chian School of
Medicine. Additional comments and suggestions were
also received from an experienced librarian at the
Karolinska Institutet and incorporated. The search was
revised, as necessary, and the final MEDLINE search is
presented in Additional file 2. The MEDLINE strategy
will be adapted to the syntax and subject headings of
other databases.
Searches will be limited to peer-reviewed full text arti-
cles in English language and letters, abstracts, and edito-
rials are to be excluded. There will be no geographical
limitation on the included studies. Contact with authors
for further information will be made when necessary.
The reference lists of all identified articles from January
2000 and beyond will also be searched for any additional
sources of information. An additional search will be
made using the newly introduced term “pressure injury”
[26] and relevant articles added.
Study records
Data management
We will implement the search strategies and import all
references identified to EndNote. The search results
from the different electronic databases will be combined
in a single EndNote library and we will remove duplicate
records of the same reports.
Selection process
Two reviewers will independently screen titles and ab-
stracts against eligibility criteria to identify potentially
included studies. Specifically, titles and abstracts are in-
cluded if they indicate that it was a population-based or
institutional-based study reporting any relevant informa-
tion on the humanistic or economic burden of chronic
wounds and/or complications thereof. In the next phase,
we will retrieve full-text copies of those articles deemed
potentially relevant. Two reviewers will independently
assess the full text of the retrieved articles for compli-
ance with our eligibility criteria. Discrepancies between
the two reviewers’judgement will be resolved by discus-
sion or by the involvement of a third reviewer. Studies,
which appeared to be relevant, but excluded at this stage
will be listed in the table “Characteristics of excluded
studies”, where a reason for exclusion will be noted.
Two reviewers will verify the final list of included stud-
ies. A PRISMA flow diagram of the study selection pro-
cedure will be prepared to provide an overview of the
decisions that are made in the data collection process.
Data collection process
Two reviewers will independently extract and manage
the data for each of the included studies using an elec-
tronic data extraction form. We will pilot the data ex-
traction form and amend it according to feedback
received from a panel of experienced colleagues. We
plan to contact study authors in case of any unclear or
missing information. Disagreements between review au-
thors will be resolved by discussion. A third review au-
thor will act as an arbiter in case disagreements cannot
be resolved.
Data items
Data will be extracted on the following:
1. Publication details: title, journal, author, year, city
and country, in which the study was conducted, type
of publication, and source of funding.
2. Design: type of study (observational studies, cross-
sectional, cohort, case-control, single arm, systemic
review/meta-analyses); aims of study, method of data
Järbrink et al. Systematic Reviews (2017) 6:15 Page 4 of 7
Content courtesy of Springer Nature, terms of use apply. Rights reserved.

collection, response rate, recruitment methods, eligi-
bility (inclusion and exclusion criteria).
3. Study participant details: number of persons
interviewed or surveyed, population characteristics
including age, gender, ethnicity, demographic
information, diagnostics, ulcer specifications,
complications.
4. Data for outcome measures. Humanistic burden:
utility score patient, utility score carer, utility
instrument/method applied, scoring algorithm,
mode of administration, utility control patient, utility
control carer, limitations in the measurement of
utility. Economic burden: cost currency, cost
sources, whether prevalence-based COI or
incidence-based COI, recall period, mode of admin-
istration, discounting (incidence-based), cost in-
patient care, cost outpatient specialist care, cost
primary care, cost pharmaceuticals, cost community
care, cost aid/utensils, cost productivity losses, prod-
uctivity loss, method of estimation, productivity loss,
per cent of full working time, cost informal care,
method of estimation, informal care per cent of full
working time, limitations/needed improvements.
The primary outcome will be impact on HRQoL by
category of ulcers and associated direct and indirect
costs. Differences in applied methodologies, ulcer speci-
fications and other uncertainties will clearly be
accounted for. Conservative valuations of costs and im-
pact on HRQoL will be prioritised. Variations that may
depend on age distribution, the categorisation of ulcer,
study design etc. will be described clearly. Secondary
outcomes will be the impact on carers’HRQoL, drop-
ping out and the reasons for that.
