12 Apr 23
By Phil Barrington
There are non-pharmacologically based treatments that have been around for centuries. Some of these have been assessed scientifically and have been found to be efficacious. This blog summarises some of these treatments.
Unlike chimeric antigen receptor T-cell (CAR-T) therapy, the treatment of chronic wounds is not really a “sexy” area of medicine. To patients, it is very important as these conditions are associated with prolonged healing and unpleasant odours. Various factors affect wound healing. Most chronic wounds are ulcers associated with ischemia, venous stasis or pressure (Koeppen, Aurich et al. 2020).
Despite the vast advances in today’s healthcare technology, the management of chronic wounds still poses a significant challenge to the medical world and are also associated with significant costs. For example, in 2005/2006, the National Health Service (NHS) cost of caring for patients with chronic wounds was estimated to be £2.3b to £3.1b per year (3% of the total estimated expenditure on health) (Naik and Harding 2017).
The use of insects or their products is not new; honey from bees, cobwebs, ant-heads to aid wound closure, and leeches to help draw excessive wound congestion have all been tried in the past.
Maggot debridement therapy (MDT) is one ancient method that has stood the test of time and is still being widely used to achieve wound debridement in difficult and chronic wounds. According to Fleischmann et al, “Australian aborigines have used maggots to clean wounds for thousands of years.” Military surgeons noted that soldiers, whose wounds became infested with maggots healed better (Fleischmann, Grassberger et al. 2004)
MDT using the larvae of the green bottle fly (Lucilia sericata) is now used to treat wounds. An important step in assisting chronic non-healing wounds progress through to healing, is wound bed preparation. This is usually achieved by effective debridement technique to remove devitalised tissue, including slough and eschar. The methods of debriding a wound can be classified as surgical, autolytic, mechanical, enzymatic, or biological. MDT mainly helps in wound healing by debridement of necrotic tissue by both mechanical and biochemical means. Mechanical debridement is achieved by the “mouth hooks” of the maggots and their rough bodies that scratch the necrotic tissue. They may also secrete a mixture of proteolytic enzymes (trypsin and chymotrypsin-like collagenase) that lyse nonviable tissue, making it easier for the maggots to digest (Naik and Harding 2017).
Cambal and colleagues published their findings of the MDT method in chronic conservative non-treatable leg ulcers in patients in whom conventional therapy failed. All ulcers were healed or minimised in size after 4–8 weeks of follow-up (Cambal, Labas et al. 2006).
Honey is one of the substances that has been used to treat infections and heal wounds, with reports dating back as far as 4000 years ago (Kapoor and Yadav 2021). The honey produced from the flowers of the Manuka tree (Leptospermum scoparium) is a uni-floral honey. The Manuka tree is indigenous to New Zealand and South East Australia and the honey is largely produced in New Zealand. It has been found that the topical application of honey clears existing wound infection rapidly, facilitates healing of deeply infected surgical wounds and halts spreading necrotising fasciitis. It has also promoted healing of infected wounds that were not responding to conventional therapy such as antibiotics and antiseptics. This also includes wounds that were infected with antibiotic-resistant bacteria such as methicillin-resistant Staphyloccocus aureus (MRSA) (Kapoor and Yadav 2021).
Methylglyoxal is the unique compound in the honey that is responsible for some of its potent antimicrobial properties. Honey is rich in glucose oxidase. This enzyme catalyses glucose to produce hydrogen peroxide which topically exerts antibacterial properties (Kapoor and Yadav 2021).
Medicinal leeches (Hirudo medicinalis) have been widely used throughout history from ancient times through to the 20th century when the advances of modern medicine brought their use to an end (National Health Service 2020).
MLT is a multi-faceted therapeutic concept. It comprises the biting stimulus, blood drawing and the injection of pharmacologically active substances found in leeches’ saliva into patients’ blood and tissues. Its therapeutic effects include anti-coagulation, blood and lymph flow stimulation and the reduction of both inflammation and pain.
The leeches are applied to the area and each treatment usually takes between 30-60 minutes. Bleeding will continue when the leech or leeches are removed so that the blood vessels are constantly flowing and free from congestion. It may be necessary to apply a leech or leeches several times a day to ensure that this flow continues.
Epidemiologists have noticed that diseases such as asthma, hay fever and autoimmune conditions are much more prevalent in the affluent Western world than in poorer countries, such as sub-Saharan Africa and India. A potential explanation is the exposure to parasitic worms that may modulate the immune system. Parasitic worms must battle constantly to prevent host defence mechanisms removing them from the body. To do this, they have evolved an arsenal of chemicals that they use to suppress the body’s immune system to prevent them from being detected and destroyed (Sarkies 2020).
As parasitic worms are ubiquitous in less developed countries, but much rarer in Europe and most of the USA, it raises the possibility that infection with parasitic worms suppresses the immune system. There is growing experimental evidence from studies in mice, that the presence of these worms prevents the development of disorders caused by overactive immunity (Sarkies 2020).
The Epigenetic Inheritance and Evolution group in collaboration with Murray Selkirk’s lab (Imperial College London) has focused on the chemical secreted by parasitic worms (Sarkies 2020). It is possible that some parasitic worms might be secreting types of small RNA molecules known as microRNAs (about 20 nucleotides in length) that have hugely important roles in development of many different types of cells, including in the immune cells. MicroRNAs exert their function by pairing to specific target messenger RNAs and causing these to be shut down. This enables microRNAs to repress a very specific set of genes.
The nematode Acanthocheilonema viteae is a filarial parasite of rodents and ES-62 is a major excretory-secretory (ES) product of this organism (Howe, Bolt et al. 2017). Animal experiments have shown that ES-62 has a protective effect against some autoimmune diseases. For example, it has a protective effect against disease in a mouse collagen-induced arthritis model of rheumatoid arthritis by suppressing pathogenic IL-17 and upregulating IL-22 production by recruiting γδ T cells (Wu, Wang et al. 2017).
