Larval therapy for leg ulcers (VenUS II): randomised controlled trial

BMJ 2009; 338 doi: http://dx.doi.org/10.1136/bmj.b773 (Published 20 March 2009)
Cite this as: BMJ 2009;338:b773

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(continued from part 1)

Discussion: As larvae of Lucilia can't cling to hairless uncreased skin as found for humans, viable tissue destroying myiasis of Lucilia is most properly bond to the existence of fleece with animals [10] or in case of man on skin folds, injuries or orifice of the body [11,12,13,14,15]. Lucilia maggots are known as sheep killers and the blow fly is feared by shepherds [16]. Fluids separated by Lucilia sericata will be the onset of alterations, when a sufficient amount of larvae stay in close contact to skin. The attack depends on doses of fluids of the larvae and by that on the amount of larvae. Pain was observed on these attacks whether or not the larvae had direct access to skin (loose or contained larvae). It is likely that the larvae's fluids are etching the skin by their proteases [17], chymotrypsin [18], collagenases [4] and nucleases [19] and they are responsible for damaging capillaries [20]. This interpretation is in accordance with the observation of doses dependant pain and that the pain decreases shortly after when the larvae are removed from the wound [4]. Some reports on larval therapy indicate that viable tissue is damaged [4,21,22,23,24] and sometimes painful [4,25,26,27]. In the case of undersupply of blood the wound area might increase. Caution is advised when exposed loops of bowel or blood vessels contain necrotic elements, as the larval secretions may dissolve the devitalized tissue [28]. In larval therapy some reports indicate, that viable tissue is damaged [4,22,29]. ZooBiotic as the biggest producer of larvae for larval therapy warns, that "if a BioFOAM dressing overlaps the wound edges, suitable protection must be applied to prevent excoriation of healthy tissue from the maggot enzymes." [23]. When a malignant (living) tumour in an ulcer was treated by larvae [25], it was peeled from healthy tissue but treatment must be stopped because intensive pain. Monarch-Labs indicate larval therapy should only be used for wounds when tissue is well supplied with blood [30]. In the case of undersupply of blood the wound area might increase. Benecke [24] refers to the US army Special Forces handbook: "When the maggots begin feeding on normal, healthy tissue, the individual will experience an increase level of pain at the site of the wound as the maggots come into contact with ?live nerves". Fleischmann points out that larval therapy are often intensively painful [26]. Nevertheless an attack of larvae onto healthy human tissue is described as rare [31,32]. Some literature indicates that only when larvae have direct access to skin, pain might occur [4] [4], as it is believed to be mainly caused by the mouth hooks and spicules [33,37]. But pain can be stopped on removal of loose or contained larvae. As the latter cannot interact with mouth hooks or spicules the end of pain comes because only little of the larvae juices are left behind when larvae are removed [4,23].

Caution is advised when exposed loops of bowel or blood vessels contain necrotic elements, as the larval secretions may dissolve the devitalized tissue, resulting in the development of an intestinal fistula or haemorrhage [37]. This has been observed in clinical practise (... although it's said that larvae are necrophages only ... it happens on a regular basis that a blood vessel becomes etched and consequently blood is observed ...) [34]. Therefore all producers of larvae give the advice on minor bleedings when larvae therapy is used. This recommendation is given for loose or bagged larvae. In the VenUS II study [1] patients treated with anticoagulation drugs are excluded as contraindicated medication in all cases on loose or bagged larvae.

Grassberger [22,35] as well as Sherman [4] pointed out that the doses of larvae are of decisive importance on side reaction of larvae during treatment. Introducing to many larvae into a wound will increase the risk of digesting healthy tissues, before larvae are removed. Other authors report on the feed of larvae on healthy human tissue by etching juices in some occasions [4,36,37,38]. Reports on starved Lucilia larvae on clean granulation tissue on larval treatment [27] can clearly be judged as out- dated. Fleischmann believes that doses of maggots are of no importance as they attack each other when starving [35]. We can confirm this but only when there is no other food - first they attack the patient's tissue. The used 3D human skin model is designed for testing chemicals on their toxicity on human skin. It becomes clear that juices of larvae are toxic to human skin cell and human fibroblasts. This is in strong contrast to the report of Prete [9], who "suggest the existence of intrinsic factors within the maggot's [juice] which may be responsible for the growth- stimulating effects [of fibroblasts] seen in maggot-infested wounds". Wound healing could not be shown in the VenUS II study.

Conclusion: Wound pain is one known disadvantage of debridement by larval therapy and is frequently observed as a side reaction. Reason for the wound pain can be found in the fact that larvae are capable of damaging viable tissue, which is most properly caused by destroying viable tissue by the enzymes of the larvae fluids. Patient's pain can be controlled by analgesics. This damaging of tissue depends on doses of larvae, as it is found in natural myiasis too. Larvae as a wound debriding agent are contraindicated when larger blood vessels are close to the wound (hazard of bleeding), when patient suffers from haemophilia or is under medication by warfarin or phenprocoumon or similar anticoaglulantia, or when larvae might get into natural body cavities, e. g. abdominal cavity, inner ear, vulva et cetera. In case patient suffers from pain perception as frequently observed when polyneuropathy on a diabetic patient is found, pain as a warning signal for destroying patient's viable tissue is easily overseen. Other patients getting analgesic medication are in the same position. Close supervision of the wound by a physician is needed and doses of larvae have to be checked carefully. As larvae's fluids are responsible for the debridement, most properly the total amount of fluids is the doses to be controlled which will depend not only on the amount but also the size of the larvae, which are continuously growing during therapy.

WARNING: debridement by larvae needs exact dosing and continuous control by medical staff.

The key facts of this letter and the motion pictures documenting the direct attack of Lucilia sericata maggots on unhurt human skin have been presented and discussed on the 8th International Conference on Biotherapy November 11-14, 2010; Los Angeles, CA [39,40]. Many of the experts on maggot therapy reported on pain during Laval Therapy in about 30 % of all cases. In addition indications were discussed that vital tissue is removed on the usage of many maggots or leaving them to long onto the wound.