Risk of bias in individual studies
As a variety of study types and data sources are likely to
be eligible from the literature, information will be re-
corded on the appropriateness of the particular study
design to estimate relevant parameters and the represen-
tativeness of the population. There are many sources for
methodological biases starting from research question it-
self, selection bias, information bias, confounding and
overall quality of a study. Therefore, studies reporting
health-related quality of life will be critically appraised
using the Joanna Briggs Institute critical appraisal tool
which is developed for prevalence data but also suitable
for quality of life data that is collected with validated
and well-recognised instruments [27]. Studies reporting
the economic burden will be appraised using the
Drummond and Jefferson checklist [28].
The quality assessment will be independently con-
ducted by two reviewers. Any discrepancies will be dis-
cussed, and if required, a third reviewer will be
consulted. Publication bias and selective reporting will
be dealt with by critically assessing study findings, plots
will be made of outcome variables against sample size
[25] and advice will be taken from GRADE guidelines
No. 5 [29].
Data synthesis
For studies on quality-of-life, a hierarchical linear model
will be used to perform a meta-regression in which qual-
ity of life is the independent variable while elicitation
method, respondents’characteristics, instrument, cat-
egory of wound and wound duration will be tested as ex-
planatory variables.
Meta-analysis of international cost data is difficult be-
cause of transferability due to geographic origin. How-
ever, all costs will be presented in the reference year of
2015 in US dollars using the consumer price index (CPI)
for each country [30] and the year 2015 purchasing
power parity (PPP) conversion factor [31, 32] to allow
for greater transparency and comparability across
studies.
Statistical analysis
Descriptive analysis will be performed based on the col-
lective information from the studies and summarised
into tables. The forest plots will be made for quality of
life and cost data indicators with their 95% confidence
intervals (C.I.s) to visualise publication bias. Further, the
subgroup analysis and sensitivity analysis will also be
performed to address the variability across studies. If the
collective evidence of studies allowed, the study out-
comes will be further stratified according the back-
ground outcome variables. Choice of meta-analysis will
also be based on the homogeneous group of studies. For
studies on quality of life (QOL), a hierarchical linear
model will be used to perform a meta-regression in
which quality of life is the independent variable while
elicitation method, respondents, instrument etc. could
be explanatory variables. Parametric meta-analyses may
be considered for cost data based on the number of the
eligible studies. The decision of fixed effect model will
be based on pooled data using the appropriate statistical
method and the choice of random-effects model will be
based on clinical and methodological diversity across the
included studies
Summary
This systematic review will be performed to critically
examine the world’s relevant literature on the humanis-
tic and economic burden of chronic wounds. Specific-
ally, we aim to identify and report the estimated
humanistic and economic burden of chronic wounds in
the categories of pressure ulcers, diabetic ulcers, venous
ulcers and arterial insufficiency ulcers and related
Järbrink et al. Systematic Reviews (2017) 6:15 Page 5 of 7
Content courtesy of Springer Nature, terms of use apply. Rights reserved.

complications for different settings and subgroups. Un-
derstanding the humanistic and economic impact bur-
den of different categories of complications among
patients with chronic wounds could inform policy
makers on the cost effectiveness of implementing early
screening and other prevention or treatment efforts.
Also, quantifying the humanistic and economic burden
of chronic wounds will help guide decision-making for
the allocation of scarce healthcare resources and fund-
ing. A further finding of this systematic review will be
the methodological assessment of the published litera-
ture. The findings of this review will also be compared
with other similar published reviews. Finally, conclusions
will be drawn from this systematic review highlighting
the burden of chronic wounds, methods of estimation
and settings and their correlates. Limitations of the stud-
ies will be discussed in detail. Implications of the review
as well as suggestions for future research will also be
provided.
Additional files
Additional file 1: PRISMA-P checklist. (DOC 83 kb)
Additional file 2: MEDLINE search strategy. (DOCX 32 kb)
Abbreviations
CINAHL: Cumulative Index to Nursing and Allied Health Literature; EQ-
5D: EuroQol-5D; GRADE: Grading of Recommendations Assessment
Development and Evaluation; HRQoL: Health-related quality of life;
HUI: Health utilities index; PRISMA-P: Preferred reporting items for systematic
reviews and meta-analyses protocols; PROSPERO: International prospective
register of systematic reviews; SF-36: Short-Form 36; SG: Standard gamble;
TTO: Time trade-off; VAS: Visual analogue scale
Acknowledgements
We are grateful to Carl Gornitzki at the university library at the Karolinska
Institutet, Sweden, for invaluable support in the refinement of the search
strategies.
