Maggots, leeches, parasitic worms

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Maggots, leeches, parasitic worms

Talk about going to extremes: In 2004, an anonymous American man with ulcerative colitis chose to eat parasitic worms instead of having his diseased colon removed. He hoped that whipworms would provide a last-ditch biological balm for painful, bloody and frequent diarrhea, and more serious complications of colitis.

If his symptoms had not improved, you would not be reading about his sojourn through planet parasite. “It did work with this individual, he seemed to get better, not just once but twice,” says P’ng Loke, a parasite immunologist at New York University who studied the case.

enlarge this image Long translucent white worm with thin whip-like tail against black background

Imagine swallowing 2000 of these guys. You just might, if you were plagued with an inflammatory bowel disease.

In the same year that Mr. A swallowed those worm eggs, two other biological treatments gained Food and Drug Administration blessing as “medical devices”: leeches for removing excess blood after surgery, and maggots for cleaning difficult wounds.

Live organisms once played a bigger role in medicine, observes Ronald Sherman, a California doctor and maggot maven. “Before we had a good method for controlling syphilis, the bacterium was killed by inducing a fever, and one of the best methods was through malaria, carried by mosquitoes.”

Ready for some greatest hits from the ancient-but-modern realm of medicinal vermin?

Wondrous whipworms

Ulcerative colitis is a chronic bowel disease that afflicts up to one American in a thousand, apparently caused by some combination of inflammation and heredity. There is no cure. To prevent holes in the colon and other nasty outcomes, the bowel is often removed — a treatment that is also used for Crohn’s, the other major inflammatory bowel disease.

enlarge this imageInside of human colon, colons walls are pinkish with dozens of little white worms stuck to them

Photo: Uma Mahadevan, UCSF
Mr. Anonymous’s colon has a heavy infestation with whipworms, which are damaging the intestinal walls. Could that bleeding be a good thing?

In 2003, Mr. Anonymous was diagnosed with ulcerative colitis, and in 2004, he went to Thailand and ate 500 eggs of Trichuris trichiura, a parasitic helminth worm, and then 1,000 more.

The symptoms abated, and when they returned in 2008, Mr. A, who’s now 35, slurped 2,000 more whipworm eggs, and again his symptoms receded.

There is some support for the idea that parasitic worms can help with ulcerative colitis. Whipworms infest almost a billion people around the world, and colitis is scarce in infected regions. Animal tests, and one human trial1 suggest that parasitic worms can help with ulcerative colitis.

This story of salvation courtesy of planet parasite might be dismissed as another tall tale told over a tall goblet of organic wheat-grass at the Health-4-All-Spa, except that Mr. A came under the scrutiny of medical experts2 eager to explore the effect of parasites on one ulcerated colon.

Although eating worm eggs twice reduced the symptoms, one person does not constitute scientific proof, says Loke, a parasite expert. “The question is whether it would work for everyone, and for whom it would do more harm than good; that’s what we worry about.”

enlarge this imageA few translucent bright pink oval-shaped eggs and some circular ones, each with darker matter inside

Image: Kimberley Evason, UCSF
Stained Trichuris trichiura eggs inside a worm from the ulcerative colitis patient who infected himself with these whipworms.

Whipped into shape?

The study did pinpoint a mechanism of help, and surprisingly, it was not, as expected, via a dampening the immune system. “When we analyzed this patient, we started thinking that the protection may be more related to restoring mucus production,” Loke says.

Mucus protects the intestinal lining from bacteria and other dangers, and Loke and his colleagues think the worms accelerated activity in genes involved in producing mucus, through a stimulating chemical called IL 22.

A second benefit probably came from faster growth of cells lining the intestine, Loke added. “We know from mouse studies of Trichuris that the mechanism of expelling the parasite from the gut involves a combination of turning over epithelial cells so worms will get sloughed off, and an increase in mucus production.”

Immunology still matters, he says, but it may be that the worms are triggering a protective immune response rather than immune suppression.