References [1] Dumville JC, Worthy G, Bland JM, Cullum N, Dowson C, Iglesias CP, Mitchell JL, Nelson EA, Soares MO, Torgerson DJ, Larvae therapy for leg ulcers (VenUS II) randomized controlled trial, BMJ 2009;338;b773 (doi:10.1136/bmj.b773). [2] Soares MO, Iglesias CP, Bland JM, Cullum N, Dumville JC, Nelson EA, Torgerson DJ, Worthy G: Cost effectiveness analysis of larvael therapy for leg ulcers. BMJ 2009;338:b825. [3] Probst W, Vasel-Biergans A: Wundmanagement, Wiss. Verlagsgesellschaft, Stuttgart (2004) [4] Sherman RA, Hall MJR, Thomas S: Medicinal Maggots: An Ancient Remedy for Some Contemporary Afflictions, Anns. Rev. Entomol, 2000, 45, 55-81. [5] Glod A, Das biochirurgische D?bridement - Wundbehandlung mit Maden, Hygiene und Umwelt Forum Siegen e.V., oeffentliche Vortraege 2001 [6] Thomas S, Jones M, Shutler S, Jones S, Using larvae in modern wound management, Journal of Wound Care, February, Vol.5, No.2 , page 60-69, 1996 [7] The 3D reconstructed model of human skin and all testing with maggots were undertaken in a specialized GMP-certified laboratory. We are grateful to Dr. M.Noll and K. Kiepfer for performing the experiments. The full report on these studies is available on request from the authors (in German). [8] Horobin AJ, Shakesheff KM, Pritchard DI, Promotion of Human Dermal Fibroblast Migration, Matrix Remodelling and Modification of Fibroblast Morphology within a Novel 3D Model by Lucilia sericata Larval Secretions, Journal of Investigative Dermatology (2006) 126, 1410-1418. doi:10.1038/sj.jid.5700256; published online 4 May 2006. [9] Prete PE. Growth effects of Phaenicia sericata larval extracts on fibroblasts: mechanism for wound healing by maggot therapy. Life Sci 1997;60:505-10. [10] Beck W, Pantchev N. Praktische Parasitologie bei Heimtieren, Schl?tersche Verlagsgesellschaft 2006, S. 28 ff. [11] Yaghoobi R, Tirgari S, Sina N. Human auricular myiasis caused by Lucilia sericata: Clinical and parasitological considerations, Acta Med Iranica 2005;43:155-7. [12] Cho JH, Kim HB, Cho CS, Huh S, Ree HI. An aural myiasis case in a 54- year-old farmer in Korea. Korean J Parasitol 1999;37:51-3 [13] Bapat SS, Pediatrics 2000;106;e6 doi: 10.1542/peds.106.1.e6 [14] Cetinkaya M, Ozkan H, Koksal M, Coskun SZ, Hacimustafaoglu M, Giri?gin O, Neonatal myiasis: a case report, The Turkish Journal of Pediatrics 2008; 50: 581-584. [15] Fone-Ching H, Yulong C, , Li-Way C, Umbilical Myiasis in a Healthy Adult, Southern Medical Journal * Volume 101, Number 10, page 1054 - 1055, October 2008. [16] Nigam Y, Dudley E, Bexfield A, Bond AE, Evans J, James J, The Physiology of Wound Healing by the Medicinal Maggot, Lucilia sericata, ADVANCES IN INSECT PHYSIOLOGY VOL. 39 # 2010 Elsevier Ltd. ISBN 978-0-12- 381387-9. DOI: 10.1016/S0065-2806(10)39002-3 [17] Pritchard DI, Horobin AJ, Brown A, WO 2007/138361 [18] Pritchard DI, Horobin AJ, Brown A, WO 2007/122423 [19] Pritchard DI, Horobin AJ, Brown A, WO 2007/122424 [20] Fleischmann W, Grassberger M, Sherman R. Maggot Therapy, Thieme, Stuttgart, New York, 2004, page 23, 34, 63. [21] Woodstock S, The Use of Viscopaste in a dressing system for larval therapy, Abstracts of "Second World Conference on Biosurgery, Porthcawl, 17 - 18th April 1997. [22] Grassberger M, Entomologie und Parasitologie, Fliegenmaden: Parasiten und Wundheiler, Denisia 6, Neue Folge 184 (2002), 507-534. [23] BioFOAM Dressing Application Guide, www.zoobiotic.co.uk [24] US Army Special Forces Medical Handbook, ST 31-91B, Chapter 22 ?Primitive Medicine", Section 3: ?Maggot Therapy for Wound Debridement", 01.03.1982. Available from www.benecke.com/apmadeninfo.html (2003-04-03), URL: http://www.fas.org/irp/doddir/milmed/sfhandbook-pt1.pdf [25] Jones M, Andrews A, Thomas S, "A case history describing the use of sterile larvae (maggots) in a malignant wound", World Wide Wounds (updated 14.02.1998, cited 10.11.2009) Available from http://www.worldwidewounds.com/1998/february/Larvae-Case-Study-Malignant- Wounds/Larvae-Case-Study-Malignant-Wounds.html [26] Fleischmann W, Grassberger M, Maden-Therapie, TRIAS, Stuttgart 2002, Page 36 [27] Weil GC, Simon RJ, Sweadner WR. Larvae or Maggot therapy in the treatment of acute and chronic pyrogenic infections. Am J Surg 1933;19:36- 48. [28] BioMonde Larven Fach und Gebrauchsinformation, 2005-10-20, [29] Woodstock S, The Use of Viscopaste in a dressing system for larval therapy, Abstracts of "Second World Conference on Biosurgery, Porthcawl, 17 - 18th April 1997. [30] Medical Maggots, Description and Natural History, www.MonarchLabs.com, Page 2. [31] Fleischmann W, Grassberger M. Maden- Therapie. TRIAS, Stuttgart 2002, Seite 27 [32] Fleischmann W, Grassberger M, Sherman R. Maggot Therapy, Thieme, Stuttgart, New York, 2004, page 23, 34, 63 [33] Protz K. Moderne Wundversorgung. Urban&Fischer, 5. Aufl. 2009, S. 17. [34] Majunke S., Dermatologische Abteilung der Universit?tsklinik Greifswald, ?Ekelhaft gesund: Maden" Report on television, ARTE vom 2007- 07-12 um 19:00 - 19:45, on the application of BioBags: (... obwohl man immer sagt, dass das [die Larven] Nekrophagen sind ... passiert es doch haeufiger Mal ... das trotzdem irgendwie ein Gefaess arrondiert wird und dann blutet...). [35] Grassberger M, Biochirurgie in der Wundbehandlung, in Wild T, Auboeck J (Ed), Mnula der Wundheilung, Kapitel 28b, Springer Verlag 2007. [36] Stewart M A, A new treatment of osteomyelitis, Surg. Gynecol. Obstet, 1934, 5: 155-165. [37] Thomas S, Jones M, Shutler S, Jones S, Using larvae in modern wound management, J. Wound Care 1996, 5:60 -69. [38] Vilcinskas A, From Traditional Maggot Therapy to Modern Biosurgery , Biologically-Inspired Systems, 2011, Volume 2, Part 1, 67-75, DOI: 10.1007/978-90-481-9641-8_4. [39] Heuer H, Heuer L, Deutsche Apotheker Zeitung 151, 336, 2011. [40] Heuer H, Heuer L, Pain release drugs in maggot therapy - uncover the physiological interaction, 8th International Conference on Biotherapy November 11-14, 2010; Los Angeles, CA

