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A major part of patients in healthcare suffer from one or multiple wounds. In the United Kingdom, 2.2 million patients received wound care within the British National Health Service (NHS) system in 2012/2013
1. The American Medicare system provided wound care to almost 15% of its beneficiaries (8.2 million patients) in 2014
2. The majority of these wounds are either caused by traumatic events (e.g. falling, accidents) or by the treatment a patient received (e.g. surgery). A wound poses several risks for every human being, because it consists of damage to the skin, which acts as natural barrier against (pathogenic) influences from the environment
3. Luckily, the human body is able to initiate a cascade of processes that removes debris and bacteria from the wound, restores damaged tissue and skin and leads to a completely healed wound
4. However, a substantial number of patients suffer from impaired or failed wound healing, i.e. a chronic or complex wound (figure 1.1).
Figure 1.1. Complex wound healing in an amputation wound of a patient with Diabetes Mellitus (left) and in a traumatic wound on the lower leg (right).
In the UK, it was estimated that 39% of wounds remained unhealed within one year
1. A prolonged or failing healing process often leads to a lower quality of life for patients, as wounds often lead to pain, functional (mobility) and psychological impairments (frustration, shame)
5. In addition, the care for wounds poses a substantial burden on healthcare budgets as it requires a high frequency of outpatient clinic visits or nurse home visits and substantial use of materials (e.g. wound dressings). For example, between May 2012 and April 2013, 5.5% (£328.8 million) of the total annual expenditure of the National Health Service in Wales was spent on the care for (chronic/complex) wounds
6. Expenditure within the complete NHS (UK) for wound care amounted up to
£5.3 billion in the same period
1, and Medicare (US) expenditures were $28 billion in
General introduction
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2014
2. Moreover, it was estimated that costs for a wound that failed to heal within one year were 2.4 times higher than costs for a healed wound
1.
The impact of wounds on both patients and the healthcare system is even increased in case of wound infection. Infection usually occurs when pathogens invade the wound and outcompete the human immune system
7. Wounds with impaired wound healing have a higher risk of wound infection because there is a prolonged exposure of tissue to possible pathogenic influences from the environment
8. It is therefore not surprising that a substantial number of patients with complex wounds suffer from wound infection; e.g.
Rondas et al. estimated in 2012 that 22% of patients with a wound in Dutch nursing homes suffered from wound infection
9. Luckily, the immune system is usually able to clear the infection before it spreads to other regions in the body. However, this immune response also results in further damage to tissue and therefore delays the healing process even more. In addition, in some patients, the immune system fails to clear the infection in time. This increases the risk of more severe complications, such as amputation (e.g. diabetic foot ulcer), or a spread of the infection to the blood stream leading to sepsis, requiring hospitalization and prolonged treatment
10. To prevent such complications, it is important to detect infection in an accurate and timely manner. This allows timely treatment with antibiotics to support the immune system in the clearance of pathogens. Moreover, the ability to accurately rule out infection prevents the unnecessary use of antibiotics or expensive antibacterial wound dressings. Inappropriate use of antibiotics favors the development of antibiotic resistance, which is a growing issue worldwide
11.
Currently, wound infection is primarily diagnosed based on clinical judgment and, if
deemed necessary, microbiological culture results. Clinical judgment of wound infection
is primarily based on assessment of clinical signs and symptoms such as pain, redness,
edema, warmth and pus (figure 1.2). However, these signs and symptoms are not always
clearly related to wound infection, in particular for patients with vascular disease or
Diabetes Mellitus
12. For example, edema might be caused by vascular insufficiency
rather than an infection, neuropathy in patients with Diabetes Mellitus limits the use of
an increase in pain as a sign of infection and redness due to skin irritation might be
wrongly interpreted as a sign of infection
13. Therefore, microbiological culture results
are often used to support the detection of wound infection. These results are meant to
identify which microorganisms are present in a wound. In addition, the microbiological
laboratory might also perform antibiotic susceptibility tests to inform the clinician about
the effectiveness of specific antibiotics to the cultured microorganisms
14.
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Figure 1.2. Two complex wounds with a wound infection (according to clinical judgment); a wound after removal of a basal cell carcinoma (left) and a diabetic foot ulcer (right).
However, it takes 3 to 5 days until microbiological culture results are available. Moreover, culture results are often difficult to interpret in terms of wound infection as they do not provide insight in the actual pathogenic effect of microorganisms in a wound
7,15. In this light, it has been questioned whether these traditional methods are able to fulfill the need for accurate and timely detection of wound infection
16,17. Therefore, the aim of this Thesis was to assess both traditional, and novel diagnostic techniques that potentially fulfill this need.
