NEWSLETTER 3 (December 2000)
A. New Internet links related to biotherapy:
Eve Iversen will start her Fulbright Grant at Cairo University Faculty of Veterinary Medicine on 1 October. The web site in which she will report her stay at the Veterinary Faculty will be through the University of California, Davis-Department of Biological and Agricultural Engineering: http://www.engr.ucdavis.edu/~bae/egypt/index.htm(no more available)
The web site in which she will report her research at the Veterinary Faculty will be through the University of California, Irvine-School of Medicine: http://www.ucihs.uci.edu/path/sherman/vet_mdt/index.htm.
(no more available)
B. Recent publications in biotherapy
Cohen-J. Feeding the fish. Brit. Med. J. 2000: 320: 181.
The revival of the use of living organisms to help in treating illnesses has grabbed the attention of the media recently. Reports of the use of leeches in plastic surgery and maggots in dermatology raise the question of which other animals may be of benefit, a concept some call "biotherapy." While there are promising studies of the use of maggots to help the healing of necrotic and infected wounds, those wounds with high moisture content defy even the larvae. Rumours of healing fish had reached Professor John Church, chairman of the International Biotherapy Society. Perhaps organisms, which live in an aquatic environment, could help to heal "wet wounds," he mused. We received anecdotes of the widespread use of such fish in southern India, and so, while traveling through the region, I decided to hunt down the practice in order to see if it worked. To my surprise, the practice was well known, particularly in rural areas. Locals with skin infections, infestations, and wounds would bathe the affected limb in the pond, while certain fish would be drawn to the lesion and nibble at it, thereby removing diseased tissue. After some searching I discovered Rishimangalam Tank, a local "holy pond" in the centre of Trivandrum, Kerala State. Through the services of an interpreter, some local boys were happy to collect some fish they recognised, using their dhotis as fishing nets. My intention had been to pickle them in a jar of gin for later identification. However, by coincidence, that very evening I met Professor Padmanabham of the fish biology department at the University of Kerala. He was familiar with Macropodus cupanus, the fish, which he identified for me, as he had written a thesis on it. He told me that the practice of bathing limbs in pools for fish to help healing was widespread; in particular, mothers brought their children to be cured of scabies. The fish live in polluted water where they survive by both aerial and gill respiration, possessing accessory labyrinthine organs. Their preferred food is mosquito larvae, and as they eat constantly they do not need starving before use, unlike some species of maggots. Once drawn to the limb by substances which diffuse from the wound into the water, they eat, enjoying living and dead tissue equally. Although they nibble at the necrotic tissue faster, the eating of the living tissue can be quite painful. Perhaps we are not all ready to have our British wounds nibbled away, but with the use of local anaesthetic cream before treatment, the day may yet come where dermatology departments offer maggot treatment for the drier lesions, and the "biopool" for the wetter ones.
Namias-Nicholas; Varela-J-Esteban; Varas-Robin-P; Quintana-Olga; Ward-C-Gillon. Biodebridement: A case report of maggot therapy for limb salvage after fourth-degree burns. Journal-of-Burn-Care-and-Rehabilitation. 2000; 21 (3): 254-257.
AB: The wound healing and antimicrobial properties of maggots are well known. Maggot debridement therapy has been used for the treatment of various conditions. For maggot debridement therapy, the larvae of the blowfly are applied over necrotic or nonhealing wounds. We used maggot debridement therapy with the larvae of Phaenicia sericata for limb salvage after bilateral lower extremity fourth-degree burns.
Bonn-D. Maggot therapy: an alternative for wound infection. The Lancet 2000; 356 (number 9236). Search in http://www.thelancet.com, in “journal search” for “maggot therapy”.
Sherman-RA; Hall-MJR; Thomas-S. Medicinal maggots: an ancient remedy for some contemporary afflictions. Annual-Review-of-Entomology. 2000, 45: 55-81; 145 ref.