Competing interests: Correspondence author (E.H.) and Co-author (L.H.) declares that as producers of larval products for debridement in wound therapy we have an interest in progress of larval therapy. Co-author (C.F.) declares that there is no conflict of interest to the rules of the International Committee of Medical Journal Editors.

Heike Elfriede Heuer, Pharmacists

Lutz Heuer, Christian Fleck

Agiltera GmbH & Co.KG

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Heike Elfriede Heuer, Lutz Heuer, AGILTERA GmbH & Co. KG, Dormagen, Germany Christian Fleck, Institute of Pharmacology and Toxicology, Friedrich Schiller University Jena, Germany Dormagen, 2011-02- 27

Dear Editor:

Published in 2009 and studied in the years before hydrogels and larval therapy have been compared in a randomized controlled clinical trial (VenUS II) [1]. The primary outcome of this study was time to heal of the largest eligible ulcers. Not surprisingly the authors found that healing was not significantly different between larvae and hydrogels, as the cause for the ulcer cannot be removed by debridement only. The cost occurred of both techniques were found to be equal, too [2]. One secondary outcomes of VenUS II was the ulcer related pain during debridement. The mean pain scores doubles for the larvae treated patients compared to the hydrogel treated ones. This occurred without significant difference between loose and contained larvae. It's known that pain is one possible consequence of larval debridement [3,4]. Nevertheless its intensity compared to hydrogels was surprisingly high.

We were interested in the reason for pain during larval treatment. As larvae are believed to remove dead tissue only, pain is something which should not occur. On the other hand previously published studies assume the pain to arise from the damage of sensitive edges of wound. Hereby, unprotected skin surrounding the wound is the main reason for pain [4,5,6]. In case maggots would attack vital cells of living tissue, this cannot be observed on patients, as it is always unclear, if the tissue remove by larval debridement was dead or still alive. In a human cell tissue experiment we checked for the possible toxicity of larval fluids. As a cell tissue in a matrix would be destroyed by the movement of the maggots within minutes, we used contained maggots only for this study. In this 3D reconstructed model of human skin, which shows the natural layers of stratum basale, stratum spinosum, stratum granulosum and stratum corneum the interaction of larvae's juices on human fibroblasts were studied [7]. After 72 h (37?C, 5% CO2, 95% humidity) of contact of human skin to larvae, which are placed in a gauze bag to focus on chemical and exclude mechanical interaction, the human skin model was analysed after fixation in paraffin and dyeing the cells using haematoxylin-eosin (HE- dying). Nearly all cells of stratum basale, stratum spinosum, stratum granulosum and stratum corneum have been destroyed on contact with the larvae's juices where the untreated samples show the usual texture of living human skin. Only some single cells existed but are not in their typical shape. Vital cells were removed in almost all parts of the human skin matrix model and fibroblasts were destroyed. Only a few, ball-shape fibroblasts were seen in the cell matrix. The observation that fibroblasts were almost fully destroyed was most confusing as there are two literature reports that the juices of Lucilia sericata maggots should have - doses dependant - positive effects on fibroblasts [8,9].

Finally we checked the influence of larvae on a restricted area of unhurt human skin in self treatment experiments. In case the larvae would attack the viable skin, pain would be expected. In these experiments Larvae therapy was investigated using five different materials / products of the biggest known producers in Europe and USA. Suprasorb F (Lohmann & Rauscher, Neuwied, Germany) was used to cover an unhurt skin area of 10 x 10 cm. Into the dressing a diagonal hole of 1 cm was cut allowing the larvae free access to the unhurt skin. Onto this "wound edge" the different dressings as directed by the producers' were placed and kept moist by 0.9% of sodium chloride solution. The time to the first onset of pain was measured and the experiment was followed until pain becomes unbearable or after reaching the mean recommended time of using larvae dressing (3 days). The analysis of skin treatment by larvae was done optically and documented by photography. The results recorded in the categories: no effect, clear effect, strong effect. The only correlation observed was the amount of larvae used. More larvae meant more deletion of skin and tissue and more pain.

In a second experiment larvae were again allowed to stay on unhurt human skin and their interaction with the skin was now documented by video of a microscope (dnt DigiMicro 2.0 Scale digital microscope camera) at a magnification of about 30-35x. For easy observation the crystal clear bottom of a Petri dish was used as a window for the video camera within the dressing. Pictures were taken during the whole time of about 24 h and the experiment was stopped, when pain becomes unbearable. In this study design optical impressions and pain could be studied parallel. In a rather short time (some hours to one day) the larvae attack the skin and etch a wound on all contact to skin surface by their juices. Pain is very strong when larvae have opened the epidermis. The intensity of pain depends on the actual physical presence onto the new wound. Many larvae meant strong pain, fewer larvae less pain, and no larvae itching only. All larvae were bred from own sources or bought from BioMonde, Barsb?ttel, Germany (BioBag 50). The larvae used were all very agile medical grade maggots. Larval therapy was undertaken according to producers' recommendations. Surprisingly within hours the larvae fluids attacks both viable skin and healthy tissue; this was followed by considerable pain. No major difference was observed if larvae were loose or contained; in the case of latter only the larvae fluids could interact with skin.

