Vox Pop
The critical nature of colonisation?, by Dr Richard J. WhiteA tale of two lesions, by Dr Keith Moore
Where is the Smart Money Going?, by Perry Lesion.
The critical nature of colonisation? by Dr Richard J. White
richard@medicalwriter.co.uk
In recent years there have been a number of articles referring to the stage of 'critical colonisation' in wounds. This has been described as a conceptual stage as it has yet to be clearly defined in clinical and microbiological terms. Some authorities have stated that it is no more or less than 'local infection'.
What then do we know of critical colonisation and what part does it play in wound pathogenesis and treatment?
First, it is claimed to be a state of delayed healing, attributable to the wound bioburden. This can only really be confirmed retrospectively in those patients who respond to topical antimicrobial treatment. We are also informed that delayed healing is due to uncontrolled protease (Matrix Metallo Protease) activity in the wound - MMPs. These enzymes are of both endogenous (neutrophil) and exogenous (bacterial) origin. The antimicrobial rationale fits insofar as the reduction of bioburden will also reduce exogenous MMPs.
Thus, there is a link between delayed healing and bioburden and critical colonisation (or local infection if you insist!).
Can we clarify further? In the opinion of many experts, local infection is accompanied by signs of host response. A locally infected wound will have a degree of surrounding, but not spreading, erythema. A recent paper on wound infection criteria has served to further clarify this situation1. We are therefore, rapidly approaching the stage where we can be more confident of our definitions and criteria for infection in different wound types.
Can critical colonisation be defined by non-clinical criteria? Certainly bacterial virulence determinants come into consideration. We have already encountered MMPs as such. As proteins we might expect them to elicit an immune response but they might be homologous to our own endogenous MMPs. The alternative approach of treating wounds with an MMP 'inhibitor' is likely to be a non-specific substrate competitor that does have the desired effect of negating the deleterious effect of proteases but does not add to our understanding of critical colonisation. Other bacterial virulence determinants such as quorum sensing, microbial synergy and biofilm formation may offer an explanation.
In critical colonisation we have delayed healing but no sign of host response. The innate immune system has not, therefore, been triggered, yet something serves to inhibit healing. Some wounds are arrested in critical colonisation whist others pass on through to infection. What determines the pathogenic pathway?
In quorum sensing, certain colonising bacteria will secrete messenger molecules to 'communicate' with fellow organisms - usually resulting in the switching on of expression of virulence. There is known to be a synergy between certain bacterial species that enables both species to thrive, each dependent upon the other. Research has shown us that in the presence of four or more species, wound infection is likely. In biofilm formation, planktonic bacteria assemble into a matrix of impervious carbohydrate, rendering them safe from antibiotics.
Research on one bacterial species associated with wound infection has provided a clue. Peptostreptococci are known to produce short chain fatty acids (SCFA). These in turn have been shown to arrest the growth of key wound cell populations in vitro. Thus, colonisation with peptostreptococci without infection might offer a bacterial explanation of critical colonisation.
Can it be described in immunological terms? The key here might lie with antigen presentation. It might also indicate that critical colonisation is not a stage that wounds may potentially enter. We know that in venous leg ulceration antigen presentation (via the Langerhans cells) is defective. These SCF might provide the explanation of altered dermal cell proliferation through the ras-mediated signalling pathways.
Whatever the explanation, bacteria play an even greater role on wound healing/non-healing than we currently recognise. These organisms provide the stimulus for the chronic inflammatory state, or immunopathology that characterises the so-called chronic wound and will be shown to be the key to critical colonisation!
Reference:
1. Cutting KF, White RJ 2005. Criteria for Identifying Wound Infection ? Revisited. Ostomy/Wound Management 51, 1 :28 ? 34
Editors note: It is pertinent to remember that if critical colonisation does exist then its manifestation in a wound may be such that as yet we have not been able to identify the relevant signs! Just because you can't see it doesn't necessarily mean it's not there. Additionally, although providing protection from antibiotic onslaught the self generated exopolysaccharide matrix of biofilms does not protect the sessile bacteria from antiseptics. This could explain why some wounds respond favorably to topical antibacterials such as iodine and silver when antibiotics have made no impact at all!
http://www.woundscience.com
A recent publication1 highlights consideration of wound healing and tumour progression as related processes. Both wounded tissue and tumours induce rapid cell proliferation, angiogenesis, cell migration through extracellular tissue and provoke a marked inflammatory response. There is one significant difference in that normal wound healing, is tightly controlled to restore tissue integrity. In contrast a solid tumour may initially grow slowly as a primary tumour but the evolution of more rapidly proliferating cells allows it to evade body defences and metastasize to regional lymph nodes and eventually distant organs. The processes involved are essentially similar; the difference lies in regulation of cell function within the two lesions.