AB: Certain fly larvae can infest corpses or the wounds of live hosts. Those which are least invasive on live hosts have been used therapeutically to remove dead tissue from wounds and promote healing. This medicinal use of maggots is increasing around the world, due to its efficacy, safety and simplicity. Given our low cultural esteem for maggots, the increasing use and popularity of maggot therapy is evidence of its utility. Maggot therapy has successfully treated many types of chronic wounds, but much clinical and basic research is needed still. In this review, the biology of myiasis and the history of maggot therapy are presented, the current status of our understanding and clinical use of medicinal maggots is discussed, and opportunities for future research and applications are proposed. Species of fly listed as being, or having been, used in maggot therapy are: Calliphora vicina, Chrysomya rufifacies, Lucilia caesar, L. cuprina, L. illustris, L. sericata, Phormia regina, Protophormia terraenovae [Phormia terraenovae], Wohlfahrtia nuba and Musca domestica.
Fleischmann-W; Russ-M; Moch-D; Marquardt-C. Biosurgery - maggots, are they really the better surgeons? (in German). Biochirurgie - sind Fliegenmaden wirklich die besseren Chirurgen. Chirurg. 1999, 70: 11, 1340-1346.
AB: Between 1 October 1996 and 31 December 1998, 123 patients (74 men, 43 women) suffering from acute (n=17) and chronic (n=21) infections and chronic wounds (n=85) were treated with sterile Lucilia sericata larvae. In most patients the indication for the use of maggots was a failure to respond to standard therapy. Healing occurred in all patients with acute infections, and chronic infections showed excellent short-term results. In chronic wounds disturbances of healing in diabetics responded best to maggot therapy, the aetiologically inhomogeneous group of leg ulcers asked for a polypragmatic approach, and the worst results were seen in chronic arterial occlusive disease (stage 4). The limited experience with "biosurgery", biased selection of patients, and lack of late results reduced the significance of the data; nevertheless, sterile maggots seem to be an astonishingly workable tool for solving problems in surgical wound treatment.
Comment in: Chirurg 1999 Nov;70(11):1285-6.
Courtenay-M; Church-JCT; Ryan-TJ. Larva therapy in wound management. Journal-of-the-Royal-Society-of-Medicine. 2000, 93: 2, 72-74.
AB: Quantitative information was collected on 70 patients treated in 9 UK hospitals with larvae [?Calliphoridae]. Larval treatment was used primarily to treat leg ulcers and generally involved 3 applications of larvae at 2-3 day intervals. After larval therapy, 30 of the wounds were fully debrided, 20 were partially debrided and 8 were unchanged. In 1 case the wound had deteriorated. The average wound size was reduced by nearly 5% and the area of slough and necrotic tissue by 68%. The area of granulation tissue increased by 26%. The number of wounds with copious or moderate exudate declined by 33%. Wound odour was reduced in 81%, and 69% of patients had less pain. There was also evidence for a reduction in bacterial growth in the wound. In the opinion of nurse practitioners, larval therapy reduced hospital stay in 34% of the patients, prevented surgery in 27%, avoided hospital admission in 16% and reduced the need for antibiotics in 26%. The nurse practioners who used LT believed that it had played a major role in management of 90% of the wounds treated with LT.
Thomas-S; Andrews-A; Jones-M; Church-J. Maggots are useful in treating infected or necrotic wounds. British-Medical-Journal-Clinical-Research-edition. 1999, No. 7186, 807-808.
AB: The use of dipteran larvae to treat infected or necrotic wounds is proposed as an alternative to antibiotics, particularly where wounds contain antibiotic resistant strains of bacteria, but also to reduce the risk of developing antibiotic resistant strains of bacteria. Commonly used larvae are those of Lucilia sericata. It is proposed that maggot therapy should be considered to clean up wounds at an earlier stage than at present.
Wolff-H; Hansson-C. Larval therapy for a leg ulcer with methicillin-resistant Staphyloccocus aureus. Acta-Dermato-Venereologica. 1999, 79: 4, 320-321; 12 ref.
AB: An 82-year-old Swedish man was admitted for hospital care during 1995 with an ulcer on his leg. The ulcer was thought to be caused by a combination of venous and arterial insufficiency. In June 1997 methicillin-resistant Staphylococcus aureus (MRSA) was found in his ulcer for the 1st time. In September 1997 the patient was introduced to larval therapy. 300 Lucilia sericata larvae 1-2 mm long were placed in the ulcer and the leg dressed. The yellowish-green necrosis in the ulcer was removed by the larvae and healthy pinkish granulation tissue could be seen. 3 further larval therapies were applied and the MRSA lost its specific-resistance gene due to mutation. The ulcer size continued to decrease and completed healing in November 1998.