Discussion and references in Part 2

Competing interests: Correspondence author (E.H.) and Co-author (L.H.) declares that as producers of larval products for debridement in wound therapy we have an interest in progress of larval therapy. Co-author (C.F.) declares that there is no conflict of interest to the rules of the International Committee of Medical Journal Editors.

Heike Elfriede Heuer, Pharmacists

Lutz Heuer, Christian Fleck

Agiltera GmbH & Co.KG

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2 February 2011

I am quite relieved to get the chance to comment on this horrendous practice as it has concerned me for some time. Firstly, I have read that a planned multidisciplinary approach using traditional methods of care produces results that are just as good in ulcer therapy as maggot therapy.

These authors seem to be forgetting that infection with fly larva also has disease status and is known as myiasis. Lucilia sericata (the green bottle fly) the larvae which are most commonly used in this biotherapy have been implicated in human cutaneous, aural and nasal. One in an ICU in which the patient died Mielke (1997). Secondly in the amniotic fluid in the ear of a neonate who subsequently died Yoneda (1990) and there are other examples. This really is the worst kind of nosocomial infection being caused it seems intentionally and there is the problem of environmental containment larvae poorly disposed of may complete their life cycle breed and spread secondary diseases like mrsa.

Competing interests: None declared

karen J Clarke, unemployed

w12 8bh

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Many interesting discussion points are raised by the correspondents above to our recent trial and economic evaluation of larval therapy and we would like to respond to the more substantive issues raised.

Firstly it might be useful to explain some of the context to the study in response to the point made by Finn and others that this was a “non-question”. Indeed, one of our most vociferous critics (see above), Dr Sherman, called loudly for such a trial back in 2002[1] when he lamented that clinical practice in this area was based on anecdote and stated that “prospective, controlled studies must address the efficacy and safety of maggot therapy”. Incidentally in the same paper he also noted the high incidence of pain in patients receiving maggot therapy. We heeded Dr Sherman’s call for research, but unfortunately he does not like the answer the research gave us.

VenUS II was commissioned (and extensively peer reviewed by) the United Kingdom National Health Service (UK NHS) in order to answer a real, current, question of importance to health service delivery in the UK at that time. In 2003, when the UK NHS Health Technology Assessment (HTA) Programme first called for researchers to undertake this work, larval therapy was being extensively promoted as speeding the healing of venous leg ulcers and widely used in the NHS for treating people with venous leg ulcers. Given the increasing use of a costly and unproven treatment, it was important to undertake the research so that future use could be informed by the evidence. Indeed, the UK larval therapy manufacturers themselves lobbied hard for this trial to be undertaken. The final trial design was the result of extensive independent peer review by clinicians, clinical trialists, medical statisticians and others. The detailed protocol was the result of collaboration between experienced wound care specialists from the fields of nursing, vascular surgery, dermatology and microbiology as well as trialists, statisticians and health economists. Importantly, and somewhat unusually in wound care, the trial was pragmatic, and therefore designed to evaluate the effects of this treatment as it is actually used (and likely to be used in the future). Patient care continued to be delivered within the NHS by highly experienced clinicians, and therefore patients were most definitely not, as suggested, deprived of pain relief or any other aspect of their usual care. Throughout the trial, participants were in close contact with, and were closely monitored by, their treating clinicians and trial nurses. In addition, participants were pre-warned that larval therapy may cause pain or discomfort and were advised to take regular analgesics for pain relief. Only a few participants elected to have the trial treatment removed due to pain and discomfort whilst others chose to continue with the treatment as they believed they would benefit. Some stated that even though they found the treatment uncomfortable, they would choose to have larvae applied again. All clinicians involved in the trial received intensive training in the use of the trial treatments; in the case of larval therapies this training was guided by (though not delivered by) the manufacturers, as was the decision to give a brief compression holiday to those receiving larval therapy, since high compression (the 4 layer bandage) is occlusive and would suffocate the larvae.[2] Indeed Dr Sherman’s own paper from 1997 makes this point rather forcefully.[3] We consulted extensively on this issue and followed clinical and manufacturers’ advice.[4,5] It would not, for example, have made any sense to deprive the hydrogel patients of compression since compression does not impact on the way hydrogel works. That said we can now take the opportunity to underline the fact that, despite the compression holiday there is very little difference in the amount of time spent in compression between the treatment groups. Patients in both the loose and bagged larvae groups spent a mean of 5 days (median of 3 days) out of compression; which is tiny compared with a median time to healing of 236 days. When we re-analyse the data adjusting for the compression holiday we see that it made no difference to time to healing.

Unfortunately Drs Sherman and Mumcuoglu betray their lack of understanding of the basic statistics used in clinical research. In the paper we state that "The rate of debridement at any time in either larvae groups was about twice that of the hydrogel group" but this refers to the hazard ratio (HR) which is the ratio of the rates at which debridement took place and not the ratio of the median times to debridement in days. The adjusted analysis to which we refer is not intended to conceal anything and was the pre-planned analysis of the trial. We presented the main results of the trial adjusted for prognostic variables, as is done in almost all trials reported in BMJ. This is done because if there is variation due to due prognostic variables, in our study the baseline size and duration of the ulcer and the trial centre, removing it by adjustment increases the power of the trial to detect a treatment difference. It cannot conceal real treatment differences, because in a randomised trial no prognostic variables are related to the randomised treatment. We have certainly not attempted to conceal the fact that larval therapy, of both types, was much better than hydrogel at debridement. However, debridement is a secondary outcome variable, healing of the reference ulcer is the primary outcome variable since clinicians debride wounds to help them heal, and there is little evidence of any treatment difference.