Funding
This research is supported through internal grant funding from the Lee Kong
Chian School of Medicine, Nanyang Technological University and by the
A*STAR BMRC Strategic Positioning Fund (SPF) for Skin Biology awarded to
the Institute of Medical Biology. The views expressed are those of the
authors and not necessarily those of the NTU or A*STAR. Lee Kong Chian
School of Medicine, NTU and A*STAR have no role as organisations in the
planning, conduct or dissemination of the systematic review.
Authors’contributions
KJ and GN initiated the protocol, conceptualised the research plan for the
proposed systematic review, wrote the manuscript and reviewed it for
important intellectual content. HS, AS, CP, RB and JC critically reviewed the
methodology, wrote the manuscript and reviewed it for important
intellectual content. All authors read and approved the final manuscript.
Competing interests
The authors declare that they have no competing interests.
Consent for publication
Not applicable.
Ethics approval and consent to participate
Not applicable.
Author details
1
Centre for Population Health Sciences (CePHaS), Lee Kong Chian School of
Medicine, Nanyang Technological University, 59 Nanyang Drive, Experimental
Medicine Building, Singapore 636921, Singapore.
2
Department of
Dermatology, Skåne University Hospital, Lasarettsgatan 15, 221 85 Lund,
Sweden.
3
Dermatology and Innate Immunity Laboratory, Lee Kong Chian
School of Medicine, Nanyang Technological University, 59 Nanyang Drive,
Experimental Medicine Building, Singapore 636921, Singapore.
4
Medical
Library, Lee Kong Chian School of Medicine, 11 Mandalay Road, Singapore
308232, Singapore.
5
Global eHealth Unit, Department of Primary Care and
Public Health, School of Public Health, Imperial College London, 3rd Floor
Reynolds Building, St Dunstan’s Road, London W6 8RP, UK.
Received: 29 April 2016 Accepted: 19 December 2016
References
1. Lazarus GS, Cooper DM, Knighton DR, Percoraro RE, Rodeheaver G, Robson
MC. Definitions and guidelines for assessment of wounds and evaluation of
healing. Wound Repair Regen. 1994;2:165–70.
2. Werdin F, Tennenhaus M, Schaller HE, Rennekampff HO. Evidence-based
management strategies for treatment of chronic wounds. Eplasty.
2009;9:e19.
3. Mekkes JR, Loots MAM, Van Der Wal AC, Bos JD. Causes, investigation and
treatment of leg ulceration. Br J Dermatol. 2003. doi: 10.1046/j.1365-2133.
2003.05222.
4. Cazander G, Pritchard DI, Nigam Y, Jung W, Nibbering PH. Multiple actions
of Lucilia sericata larvae in hard‐to‐heal wounds. Bioessays. 2013.
doi: 10.1002/bies.201300071.
5. The Wound Healing Society. Chronic wound care guidelines. 2006.
http://woundheal.org/documents/final_pocket_guide_treatment.aspx.
Accessed 21 Mar 2016.
6. Gosain A, DiPietro LA. Aging and wound healing. World J Surg Mar. 2004;
28(3):321–6.
7. Gould L, Abadir P, Brem H, Carter M, Conner-Kerr T, et al. J Am Geriatr Soc.
2015. doi: 10.1111/jgs.13332.
8. Halter JB, Musi N, McFarland Home F, Crandall JP, Goldberg A, Harkless L, et
al. Diabetes and cardiovascular disease in older adults: current status and
future directions. Diabetes. 2014. doi: 10.2337/db14-0020.
9. Walker N, Rodgers A, Birchall N, Norton R, MacMahon S. Leg ulcers in New
Zealand: age at onset, recurrence and provision of care in an urban
population. N Z Med J. 2002;115(1156):286–9.
10. Sen CK, Gordillo GM, Roy S, Kirsner R, Lambert L, Hunt TK, et al. Human skin
wounds: a major and snowballing threat to public health and the economy.
Wound Repair Regen. 2009. doi: 10.1111/j.1524-475X.2009.00543.x.
11. Chen WY, Rogers AA. Recent insights into the causes of chronic leg
ulceration in venous diseases and implications on other types of chronic
wounds. Wound Repair Regen. 2007;15(4):434–49.