There has been increasing interest in understanding the role of the human gut microbiome to elucidate the therapeutic potential of its manipulation. Faecal microbiota transplantation (FMT) is the administration of a solution of faecal matter from a donor into the intestinal tract of a recipient, to directly change the recipient’s gut microbial composition. FMT has been used to successfully treat recurrent Clostridium difficile infection. There are preliminary indications to suggest that it may also carry therapeutic potential for other conditions such as inflammatory bowel disease, obesity, metabolic syndrome, and functional gastrointestinal disorders (Gupta, Allen-Vercoe et al. 2016).
The first known description of the use of faeces as therapy was described by Ge Hong in fourth-century China for the treatment of a variety of conditions including diarrhoea. In 1958, Eiseman and colleagues described the use of faecal enemas as a treatment for pseudomembranous colitis, marking the introduction of FMT into mainstream medicine (Gupta, Allen-Vercoe et al. 2016).
C. difficile is a Gram-positive, anaerobic, spore-forming, and toxin-producing bacillus. It is a leading nosocomial infection and is becoming an increasingly virulent and severe epidemic. CDI causes symptoms ranging from mild watery diarrhoea to potentially lethal conditions such as pseudomembranous colitis (CDC.gov). The standard treatment is a course of vancomycin or metronidazole, however, a significant portion of patients with CDI goes on to develop recurrent CDI (rCDI), which can lead to significant morbidity and mortality.
FMT has been used to treat successfully rCDI, and although mostly based on case series, there has been an average 87–90% cure rate (defined by resolution of diarrhoea) for the over 500 cases that have been reported in the literature to date.
The mechanisms by which FMT exerts its therapeutic effects in patients with CDI has not yet been fully elucidated. However, the most likely scenario is competitive exclusion of the pathogen with the microbiota outcompeting C. difficile for nutrients and creating an environment that is unfavourable for its growth.
All the therapies mentioned in this article have clinical evidence of benefit and there is increasing scientific evidence that explains the potential mechanisms of action. Careful explanations must be provided to patients (who will probably expecting a tablet or an injection) as to why these unconventional approaches may be beneficial.
Bacteriophages (BPs) are viruses that can infect and kill bacteria without any negative effect on human or animal cells. For this reason, it is supposed that they can be used, alone or in combination with antibiotics, to treat bacterial infections (Principi, Silvestri et al. 2019).
BPs have a very narrow spectrum of activity, which avoids the most important problem strictly related to the antibiotic administration, i.e., the influence on the entire microbiome with elimination of potentially beneficial bacteria, the overgrowth of secondary pathogens and the emergence of resistant bacteria (Principi, Silvestri et al. 2019). The greatest number of studies in humans have investigated the use of BPs for topical treatment of skin bacterial infections. The topical application of BPs cured burns infected by multidrug-resistant P. aeruginosa and allowed successful skin grafting in 18 out of 30 adult patients in whom this therapy was used (Abdul-Hassan, El-Tahan et al. 1990).
Abdul-Hassan, H., E. El-Tahan, B. Massoud and R. Gomaa (1990). “Bacteriophage therapy of Pseudomonas burn wound sepsis.” Ann. Medit. Burn Club 3: 262-264.
Cambal, M., P. Labas, M. Kozanek, P. Takac and Z. Krumpalova (2006). “Maggot debridement therapy.” Bratislavske lekarske listy 107(11-12): 442-444.
CDC.gov “FAQs for Clinicians about C. diff.” https://www.cdc.gov/cdiff/clinicians/faq.html#:~:text=diff%3F-,C.,of%20all%20episodes%20of%20AAD.
Fleischmann, W., M. Grassberger and R. Sherman (2004). Maggot therapy: a handbook of maggot-assisted wound healing, Georg Thieme Verlag.
Gupta, S., E. Allen-Vercoe and E. O. Petrof (2016). “Fecal microbiota transplantation: in perspective.” Therap Adv Gastroenterol 9(2): 229-239.
Howe, K. L., B. J. Bolt, M. Shafie, P. Kersey and M. Berriman (2017). “WormBase ParaSite – a comprehensive resource for helminth genomics.” Mol Biochem Parasitol 215: 2-10.
Kapoor, N. and R. Yadav (2021). “Manuka honey: A promising wound dressing material for the chronic nonhealing discharging wounds: A retrospective study.” Natl J Maxillofac Surg 12(2): 233-237.
Koeppen, D., M. Aurich, M. Pasalar and T. Rampp (2020). “Medicinal leech therapy in venous congestion and various ulcer forms: Perspectives of Western, Persian and Indian medicine.” J Tradit Complement Med 10(2): 104-109.
Naik, G. and K. Harding (2017). “Maggot debridement therapy: the current perspectives.” Chronic Wound Care Management and Research Volume 4: 121-128.
National Health Service (2020). Leech Therapy (Hirudotherapy) – Patient Information. P. S. Department. University Hospital Coventry and Warwickshire.
Principi, N., E. Silvestri and S. Esposito (2019). “Advantages and Limitations of Bacteriophages for the Treatment of Bacterial Infections.” Frontiers in Pharmacology 10.
Sarkies, P. (2020, 3 July 2020). “Why catching a parasite might be the best thing for your allergies.” Retrieved 13 December 2022, 2022, from https://lms.mrc.ac.uk/why-catching-a-parasite-might-be-the-best-thing-for-your-allergies/.
Wu, Z., L. Wang, Y. Tang and X. Sun (2017). “Parasite-Derived Proteins for the Treatment of Allergies and Autoimmune Diseases.” Front Microbiol 8: 2164.
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