We intended a larger sample size, and this study was originally planned to have the same power as the VenUS I trial [6], with three groups of 200 participants. However, recruitment into this trial proved extremely difficult and even after approaching many more centres and an extension to the trial we were able to recruit fewer than half the target number. Having done the trial we have to report the results that we have. We do not believe a proposed treatment effect of 37% (relative risk (RR) 1.37) is excessively demanding. For example, other treatments for leg ulcers have shown similar, or greater, treatment effects: pentoxifylline (RR = 1.70 [7]) and therapeutic ultrasound (RR = 1.49) [8]. The original larval therapy trial reported a RR for debridement with larvae of 1.52 compared with control [9].

The upper confidence limit for the median survival time is unable to be estimated because it is calculated from the Kaplan Meier survival curve. To estimate the median survival time we draw a horizontal line through survival = 0.5 and where it intersects the survival curve we can read the median time off the horizontal time axis. We can calculate a 95% confidence interval for the survival proportion, the Greenwood bounds, at each time point. Where the median line intersects these bounds provides the confidence interval for the median time. Sometimes, as for hydrogel here, the upper bound does not get below 0.5 survival for any follow-up time.

Some wounds were not healed in each treatment group, the longest period observed being 365 days. This was the maximum (pre-specified) follow-up time for the trial. It is not true that all wounds healed in the maggot therapy group. As Figure 2 of our paper shows, the estimated proportion healed at one year is about 70%. We do not quote the actual proportion healed, because not everybody could be observed for the full year and did not have the same opportunity to heal. Survival analysis is the way we get round this problem of follow-up data. The final proportion healed is poorly estimated due to varying follow-up time and we do not use it. The most powerful comparison is the survival analysis comparison using the hazard ratio.

Mr Morgan requires further explanation regarding the technique used to determine bacterial load. This was assessed using quantitative surface swabs, where the sample was taken from viable tissue at the wound surface with light pressure to extract wound fluid. Whilst wound biopsies are commonly cited as the gold standard for measurement of bacterial load, this technique requires specialist skill to remove deeper tissues for analysis [10,11] and is a more painful procedure for the patient. Studies suggest swabs are a viable alternative to biopsies in clinical practice when diagnosing infection [10-12]. Unfortunately, there are no published data reporting the agreement of bacterial load estimates from tissue biopsies and swabs, for example using the Bland-Altman method [13]. It is possible that swabbing may have under-estimated the bacterial load assessment in this trial, however and most importantly, there is no reason to believe that this sampling approach would be biased against one or other of the treatment groups. If larval therapy did impact on bacterial load we would have expected to see this with the use of surface swabs.

Contrary to the suspicions of Drs Sherman and Mumcuoglu, we would have been delighted to find a significant healing difference in favour of larval therapy – what possible motive could we have for not finding one? Finding an important treatment effect would have meant that we could help improve the quality of life of venous ulcer patients and would have also improved our citation count greatly and hence our marketability as researchers!

1 Sherman RA. Maggot therapy for foot and leg wounds. Int J Lower Extremity Wounds 2002; 1:135-142.

2 Wu P, Nelson EA, Reid WH, Ruckley CV, Gaylor JDS. Water-vapour transmission rates in burns and chronic leg ulcers: Influence of wound dressings and comparison with in vitro evaluation. Biomaterials; 17(14): 1373-77. 1997

3 Sherman RA. A new dressing design for use with maggot therapy. Plastic and Reconstructive Surgery 1997; 100:451-56.

4 Fogh K, Hansson C. News in the Treatment of Venous Leg Ulcers. Forum for Nord Derm Ven 2006; 11:14-18.

5 Wolff H, Hansson C. Larval therapy--an effective method of ulcer debridement. Clin Exp Dermatol 2003; 28:134-137.

6 Iglesias C, Nelson EA, Cullum NA, Torgerson DJ VenUS I: a randomised controlled trial of two types of bandage for treating venous leg ulcers. Health Technol Assess 2004; 8:iii, 1-105.

7 Jull A, Arroll B, Parag V, Waters J. Pentoxifylline for treating venous leg ulcers. Cochrane Database Syst Rev 2007; CD001733.

8 Al-Kurdi D, Bell-Syer SE, Flemming K. Therapeutic ultrasound for venous leg ulcers. Cochrane Database Syst Rev 2008; CD001180.

9 Wayman J, Nirojogi V, Walker A, Sowinski A, Walker MA. The cost effectiveness of larval therapy in venous ulcers. J Tissue Viability 2000; 10:91-94.

10 Bill TJ, Ratliff CR, Donovan AM, Knox LK, Morgan RF, Rodeheaver GT. Quantitative swab culture versus tissue biopsy: a comparison in chronic wounds. Ostomy Wound Manage 2001; 47:34-37.

11 Davies CE, Hill KE, Newcombe RG, Stephens P, Wilson MJ, Harding KG, Thomas DW. A prospective study of the microbiology of chronic venous leg ulcers to reevaluate the clinical predictive value of tissue biopsies and swabs. Wound Repair Regen 2007; 15:17-22.

12 Gardner SE, Frantz RA, Saltzman CL, Hillis SL, Park H, Scherubel M. Diagnostic validity of three swab techniques for identifying chronic wound infection. Wound Repair Regen 2006; 14:548-557.

13 Bland JM, Altman DG. Statistical methods for assessing agreement between two methods of clinical measurement. Lancet 1986; i, 307-310.

Competing interests: AN has a PhD student funded by, and has been reimbursed for speaking at educational events by, Convatec UK, a manufacturer of wound products. The remaining authors declare that they have no competing interests.

Competing interests: None declared

Nicky Cullum, Deputy Head of Department (Research)

Rebecca Ashby, Martin Bland, Jo Dumville, Cynthia Iglesias, Arthur Kangombe, Marta Soares, David Torgerson (all University of York) and E Andrea Nelson, Gill Worthy (University of Leeds)

Department of Health Sciences, University of York, YO10 5DD

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Dear Editor:

We read with interest the publication by Dumville et al. (1), describing a prospective, randomized study of maggot debridement therapy (MDT) that followed subjects through to the point of wound healing. Evidence of effective and efficient maggot debridement abounds, and the authors contributed to that evidence by demonstrating maggot debridement to be 2-5 times faster than their standard non-surgical therapy. Many policy-makers have postponed embracing maggot therapy until there was proof that wounds debrided by medicinal maggots would ultimately heal as well as conventionally debrided wounds. Thanks to Dumville and colleagues, their wait is now over.

