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

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

Rapid Response:

Maggot Therapy: Apparently a good treatment despite poor study and inadequate analysis

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: No competing interests

14 May 2009
Ronald A Sherman
Retired, Assistant Researcher, University of California
Kosta Y. Mumcuoglu, PhD
Irvine, CA 92617