12. Frykberg RG, Banks J. Challenges in the treatment of chronic wounds. Adv
Wound Care (New Rochelle). 2015;4(9):560–82.
13. Posnett J, Franks PJ. The burden of chronic wounds in the UK. Nurs Times.
2008;104(3):44–5.
14. Phillips CJ, Humphreys I, Fletcher J, Harding K, Chamberlain G, Macey S.
Estimating the costs associated with the management of patients with
chronic wounds using linked routine data. Int Wound J. 2015.
doi: 10.1111/iwj.12443.
15. Augustin M, Brocatti LK, Rustenbach SJ, Schaüfer I, Herberger K. Cost-of-
illness of leg ulcers in the community. Int Wound J. 2014. doi: 10.1111/
j.1742-481X.2012.01089.x.
16. Walshe C. Living with a venous leg ulcer: a descriptive study of patients’
experiences. J Adv Nurs. 1995;22(6):1092–100.
17. Augustin M, Maier K. Psychosomatic aspects of chronic wounds. Dermatol
Psychosom. 2003. doi:10.1159/000070529.
18. Reiber GE, Boyko EJ, Smith DG. Lower extremity foot ulcers and
amputations in diabetes. Diabetes in America. 1995;2:409–27.
19. Diabetes in North America: millions of feet at risk of amputations. 65th
Annual Sessions of the American Diabetes Association, International
Diabetes Federation. San Diego, 11 June 2005.
20. Campbell LV, Graham AR, Kidd RM, Molloy HF, O'Rourke SR, Colagiuri S. The
lower limb in people with diabetes. Position statement of the Australian
Diabetes Society. Med J Aust. 2000;173(7):369–72.
Järbrink et al. Systematic Reviews (2017) 6:15 Page 6 of 7
Content courtesy of Springer Nature, terms of use apply. Rights reserved.

21. Larsson J, Agardh CD, Apelqvist J, Stenström A. Long term prognosis after
healed amputation in patients with diabetes. Clin Orthop Relat Res. 1998;
350:149–58.
22. Carter MJ. Economic evaluations of guideline-based or strategic
interventions for the prevention or treatment of chronic wounds. Applied
health economics and health policy. 2014. doi: 10.1007/s40258-014-0094-9.
23. Graves N, Finlayson K, Gibb M, O'Reilly M, Edwards H. Modelling the
economic benefits of gold standard care for chronic wounds in a
community setting. Wound Practice & Research: Journal of the Australian
Wound Management Association. 2014;22(3):163.
24. Hjort A, Gottrup F. Cost of wound treatment to increase significantly in
Denmark over the next decade. J Wound Care. 2010;19(5):173.
25. Moher D, Shamseer L, Clarke M, Ghersi D, Liberati A, Petticrew M, et al.
Preferred reporting items for systematic review and meta-analysis protocols
(PRISMA-P) 2015 statement. Syst Rev. 2015. doi: 10.1186/2046-4053-4-1.
26. The National Pressure Ulcer Advisory Panel –NPUAP. National Pressure
Ulcer Advisory Panel (NPUAP) announces a change in terminology from
pressure ulcer to pressure injury and updates the stages of pressure injury.
Washington DC April 13 2016. http://www.npuap.org/national-pressure-
ulcer-advisory-panel-npuap-anno Assessed 15 Aug 2016.
27. Munn Z, Moola S, Riitano D, Lisy K. The development of a critical appraisal
tool for use in systematic reviews: addressing questions of prevalence.
International Journal of Health Policy & Management (IJHPM). 2014. doi: 10.
15171/ijhpm.2014.71.
28. Drummond MF, Jefferson TO. Guidelines for authors and peer reviewers of
economic submissions to the BMJ. BMJ. 1996;313:275.
29. Guyatt GH, Oxman AD, Montori V, Vist G, Kunz R, Brozek J, Alonso-Coello P,
Djulbegovic B, Atkins D, Falck-Ytter Y, Williams Jr. JW, Meerpohl J, Norris SL,
Akl EA, Schunemann HJ. GRADE guidelines: 5. Rating the quality of
evidence—publication bias. J Clin Epidemiol. 2011. doi: 10.1016/j.jclinepi.
2013.02.003.