Given the expertise of the study team, we were surprised by the poor study design and inadequate analysis. A few points will reveal the magnitude of these deficiencies and may even suggest testable hypotheses to explain why the quickly-debrided MDT wounds did not heal faster than the conventionally treated wounds. More importantly, only by addressing the problems with this study will the next clinical investigation answer the questions that still remain: is debridement beneficial in the healing of venous stasis ulcers, and how should that debridement be carried out.

The study objective was reportedly to evaluate the efficacy and safety of maggot-induced wound healing, but the administration of larval dressings was limited to the initial debridement only. Having used maggot therapy as a debridement tool in this way, the primary endpoint should have been debridement efficacy, with wound closure as the secondary endpoint. To test the effect of maggot therapy on wound healing, the investigators should have done two additional steps: monitored the need for repeated debridement or growth promotion, and permitted the re- application of maggot therapy --- either routinely or at least for wounds that were not healing “adequately” (however they wished to define it). This is the way it is used clinically for wound healing.

Since the 1930’s, clinicians have noted that wounds treated with MDT beyond the point of complete debridement heal faster than wounds whose larval therapy terminated once the wound is clean (2). The waning of maggot therapy’s growth-stimulating and antimicrobial benefits has been demonstrated by several recent studies. (3-4).

The wound-healing benefits of maggot therapy may cease shortly after stopping maggot therapy because the maggots themselves are no longer physically stimulating the wound bed, and because their secretions are no longer bathing the tissue. Maggots and their secretions have been shown in vivo and/or in vitro to be antimicrobial (5-11), to promote tissue growth (12-19), to increase local perfusion (3) and to dissolve and inhibit the formation of biofilm (20). After larval therapy is stopped, the wound could become susceptible again to microbial attack, biofilm formation, necrosis, inflammation and ultimately impaired healing. Intermittent maggot therapy is now recognized as a form of “maintenance debridement;” it is also the accepted method of administering maggot therapy when the goal is to stimulate wound healing.

Since the wounds were digitally photographed weekly, it would be simple to determine when and where the healing time saved by maggot therapy’s rapid debridement was lost. As others have done in the past (12- 14), the authors should have plotted the wound dimensions or “rates of wound closure” over time. In this way it may have been possible to determine if there was no growth-promoting effect at all, or if there was indeed hastened wound closure for some period of time after maggot debridement, which was then lost. Prior studies have suggested the loss of wound healing and antimicrobial effects occurs 2-3 weeks after discontinuing larval therapy (4).

A design flaw even more egregious was the withholding of compression therapy during treatment of maggot-treated subjects. This, alone, put the maggot-treated group at a significant disadvantage. Touted as a study of “maggot therapy vs hydrogel,” the study actually compared maggot therapy to hydrogel with optimized compression therapy. This unfair handicap is particularly shocking given the authors’ long research experience documenting that (in their own words) “compression increases ulcer healing rates compared with no compression” (21).

In light of this biased study design, the authors should have been impressed that the maggot-debrided wounds healed as quickly as control wounds. But instead, they were highly critical of maggots and those who choose to use them, because maggot-debrided wounds did not heal significantly faster than control wounds. How did the researchers define “significantly faster” healing?

In their VenUS I study (22), the authors sought a 15% benefit in wound healing to conclude that one method of compression therapy was better than another. This VenUS II study was designed to detect a benefit of maggot therapy only if healing occurred in less than 64% of the time it took control wounds to heal. In other words, for maggots to prove their worth in the current study, the researchers demanded a 37% benefit compared to hydrogel and compression therapy. This target is far more demanding than what most therapists or policy makers would consider as being of clinical benefit. Again, those who designed this study required from larval therapy more than twice what they accept as “significant benefit” in their studies of conventional modalities.

Other critical details also were not completely discussed or disclosed. For example, readers are not informed of the frequency of maggot treatments, even though this is a crucial element in comparing this study to earlier studies and crucial to interpreting the resulting speed and efficiency of debridement.

We are told that “the median time to healing in the larvae group was 236 days (95% confidence interval 147 to 292) and in the hydrogel group was 245 days (166 to upper limit not estimable).” But why was the upper limit not estimable? Did some of the hydrogel-treated wounds not heal? If so, how many? What was the longest period of time that they were observed not to have healed? Was there any significance between the number of non- healed wounds in the hydrogel group and the number in the maggot therapy group (all wounds appear to have healed in the larval therapy group)? Were the non-healed wounds at least getting smaller, or were they stagnant, non -healing?

Bagged and loose larvae were repeatedly grouped together in maggot-vs -hydrogel comparisons, but the evidence to support that grouping was poorly presented. For example, we are told that debridement with bagged larvae took twice as long (28 vs 14 days) as with loose larvae, but we are told that “after adjustment” the difference was found not to be significant. Therefore, the authors compared the combined speed of maggot debridement with hydrogel debridement (median time to debridement 72 days) and stated that MDT was only twice as fast as hydrogel. The fact that the difference between loose and bagged larvae failed to achieve statistical significance is no reason to avoid mentioning that loose larvae actually debrided wounds 5 times as fast as hydrogel! Why was this comparison not made in the text? The difference likely achieved statistical significance; if it did not, we believe the authors would have noted that. It was wrong to compare the combined “maggot-treated debridement” groups vs hydrogel without comparing the individual loose maggot- and bagged maggot-treated groups with the hydrogel group, especially if each of these “pure” treatment arms were associated with debridement rates significantly different from the hydrogel control.

One of the few pieces of data that received thorough discussion was treatment-associated pain: “significantly more pain was experienced by participants in both larvae groups” than the hydrogel group, during “the 24 hours before removal of the first debridement treatment.” Since larvae were left on the wounds for three to four days, “24 hours before removal would mean the pain began at least 48 hours after the larvae were placed. The package insert (data card) clearly states that “[some patients] have reported an increase in wound pain following their application . . . . “ The manufacturer recommends adequate analgesia and removing the maggots at 48 hours. Earlier publications also have warned therapists that the most common adverse event associated with maggot therapy is pain, usually occurring about 24-36 hours into therapy (23). It has long been an accepted part of maggot therapy to provide liberal access to analgesia for the 5-30% of individuals who report pain (they are identifiable in advance since they are the patients who already experience pain with their dressing changes) and to halt their treatment as soon as pain is not adequately controlled, usually within 30 to 48 hours (23).