Rayman-A; Stansfield-G; Woollard-T; Mackie-A; Rayman-G. Use of larvae in the treatment of the diabetic necrotic foot. Diabetic-Foot. 1998, 1: 1, 7...13..
AB: The management of gangrenous digital lesions in the ischaemic diabetic foot where vascular intervention is not possible or has been unsuccessful is limited. Local surgical and enzymatic debridement is often considered hazardous and many surgeons choose to leave necrotic toes to autoamputate. Unfortunately, autoamputation can be a protracted process, and unpleasant for the patient and relatives; there is also a risk of recurrent infection. This article describes the authors' experience of using Lucilia sericata larvae to excise dry gangrenous toes. Three case reports are presented of a 52-year-old man, and 76- and 78-year-old women.
Thomas-S. A wriggling remedy. Chemistry-and-Industry-London. 1998, No. 17, 680-683.
Hinshaw, J. Larval therapy: A review of clinical human and veterinary studies. 2000. http://www.smtl.co.uk/World-Wide-Wounds/2000/oct/Janet-Hinshaw/Larval-Therapy-Human-and-Veterinary.html
Oommen-T. Larva therapy [letter]. Journal-of-the-Royal-Society-of-Medicine, 2000; 93(7): 394.
Prentis-T. Caring for a patient having leech therapy. Nursing-New-Zealand: 1998 Dec-1999 Jan; 4(11): 21.
Prentis-T. Nursing care in leech therapy. Nursing-New-Zealand. 1998 Dec-1999 Jan; 4(11): 19-20.
Chun-JK; Sterry-TP; Margoles-SL; Silver-L. Salvage of ear replantation using the temporoparietal fascia flap. Ann-Plast-Surg. 2000 Apr; 44(4): 435-9.
AB: The authors report a case involving a 46-year-old man who sustained a traumatic amputation of approximately 60% of his ear from a human bite. The ear was replanted microsurgically without the benefit of venous anastomosis. Blood transfusion was not required despite the use of leech therapy and systemic anticoagulation. The replantation appeared to be a success at the time of his discharge from the hospital, but during the late postoperative period the replanted ear became progressively necrotic. The failing ear replantation was rescued successfully with the use of temporoparietal fascia flap reconstruction.
Bapat-RD; Acharya-BS; Juvekar-S; Dahanukar-SA. Leech therapy for complicated varicose veins. Indian-Journal-of-Medical-Research. 1998, 107: June, 281-284.
Fujita-Y; Kaji-S. Apitherapy - a review (in Japanese). Honeybee-Science. 1999, 20: 1, 17-26.
Choi-SeokHwa; Kang-SungSoo; Choi-SH; Kang-SS. Bee venom therapy of tail-docked dog (in Korean). Korean-Journal-of-Veterinary-Clinical-Medicine. 1998, 15: 2, 247-250.
Walterspiel, JN, Schad, GA and Buchanan GR. Direct transfer of adult hookworms (Ancylostoma duodenale) from dog to child for therapeutic purposes. J. Parasit. 1984; 70: 217-219.
AB: To induce chronic and continuous intestinal blood loss as therapy for congenital polycythemia in a 3 year old child, adult Ancylostoma duodenale were transferred directly from a dog to the patient via a nasoduodenal tube. By transferring adult worms, larval migration via the skin, blood and lungs –with possible attendant undesired side effect- was avoided. Furthermore, by eliminating larval migration with associated intimate tissue contact, immunogenicity was presumably reduced, and a known number of adult worms could be delivered directly to the final predilection site, the small intestine. An eosinophilic reaction op up to 23,000 cells/mm3 was observed, which may have adversely affected attempted superinfection. The relatively small numbers of parasites given on three separate occasions did not result in blood loss to a degree sufficient to eliminate the need for other forms of therapy.