Before worms could be considered a treatment for ulcerative colitis, “we hope to understand the mechanism a bit better,” says Loke. “In the ideal situation, we’d like to activate this response without using the worms themselves.”

Amen.

Light pink tube with red spots down the middle and an ovular cell at its wall that looks like an opening

Photo: Professor David B. Fankhauser, University of Cincinnati Clermont College.
Goblet cells (arrow) in the intestinal lining create protective mucus. Increased mucus production could explain how whipworms treat ulcerative colitis.

Worms v. asthma

There’s been some hope that regulating the immune system could help with asthma, but the improvements in patients in a clinical trial3 of hookworms were, disappointingly, not statistically significant.

A 5-centimeter wound

Rollover to see effects of maggot treatment

open wound, with whitish liquid covering much of it

BEFORE: After 18 months of conventional treatment, this wound was infected with dangerous methicillin-resistant staph aureus (MRSA) and covered with a thick layer of a dying tissue called slough.
AFTER: Six days later, after three maggot treatments, the same wound is free of slough and rich in granulation tissue, which supports healing and scar formation. MRSA could not be detected. All credit to those creepy-crawly maggots in the middle!
Evidence Based Complementary and Alternate Medicine4 and Oxford University Press (creative commons license)

But 13 of the 16 patients who swallowed hookworms decided not to get de-wormed afterwards, which suggests some perceived benefit, admits study author John Britton, in the division of epidemiology and public health at the University of Nottingham (United Kingdom). “We weren’t able to measure anything objective; hence the implication that larger, longer (and simpler) trials are needed.”

If you are tempted by do-it-yourself worm treatment for asthma, Britton has simple advice: “Don’t. There’s no evidence that it works.”

Both the benefits and the risk remain to be documented, says Loke, who tracked Mr. Anonymous, “and we don’t understand that fully. Worms can cause symptoms of colitis” and in the case of Mr. A, “are causing damage to the gut. But we think the gut is activating a healing response against the worms, and one benefit of that is the side effect of helping colitis.”

Marvelous maggots

While people have long used live organisms for medical purposes, many trace the scientific foundations of maggot therapy to World War I, when surgeon William Baer observed that maggot-infested wounds were often the cleanest and quickest to heal.

enlarge this imageClose-up of green-bodied fly with big red eyes perched on bright yellow flower

Baby animals usually are cuter than the adults, but nobody told the green bottle fly!

In 1929, Baer reported complete success after treating 21 bone infections with maggots, and fly larvae quickly gained acceptance for wound treatment. But when antibiotics became widespread in the 1940s, healing became simply a matter of sprinkling a magic powder, and maggots were forgotten.

With diabetes becoming epidemic, and with so many bacteria immune to antibiotics, maggot use is again on the upswing. One key use is treating foot ulcers: slow-healing sores that affect about 15 percent of people with diabetes, and force 70,000 amputations each year in the United States.

Maggots are usually used to clean wounds, but they have many capabilities:

Removing dead tissue, using their raspy exterior as biotic sandpaper

Secreting enzymes that break down proteins in the diseased tissue, which the maggot then ingests

Improving oxygen supply to the wound

Killing bacteria — In one German study5, maggot secretion was as deadly as antiseptic

Attacking biofilms that protect bacteria from immune and antibiotic attack A 2010 study6 showed that fluids from the blowfly Lucilia sericata caused a “complete breakdown” in biofilm, allowing two antibiotics to kill Staphylococcus aureus bacteria.

Since Baer’s time, the common green-bottle fly, Phaenicia sericata, has been the preferred medical maggot, because it devours dead tissue, but not living flesh. Flies must be sterilized before use, and because the eggs quickly hatch into larvae (maggots), air-shipment is necessary, says Ronald Sherman, laboratory director of maggot-maker Monarch Labs.

The healing never stops

Sherman says he became interested in blending entomology and medicine when he read about Baer during medical school. “I was always interested in medical entomology, the intersection of health and insects, but usually that was in the context of insects that cause disease. I was also interested in the beneficial uses of insects.”