Why would the researchers not heed these warnings to protect their study subjects from unnecessary and avoidable pain? Was it purely lack of experience with maggot therapy by the authors who described their shock over the fact that these spine-covered larvae could even cause pain when they get big and crawl (scratch) over sensitive wounds? By warning readers against using maggot therapy, even for debridement, because of “significant pain” (pain which had no impact on quality of life scores), the authors make the serious error of confusing statistical significance with clinical significance. It is unfair to describe the pain in this way when it occurred only once during the entire study and made no impact on the quality of life scores. It is unfair to warn readers about the pain of maggot therapy without also warning that this pain occurred because the researchers had not followed prescribing guidelines.

The authors noted that some of their results were contrary to that of many earlier studies and expert opinion, but explained that difference primarily by asserting that their study was bigger and better. They failed to acknowledge many earlier controlled and even prospective studies, and they failed to adequately discuss many of the factors that we elucidated in this critique. It was valid for the authors to question the value of debridement in general, not just maggot debridement; but without evidence that the wounds received adequate debridement throughout the entire period of wound healing, this study fails to provide any more evidence about the value of debridement than it does about the value of maggot therapy for wound healing.

The true significance of this study may be in demonstrating that the time saved by larval debridement --- and possibly many of the benefits seen with other debridement modalities --- may be lost if we do not continue to address the quality of the wound and its response to treatment throughout the entire healing process. The fact that subjects in all three study arms failed to heal as quickly as expected further supports our contention that this study design was not consistent with good clinical practice. Eight months to heal a 12 square cm wound must not be accepted as our “standard of care.”

References:

1. Dumville et al, 2009, Larval therapy for leg ulcers (VenUS II): randomised controlled trial BMJ. 338:b773

2. Baer WS, 1931. The treatment of chronic osteomyelitis with the maggot (larva of the blow fly). J Bone Joint Surg. 13:438-75.

3. Wollina U et al, 2002. Biosurgery supports granulation and debridement in chronic wounds—clinical data and remittance spectroscopy measurement. Int J Dermatol. 41:635-9.

4. Sherman RA and Shimoda KJ, 2004. Presurgical maggot debridement of soft tissue wounds is associated with decreased rates of postoperative infection. Clin Infect Dis. 39:1067-70.

5. Thomas S et al, 1999. The anti-microbial activity of maggot secretions: results of a preliminary study. J Tissue Viability. 9:127-32.

6. Mumcuoglu KY et al, 2001. Destruction of bacteria in the digestive tract of the maggot of Lucilia sericata (Diptera: Calliphoridae). J Med Entomol. 38:161-6.

7. Bexfield A et al, 2004. Detection and partial characterization of two antibacterial factors from the excretions/secretions of the medicinal maggot Lucilia sericata and their activity against methicillin-resistant Staphylococcus aureus (MRSA). Microbes Infect. 6:1297-304.

8. Armstrong DG et al, 2005. Maggot therapy in "lower-extremity hospice" wound care: fewer amputations and more antibiotic-free days. J Am Podiatr Med Assoc. 95:254-7.

9. Huberman L et al, 2007. Antibacterial properties of whole body extracts and haemolymph of Lucilia sericata maggots. J Wound Care. 16:123- 7.

10. Tantawi TI et al, 2007. Clinical and microbiological efficacy of MDT in the treatment of diabetic foot ulcers. J Wound Care. 16:379-83.

11. Bowling FL et al, 2007. Larval therapy: a novel treatment in eliminating methicillin-resistant Staphylococcus aureus from diabetic foot ulcers. Diabetes Care. 30:370-1.

12. Sherman RA et al, 1995, Wyle F, Vulpe M. Maggot therapy for treating pressure ulcers in spinal cord injury patients.J Spinal Cord Med. 18:71-4.

13. Sherman RA, 2002. Maggot versus conservative debridement therapy for the treatment of pressure ulcers. Wound Repair Regen. 10:208-14.

14. Sherman RA, 2003. Maggot therapy for treating diabetic foot ulcers unresponsive to conventional therapy. Diabetes Care. 26:446-51.

15. Sherman RA et al, 2007. Maggot Therapy for Problematic Wounds: Uncommon and Off-label Applications. Adv Skin Wound Care. 20:602-610.

16. Prete PE, 1997. Growth effects of Phaenicia sericata larval extracts on fibroblasts: mechanism for wound healing by maggot therapy. Life Sci.;60:505-10.

17. Horobin AJ et al, 2005. Maggots and wound healing: an investigation of the effects of secretions from Lucilia sericata larvae upon the migration of human dermal fibroblasts over a fibronectin-coated surface. Wound Repair Regen. 13:422-33.

18. Horobin AJ et al, 2006. Promotion of human dermal fibroblast migration, matrix remodelling and modification of fibroblast morphology within a novel 3D model by Lucilia sericata larval secretions. J Invest Dermatol. 126:1410-8.

19. Smith AG et al, 2006. Greenbottle (Lucilia sericata) larval secretions delivered from a prototype hydrogel wound dressing accelerate the closure of model wounds. Biotechnol Prog. 22:1690-6.

20. van der Plas MJ et al, 2008. Maggot excretions/secretions are differentially effective against biofilms of Staphylococcus aureus and Pseudomonas aeruginosa. Journal of Antimicrobial Chemotherapy. 61: 117–122.

21. O'Meara S et al, 2009. Compression for venous leg ulcers. Cochrane Database Syst Rev. (1):CD000265; update of Cochrane Database Syst Rev. 2001; (2):CD000265.

22. Nelson EA et al, 2004. Randomized clinical trial of four-layer and short-stretch compression bandages for venous leg ulcers (VenUS I). Br J Surg. 91:1292-9.