C. Letters to the editor
The editorial board received the following article from Dr. Venning. Although the subject is related to biological control rather than to biotherapy, we thought that it might interest our readers.
Venning-G R. Dengue Fever – An unsolved problem and an opportunity for biotherapy with dragonfly larvae
Dengue fever is a common disease in tropical latitudes throughout the world.It is sporadic and mainly an urban problem. Although uncomplicated dengue is not very serious, the complication of dengue haemorrhagic fever is one of the world’s top ten killers in childhood, and there is no preventive inoculation and no existing treatment.It is a mosquito borne disease carried by Aedes aegypti, which commonly breeds in water containers in people’s homes. (‘Dengue and Dengue Haemorrhagic Fever’, Ed. D J Gubler and G Kano, published by CAB International 1997).
Existing Control Measures
In Singapore and Cuba some measure of control has been achieved by police action against home owners found to have exposed water containers in and around their homes.These are unusual police states and this approach is not possible in other third world cities.(‘Epidemiological News Bulletin, Jan. 1999 vol 25, no.1, published by Qurantine and Epidemiology Dept, Environment Building, 40 Scotts Road, Singapore 228231. Editor Prof Goh Kee Tai.).
The Biotherapy Solution
One of the first pieces of evidence for the efficacy and feasibility of biotherapy using dragonfly larvae for the control of Aedes aegypti in an urban setting was published in 1990. (Sebastian et al, Bulletin of Entomological Research 1990, 80 223-232. Abstract follows.) Suppression of Aedes aegypti was established using dragonfly larvae with community participation in a controlled trial in Yangon Myanmar.Control was achieved with only four dragonfly larvae placed in each household water container at monthly intervals.This is in contrast to the logistic difficulties encountered with other attempts. There were problems with mass rearing of larvae of Toxorhynchites species, and the need for weekly treatments was also a problem in American trials (J Med Entomol 1986, 23 573-9).
Other approaches have included larvicidal bacteria and larvivorous fish (Monograph on Dengue/Dengue haemorrhagic fever, WHO, New Delhi 1993, page 144), predatory copepods (Vientiane & Vietnam, Laos). (Am J Trop Med Hyg, 1995 53 324-30) and Chinese catfish in Guangdong province (Bull WHO 1987 65 503-6).The copepod trials in Laos and Vietnam and the Chinese catfish trials were all conducted in small villages, whereas in the Yangon study there was almost complete eradication of Aedes aegypti in an urban area with over 400 housing units with no change in a similar control area.
The Way Forward
The Yangon study showed that control of Aedes aegypti is feasible with community participation in an urban setting. It is sad that no-one has repeated this during a dengue epidemic with monitoring of the epidemic as the objective, rather than mosquito counts.The key to success will of course be expert advice on the rearing of the dragonfly larvae. Professor Philip Corbet, now retired, is the world expert who supervised the Yangon study and he would be willing to give advice in future studies. In addition, Professor D A L Davies is another dragonfly expert who is willing to advise on the choice of dragonfly species in other countries.
There are several Biotherapy approaches to the control of dengue fever, for which there is no vaccination available, and no medical treatment.These have included larvicidal bacteria, larvivorous fish and copepods and the predatory larvae of toxirhynchites species and dragonfly larvae.The simplicity of the dragonfly approach requiring only once-a-month provision of four larvae suggests that this method should be tested on a wider scale during epidemics now that control of the Aedes aegypti vector has been clearly demonstrated.
For further information, contact the author by fax at: ++ 44 1494 463318.
The following article was sent to the editorial board by John Newell
Newell, John. Parasites key to preventing diabetes
British research has revealed that the parasites responsible for the common tropical disease schistosomiasis (bilharzia) hold the key to the prevention of insulin dependent diabetes, also known as Type A diabetes. Research has shown that mice bred to develop Type 1 diabetes do not do so if they are infected with the eggs of schistosome parasites.
The scientists responsible for the discovery believe that within three years they will have identified the substance in the egg that is responsible for preventing diabetes. It should then be possible to test it, or a drug based on it, as a means of preventing the onset of Type 1 diabetes. A similar treatment may also be effective in preventing other diseases caused in the same way as Type 1 diabetes, including rheumatoid arthritis and inflammatory bowel disease, and possible asthma.