30. Organisation for Economic Co-operation and Development. Consumer prices
(MEI). https://stats.oecd.org/index.aspx?queryid=221. Accessed 15 Mar 2016.
31. Organisation for Economic Co-operation and Development. PPPs and
exchange rates: purchasing power parities for GDP. https://stats.oecd.org/
Index.aspx?DataSetCode=SNA_TABLE4. Accessed 15 Mar 2016.
32. Meacock R, Dale N, Harrison MJ. The humanistic and economic burden of
systemic lupus erythematosus: a systematic review. Pharmacoeconomics.
2013;31:49–61. doi:10.1007/s40273-012-0007-4.
• We accept pre-submission inquiries
• Our selector tool helps you to find the most relevant journal
• We provide round the clock customer support
• Convenient online submission
• Thorough peer review
• Inclusion in PubMed and all major indexing services
• Maximum visibility for your research
Submit your manuscript at
www.biomedcentral.com/submit
Submit your next manuscript to BioMed Central
and we will help you at every step:
Järbrink et al. Systematic Reviews (2017) 6:15 Page 7 of 7
Content courtesy of Springer Nature, terms of use apply. Rights reserved.

1.
2.
3.
4.
5.
6.
Terms and Conditions
Springer Nature journal content, brought to you courtesy of Springer Nature Customer Service Center GmbH (“Springer Nature”).
Springer Nature supports a reasonable amount of sharing of research papers by authors, subscribers and authorised users (“Users”), for small-
scale personal, non-commercial use provided that all copyright, trade and service marks and other proprietary notices are maintained. By
accessing, sharing, receiving or otherwise using the Springer Nature journal content you agree to these terms of use (“Terms”). For these
purposes, Springer Nature considers academic use (by researchers and students) to be non-commercial.
These Terms are supplementary and will apply in addition to any applicable website terms and conditions, a relevant site licence or a personal
subscription. These Terms will prevail over any conflict or ambiguity with regards to the relevant terms, a site licence or a personal subscription
(to the extent of the conflict or ambiguity only). For Creative Commons-licensed articles, the terms of the Creative Commons license used will
apply.
We collect and use personal data to provide access to the Springer Nature journal content. We may also use these personal data internally within
ResearchGate and Springer Nature and as agreed share it, in an anonymised way, for purposes of tracking, analysis and reporting. We will not
otherwise disclose your personal data outside the ResearchGate or the Springer Nature group of companies unless we have your permission as
detailed in the Privacy Policy.
While Users may use the Springer Nature journal content for small scale, personal non-commercial use, it is important to note that Users may
not:
use such content for the purpose of providing other users with access on a regular or large scale basis or as a means to circumvent access
control;
use such content where to do so would be considered a criminal or statutory offence in any jurisdiction, or gives rise to civil liability, or is
otherwise unlawful;
falsely or misleadingly imply or suggest endorsement, approval , sponsorship, or association unless explicitly agreed to by Springer Nature in
writing;
use bots or other automated methods to access the content or redirect messages
override any security feature or exclusionary protocol; or
share the content in order to create substitute for Springer Nature products or services or a systematic database of Springer Nature journal
content.
In line with the restriction against commercial use, Springer Nature does not permit the creation of a product or service that creates revenue,
royalties, rent or income from our content or its inclusion as part of a paid for service or for other commercial gain. Springer Nature journal
content cannot be used for inter-library loans and librarians may not upload Springer Nature journal content on a large scale into their, or any
other, institutional repository.
These terms of use are reviewed regularly and may be amended at any time. Springer Nature is not obligated to publish any information or
content on this website and may remove it or features or functionality at our sole discretion, at any time with or without notice. Springer Nature
may revoke this licence to you at any time and remove access to any copies of the Springer Nature journal content which have been saved.
To the fullest extent permitted by law, Springer Nature makes no warranties, representations or guarantees to Users, either express or implied
with respect to the Springer nature journal content and all parties disclaim and waive any implied warranties or warranties imposed by law,
including merchantability or fitness for any particular purpose.
Please note that these rights do not automatically extend to content, data or other material published by Springer Nature that may be licensed
from third parties.
If you would like to use or distribute our Springer Nature journal content to a wider audience or on a regular basis or in any other manner not
expressly permitted by these Terms, please contact Springer Nature at
onlineservice@springernature.com