23. Sherman RA, 2002. Maggot therapy for foot and leg wounds. Int J Low Extrem Wounds. 1:135-42.

Authors: Ronald A. Sherman, MD, MSc, DTM&H (London) Retired, Assistant Researcher, University of California, Irvine; 92617 Director, BioTherapeutics, Education & Research Foundation Laboratory Director, Monarch Labs Clinic Physician, Orange County Health Care Agency, Santa Ana, CA

Kosta Y. Mumcuoglu, PhD Senior Research Scientist, Department of Parasitology Hebrew University-Hadassah Medical School, Jerusalem, Israel.

Competing interests: Disclosures: Both authors have conducted clinical and laboratory studies of maggot therapy over the past 15+ years, and both have laboratories that produce medical grade maggots. Dr. Sherman is Director of the BioTherapeutics, Education & Research Foundation; Dr. Mumcuoglu is President of the International Biotherapy Society. Both of these organizations provide educational and material support to therapists, patients, and the public at large to help understand and advance maggot therapy, leech therapy, phage therapy, and other “biotherapeutic” modalities using live organisms.

Competing interests: None declared

Ronald A Sherman, Retired, Assistant Researcher, University of California

Kosta Y. Mumcuoglu, PhD

Irvine, CA 92617

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Although larval therapy cleared the ulcers, it did not have any impact on the time to healing. If one looks in Table 1 it seems that approximately 70% of patients in the hydrogel-group received high compression (i.e. had a ankle brachial index>0.8) whereas the corresponding figure in the larval groups was around 50%. We know that compression is one of the corner stones in the treatment of chronic venous ulcers. Maybe more intensive compression in the larval group would have changed the results, i.e. reduced the time to healing in this group.

Competing interests: None declared

Competing interests: None declared

Anders Ternhag, MD, PhD

Dep of Medicine Solna, Infectious Diseases Unit , Karolinska Institute, Stockholm, Sweden

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It is not clear whether pain was reduced. The foundation flaw is that it doesn’t appear that treatment for venous ulcers was applied, namely attending to the venous return physiology. It would be interesting to know how the larvae would have benefitted the treatment if the vascular aspect had been addressed.

Competing interests: None declared

Competing interests: None declared

Jon P Driver-Jowitt, Orthopaedic Surgeon

3 Norfolk Road, Newlands Cape Town 7700

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25 March 2009

Why use maggots in the treatment of venous leg ulcers ? The most important treatment in this group of patients is compression combined with a duplex scan to evaluate the superficial venous system for incompetence leading to surgery. Why use hydrogel, when the wound is exudating? A dressing capable of absorbing exudate would be more prober. Maggots are useful in debriding, especially in diabetic foot ulcers, but only for debriding purposes. A lot of effort - for what use ?

Competing interests: None declared

Competing interests: None declared

Rolf Jelnes, consultant

Sygehus Soenderjylland, 6400 Denmark

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Maggots can "eat the flesh" in perinea of the Merino sheep widely farmed in Australia, New Zealand and South Africa. This was avoided, on the farm that I used to stay on as a boy in South Africa, but cutting the wool away from the perineum supposedly to stop flies from laying their eggs there. In reality the problem was probably prevented by preserving the health of the tissues by preventing an inflammatory response from developing under wool encrusted with faeces and sodden with urine. The Australians are more aggressive in their prophylaxis resorting to mulesing.

"Mulesing involves the cutting away of a flap of skin from the backside and tail of lambs. Australian wool producers use mulesing to reduce the risk of flystrike, which occurs when blowflies lay eggs in the moist wool around the sheep’s backside. The eggs develop into maggots that eat the sheep’s flesh, causing pain and suffering. Sheep with flystrike often need to be euthanized. The Australian Government, the Australian Veterinary Association and RSPCA Australia recognise that, in the absence of a humane alternative, mulesing is a necessary part of sheep husbandry because it prevents or minimises the pain and suffering of sheep caused by flystrike"(Wikipedia).

The success of mulesing would seem to be consistent with Virchow's cell theory, as applied to the use of maggots in leg ulcers, and considered in my earlier rapid response.

Competing interests: None declared

Competing interests: None declared

Richard G Fiddian-Green, FRCS, FACS

None

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23 March 2009

The VenUS II trial effectively shows that larval therapy can debride wounds in a shorter time than that required for the comparator (hydrogel). In this regard it is in complete agreement with the current product claims for free range and contained larval therapies - rapid debridement. With regard to healing, as Dr Finn indicates there is no expectation that larval therapy would heal the background problems with VLU as the larvae will not treat the underlying condition. However, I would like to highlight that in the free range and contained larval treatment arms of the study, a holiday from continued treatment with compression bandages was undertaken, while in the comparator arm (hydrogel) compression was maintained throughout. This introduces a difference between the main treatment arms that could be important when analysing the time taken to healing, as on average a 14 to 25 day compression holiday would have been introduced in patients treated with larvae. This potentially delays any treatment to healing (through restoring moisture balance by compression) and confounds the study. Since we started supplying larvae in the UK we have always indicated that the larvae can be used under compression bandages provided that these bandages are not occlusive. This simply avoids the suffocation of the larvae. I feel that the important differences in compression treatment regimes in the different arms of the study should have been noted in both the abstract and discussion sections, as the comparison is not only the action of larvae but the temporary removal of compression. If anyone then links this particular piece of work to the treatment of wounds that do not require compression (most of the wounds currently treated with larvae) this important difference is then highlighted. With regard to the method used to determine the bacterial load of a wound, there has to be a massive extrapolation from the number of bacteria present in a surface swab to the number of bacteria present in a wound itself. I would like to see some validation or cross-reference of the swab method so that it can be used to determine the bacterial load in a wound that is greater than 5cm2 and covered with over 25% slough. Otherwise all that the method measures is the bacterial load of the swab itself. I would have expected that if a wound had been debrided (visually clean), that the removal of a lump of slough (usually defined as material containing bacteria) or necrotic material (regarded as a food for bacteria) must reduce the bacterial load, or anyone would have to question the method used.

Competing interests: Work for ZooBiotic Ltd

Competing interests: None declared

James A. W. Morgan, R&D Director

Dunraven Business Park, Coychurch Rd, Bridgend CV31 3BG

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