MOUSE MOVE SPARKS BREAKTHROUGH DISCOVERY
The breakthrough discovery was made when Dr. Anne Cooke of the Pathology Department of Cambridge University, who is studying diabetes using mice, which are genetically predestined to develop the Type 1 form, moved from London to Cambridge taking a colony of mice with her. The mice became accidentally exposed to parasitic and other infections. As a result only 50% instead of the normal 80% of the mice developed Type 1 diabetes.
Type 1 diabetes is rare in the developing world where tropical parasitic diseases such as schistosomiasis are rife. In contrast, it is on the increase in the developed world where vaccination and improved hygiene have virtually eliminated parasitic infections. This led Anne Cooke and her colleague parasitologist Dr. David Dunne to consider whether such infections might be preventing the development of Type 1 diabetes, as they had to some extent in her mice.
PARASITE EGGS COMPLETELY PROTECTED MICE
To test the hypothesis they infected mice genetically programmed to develop Type 1 diabetes with schistosome eggs and larvae. Dr. Cooke and Dr. Dunne found that these reduced the incidence of diabetes. When the mice were infected early in life so they had not had time to begin to develop diabetes, then none of them went on to develop the disease. They were totally protected by the infection. Further research showed that it is some component of the egg, rather that later stages of the parasite’s development that confers protection.
The way in which Type 1 diabetes is caused suggests how the infection may be having its effect. The disease is caused by an autoimmune reaction, in which the human immune system attacks some part of its own body as if it were a microorganism that had gained access to the body. In Type 1 diabetes the targets for attack are the cells in the pancreas, which produce insulin.
HOW SCHISTOSOME INFECTION ALTERS THE IMMUNE RESPONSE
It is known that in people chronically infected with schistosome, the nature of the immune response to infections becomes altered, in a way, which reduced the strength of the part of the response which, if misdirected, can cause autoimmune diseases. This is probably why Type 1 diabetes, as well as rheumatoid arthritis, are relatively rare in developing countries in the tropics, where chronic infection with schistosomes is very widespread.
The low prevalence of human schistosome infections in the developed world is a relatively recent phenomenon. On an evolutionary timescale, infection with parasites is the normal human condition. So the current increase in the incidence of Type 1 diabetes in developed countries may be due to the new (on an evolutionary time scale) absence of parasitic infections, revealing a susceptibility to autoimmune diseases, which previously would have been hidden and so would not have been eliminated by evolutionary proceses.
DRUG TO PREVENT TYPE 1 DIABETES COULD BE TESTED IN THREE YEARS
Dr. Cooke, Dr. Dunne and their Cambridge colleagues are now working to identify the antigen or antigens in the schistosome egg, which are responsible for altering the immune response and preventing the autoimmune destruction of insulin-producing pancreatic cells. They estimate that this may take about three years, after which it would be possible for a pharmaceutical company to begin the work of developing a drug upon the vital egg component.
At present Type 1 diabetes is usually diagnosed only after the majority of the insulin producing cells have already been destroyed. But much work is going into finding ways to identify those at risk earlier. When such diagnostic techniques are available, then a drug developed from Dr. Cooke’s work could be given prophylactic to protect those at risk. If the same drug could be given to people already affected by Type 1 diabetes, but with insulin producing cells still surviving, then research suggests it may be possible to cause such cells to regenerate, once the autoimmune reaction destroying them has been terminated.
RHEUMATOID ARTHRITIS AND ASTHMA TOO
Other autoimmune conditions as well as Type 1 diabetes may be prevented and possible treated in the same way. Rheumatoid arthritis, inflammatory bowel disease and asthma are among the possibilities.
For more information contact Dr. Anne Cooke, Department of Pathology, Tennis Court Road, University of Cambridge CB21 QP, UK, Tel.: ++ 44 1223 337733 or Emma Wilkinson, Wellcome Trust, Tel.: 0171 6118846, Facsimile: 0171 6118416.
Copyright © 2007 Hebrew University, Jerusalem, Israel
Last modified: 01/01/07