Chronic wounds that may persist for many years theoretically may even mimic a slow growing non-metastatic tumour as cell turnover will continue for the lifetime of the wound and only be switched off when the wound closes in response to an appropriate therapy. The microenvironment generated by chronic tissue repair may also lead to tumour development as indicated by the association of chronic wound lesions with malignancy.
In a study examining gene expression of human cultured fibroblasts responding to serum Chang and his co-workers1 demonstrated a programmed sequence including expression of genes that represent induction of cell motility, extracellular matrix remodelling, cell-cell signalling and aquisition of a myofibroblast phenotype. All functions that would be expected to be involved in the healing process. The authors then went on to monitor expression of these genes in normal and malignant tissue. In normal control tissue gene expression was identical to that seen in quiescent fibroblasts whereas in breast, lung and gastric carcinomas serum response gene expression pattern was observed in a subset of tumours. Over a 5 year period patients with tumours expressing the serum response gene pattern were more likely to suffer tumour metastasis and death than those with negative tumours.
Thus it appears that tumours expressing wound associated features are more aggressive and less likely to respond to treatment leading to a conclusion that an understanding of cell regulation in the wound environment may lead to novel anti-cancer therapies.
From the perception of the wound healing researcher this raises interesting possibilities. In 1970 President Nixon "declared war" on cancer and in the following 3 decades billions of dollars have been spent investigating the disease worldwide. In contrast the amount spent on wound healing research is insignificant. However cross fertilisation between the two fields could prove fruitful from the wound researchers perspective. For example metalloprotease inhibitors developed for prevention of tumour metastasis may theoretically improve healing of chronic wounds expressing high levels of proteases that inhibit healing. Understanding how tumours generate their blood supply may reveal how to stimulate angiogenesis in chronic wounds.
At a more pragmatic level maybe wound healers should tap into the cancer dollars by re-orienting their research proposals so that they are targeted at wound healing and cancer by stressing the value of understanding these two related lesions.
1) Chang, H. Y., J. B. Sneddon, et al. (2004). "Gene Expression Signature of Fibroblast Serum Response Predicts Human Cancer Progression: Similarities between Tumors and Wounds." PLoS Biol 2(2): E7
The fulltext article can found at
http://www.plosbiology.org
Medical device companies have invested time and money in developing products designed to enhance and accelerate the healing process. These products include recombinant growth factors, a variety of grafting systems, protease modulators and topical antimicrobials.
All of these systems have been subjected to a variety of clinical trials both before and after launch of the product. Which of these approaches produces the most benefit to the patient in the shortest time span? The answer is we do not know. Although altruism may play a part in the development of a new product for the medical device or pharmaceutical company involved they are answerable to their shareholders and investors so the question at the top of their agenda is "when do we get a return from our investment?" Only the sales figures can answer that one. And sales rely not only on marketing efficiency but also on long-term product efficacy.
It is well established that infection has a detrimental effect on healing and could well be the single most important factor that inhibits healing. Current resources to manage infected wounds include; systemic antibiotics and a limited selection of topical antibiotics, topical antiseptics of which the safest and most efficacious appear to be iodine, silver and honey and occlusion when aerobic infection is present.
It has recently been announced that Agennix Inc., Houston Texas has received $850,000 NIH Funding to fund clinical trials examining recombinant lactoferrin gel (rhLF Gel) for treatment of patients with diabetic foot ulcers. Lactoferrin is a naturally occurring substance that can be found in most body fluids and is produced by neutrophils. It is anti-inflammatory and also has the ability to stimulate the immune system. Its clinical efficacy is currently being assessed in Phase 2 clinical trials not only for treatment of diabetic foot ulcers but also for cancer and asthma.
Lactoferrin is iron binding and can exert a potent antimicrobial effect. Researchers have identified (http://www.uihealthcare.com) that some bacteria are sensitive to the presence of lactoferrin and are unable to develop biofilm capability. This subsequently left the bacteria vulnerable to the effects of antimicrobials. With green issues gaining momentum in the 21st century and lactoferrin a naturally occurring antimicrobial then this could be where the smart money is going to see a return on its investment. A new "green" product that not only possesses antimicrobial properties but furthermore provides a stimulus to healing should be a welcome addition to the wound healing armamentarium. Investigating rhLF and its potential to not only enhance healing through its anti-inflammatory, immunomodulatory and antibacterial activity could hit pay dirt sooner than may be expected. We eagerly await findings of the current and future trials.