As investigations in maggot therapy started to ramp up the 1980s, he recalls a “huge wave of resistance [that] was not all due to revulsion” at the thought of hosting insects.

Part of the problem was resistance to change, he says, especially “When that change is associated with these negative, emotional connotations: death, flies, an unhygienic environment.”

Some resistance, he says, came from doctors “who saw that patients were lining up for [maggot] treatment. People … were canceling amputation surgeries … just to give maggot therapy a try!” According to Sherman7, some studies show that maggots can “salvage” 40 to 50 percent of limbs and digits scheduled for amputation.

One study8 found that although 43 percent of patients had flies escaping from their wounds, and 19 percent eventually needed amputation, 89 percent would use maggots again.

enlarge this imageTwo transparent medicine bottles filled with medicinal maggots

Courtesy Ronald Sherman
A bottle of chemically sterilized maggots costs about $100, plus shipping. Because the adult flies can be infectious, they must be restrained with cheesecloth or a special-purpose dressing.

Flies on trial

Other studies are less definitive. For example, in a randomized trial9 of wounds published in 2009, larvae-infested leg wounds were more painful, and while maggots were better at cleaning, they did not hasten healing or reduce bacterial infections.

A review10 of randomized treatments for diabetic foot ulcers found that “one small trial suggested that larvae resulted in a more than 50 percent reduction in wound area compared with hydrogel.” (Hydrogels are new dressings that keep wounds moist.)

Why only “one small trial” for the common diabetic foot ulcers? Because the gold standard for selecting therapies requires that neither doctor nor patient know which treatment was used — but this “double-blind” is doubly difficult when the medical device is a mess of growing flies!

Sherman, who is a maggot entrepreneur as well as medical doctor, says maggot therapy ought no longer be considered a last resort. “Most clinicians come to it either because their patients, or they themselves, are at a dead end. Facing amputation, they’ve run out of options. Once they see what maggots can do, and recognize how simple, inexpensive, and relatively safe they are, they recognize that they don’t have to wait so long, and in the future will think about maggot therapy … before the wound has progressed, before the infection has progressed.”

enlarge this image Illustration of 17th century woman standing at table with leech on her left forearm, table holds large jar with leeches

Image: Rsabbatini
Leeching was standard practice until the mid-1800s. Leech saliva contains anesthetics, which could also explain why this lady is so cool, calm and collected with her slithery pals!

Maggot therapy is occurring “throughout the world,” Sherman says. “Twenty-four labs are producing medical grade maggots and providing them in 40 countries. In the United States alone, about 2,000 centers are regularly using maggot therapy. The treatments are included in textbooks, review articles on wound care and conferences.”

Leapin’ Leeches!

Leeches — bloodsucking aquatic worms — have been a part of medicine for at least 2,000 years. The Encyclopedia Britannica tells us that “Throughout most of Western history, leeching-or leechcraft-became such a common practice that a physician was commonly referred to as a ‘leech.'”

Modern-day “leeches” use leeches to drain excess blood after surgery. “The classic use is when a finger is reattached surgically,” says Kosta Mumcuoglu, a parasitologist at Hebrew University in Jerusalem. “Even if the surgeon succeeds nicely in reattaching the arteries, they often have problems with the veins, so blood can enter the finger but not return to the body. Then it’s a short time until the blood in the finger coagulates and the patient loses the finger.”

Surgeons may try to improve circulation with further surgery or anti-coagulants like heparin, says Mumcuoglu, president of the International Biotherapy Society. But if circulation is still stuck, “The skin may start to turn brown or violet, and any time now, the finger is going to be lost.”

enlarge this imageGory finger with 2 leeches, gauze, and visible suture line.

Courtesy Kosta Mumcuoglu, Hebrew University11
After finger-reattachment surgery, leeches excess blood that would otherwise clot and kill the finger. Those white objects are holding the surgery tight. Children whose fingers have been caught in doors are major beneficiaries of this surgery, but snowblowers can also amputate fingers.