OUTLINE OF THE THESIS
This Thesis consists of four parts; the general introduction (part I), two subsequent parts in which traditional (part II) and novel (part III) diagnostic techniques are assessed, and a general discussion and summary (part IV)
Before the assessment of different diagnostic techniques, chapter 2 completes the
introductory part of this thesis by describing the wound healing process, the
pathophysiology of impaired wound healing and current treatment options for complex
wounds. In addition, this chapter introduces several diagnostic and therapeutic
innovations in wound care.
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Part II of this thesis focuses on the assessment of traditional diagnostic techniques for wound infection. Chapter 3 assesses two different wound sampling methods for microbiological culture and zooms in on possible differences in the discovery of microorganisms, while chapter 4 focuses on the assessment of wound infection by different clinical experts based on both clinical signs and symptoms of wound infection and microbiological culture results.
Part III subsequently investigates whether novel diagnostic techniques are able to overcome the imperfections and limitations of traditional techniques. Chapter 5 and 6 assess the use of enzyme assays as a fast and easy diagnostic tool for the detection of wound infection. Where chapter 5 describes the first clinical study performed with the enzyme assays, chapter 6 assesses a further developed prototype diagnostic test device with incorporated enzyme assays. Chapter 7 investigates the relation between wound pH and wound infection as pH measurements are inexpensive, easy to perform and provide results within a few seconds. Part III is concluded by chapter 8 that describes a pilot study in which the ability of an electronic nose to differentiate between infected and non-infected wounds is explored. Over the past years, there has been an increasing interest in the use of electronic noses to differentiate between disease and no disease, e.g. for lung cancer and colorectal cancer. However, the potential use as a fast and easy diagnostic device for wound infection has not been explored before.
This thesis concludes with a general discussion, summary and acknowledgments in part
IV. The general discussion in chapter 9 puts the main findings of the assessments of the
traditional (chapters 3 and 4) and novel (chapters 5-8) diagnostic techniques for wound
infection in perspective and reflects on the implications for both research and clinical
practice. The general summary (in English and Dutch) and the acknowledgments can be
found in chapter 10.
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REFERENCES
1. Guest JF, Ayoub N, McIlwraith T, et al. Health economic burden that different wound types impose on the UK's National Health Service. International wound journal. 2017;14(2):322-330.
2. Nussbaum SR, Carter MJ, Fife CE, et al. An Economic Evaluation of the Impact, Cost, and Medicare Policy Implications of Chronic Nonhealing Wounds. Value in health : the journal of the International Society for Pharmacoeconomics and Outcomes Research. 2018;21(1):27-32.
3. Velnar T, Bailey T, Smrkolj V. The wound healing process: an overview of the cellular and molecular mechanisms. The Journal of international medical research. 2009;37(5):1528-1542.
4. Demidova-Rice TN, Hamblin MR, Herman IM. Acute and impaired wound healing: pathophysiology and current methods for drug delivery, part 1: normal and chronic wounds: biology, causes, and approaches to care. Advances in skin
& wound care. 2012;25(7):304-314.
5. Deufert D, Graml R. Disease-specific, health-related quality of life (HRQoL) of people with chronic wounds—A descriptive cross-sectional study using the Wound-QoL. Wound Medicine. 2017;16:29-33.
6. 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. International wound journal. 2016;13(6):1193- 1197.
7. Bowler PG, Duerden BI, Armstrong DG. Wound microbiology and associated approaches to wound management. Clinical microbiology reviews.
2001;14(2):244-269.
8. Bowler PG. Wound pathophysiology, infection and therapeutic options. Annals of medicine. 2002;34(6):419-427.
9. Rondas AA, Schols JM, Stobberingh EE, Halfens RJ. Prevalence of chronic wounds and structural quality indicators of chronic wound care in Dutch nursing homes. International wound journal. 2015;12(6):630-635.
10. McCosker L, Tulleners R, Cheng Q, et al. Chronic wounds in Australia: A systematic review of key epidemiological and clinical parameters. International wound journal. 2018.
11. Lipsky BA, Dryden M, Gottrup F, Nathwani D, Seaton RA, Stryja J. Antimicrobial stewardship in wound care: a Position Paper from the British Society for Antimicrobial Chemotherapy and European Wound Management Association.
The Journal of antimicrobial chemotherapy. 2016;71(11):3026-3035.
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