Evolution plays two contrasting roles in our story: To avoid bleeding to death, mammals have evolved a powerful “coagulation cascade” that clots blood outside blood vessels. Because clotting could be deadly to leeches, they, like their bloodsucking brethren the ticks, mosquitoes and vampire bats, have evolved anti-coagulants.

One chemical in leech saliva, for example, blocks thrombin, which helps platelets clump to start a blood clot.

Not only do leeches produce prodigious amounts of clot-blockers, but they also have chemicals that relax blood vessels, which contributes to their utility in surgery. In 2004, leeches garnered FDA approval as a “medical device.”

The chemicals in leech saliva, aided by some manual clot removal, ensure that the skin around a surgery will bleed for hours or days after leeching. Even though the patient may need a blood transfusion, after a few days, “new blood vessels are growing in the area, and the circulation becomes normal, and we have a good feeling that we have saved the finger,” Mumcuoglu says.

Medical care for the medicinal leech (ca. 184112)

“Whenever any disease prevails amongst the leeches, (and it is always of an epidemic nature), [a leech expert] recommends us to separate the dead from the suffering and healthy, and place the latter in separate earthen jars; to about fifty leeches we should give three quarts of rain water of about a month’s standing, of a medium temperature, adding to it about two pints of charcoal: after three days, the water should be changed, but the charcoal may remain.”

Good to know. And when the little bloodsuckers get hungry…

Leeches also secrete anti-inflammatory compounds that are being tested against diseases linked to inflammation. In a randomized trial13 in Germany, four to six leeches, which attached for an average of 70 minutes, led to a significant decrease in pain of osteoarthritis of the knee after seven days, compared to the anti-inflammatory drug diclofenac. Leech treatment also significantly improved stiffness, function and general arthritis symptoms, for the entire 91-day study.

In 2008, the same researchers14 found that leeches. when compared to diclofenac, produced significant benefits in pain, mobility and quality of life for osteoarthritis of the thumb.

Solution: Outsourcing?

Still, leeches may never regain their former medical prominence. In London, in 1846, “at least tens of millions of leeches” were imported each year. A reservoir in Norwich, one author15 wrote, “might at least aid in supplying the quantity needed for our own consumption, instead of being almost entirely dependant, as we at present are, on a foreign supply.”

Modern leeching also faces modern problems:

Leeches can carry bacterial and viral disease. A study16 of a delayed infection after breast reconstruction reported infection rates from 2.4 percent to 20 percent.

Leeches may wander away from the wound and bite somewhere else, although they can be “leashed” into place with surgical thread.

Spent leeches can be infectious, and should be humanely euthanized by dunking in high-concentration ethanol. (We knew you’d ask…)

A 2007 study17 found that medicinal leeches may actually be members of three species, which raises questions about their biology and may flout the FDA, which defines this medical device as Hirudo medicinalis and nada mas.

enlarge this image

However, this last finding may be key to further progress, says Mark Siddall of the American Museum of Natural History, who led the group that identified three species. “This raises the tantalizing prospect of three times the number of anti-coagulants, and three times as many [other] biomedically important developments…”

Top: Hirudo medicinalis, the European medicinal leech. Bottom: Hirudo verbana, a related species, also used for leeching.

Did we forget what parasitologists call the “Yuck! factor”? Do patients squirm at the thought of attaching primitive bloodsuckers to their wounds? Generally not, says Mumcuoglu. “We have less problem with leeches than with maggots. We explain, ‘This is your last chance, if you don’t want to lose the finger, we have to try this.’ … Nobody has rejected the treatment.”

Terry Devitt, editor; S.V. Medaris, designer/illustrator; Jenny Seifert, project assistant; David J. Tenenbaum, feature writer; Amy Toburen, content development executive

Bibliography

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  2. IL-22+ CD4+ T Cells Are Associated with Therapeutic Trichuris trichiura Infection in an Ulcerative Colitis Patient, M.J. Broadhurst et al, Science Translational Medicine, 1 Dec. 2010.
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