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Parasitic worms are usually bad news, but perhaps not if you  have allergies. Matt Kaplan reports on a radical new therapy

HOOKWORMS, whipworms, pinworms, flukes: mere mention of the panoply of parasitic worms that plague humans is enough to make most of us shudder. Not John Turton. In the mid-1970s, while working at the UK's Medical Research Council Laboratories in Surrey, he intentionally infected himself with hookworms in an attempt to relieve his chronic hay fever. It worked. For two summers while he harboured the parasites, his allergy abated, only to return when he was free of them (The Lancet, vol 308, p 686).

Turton's grim experiment came at a time when it was emerging that people living in regions where parasitic worm infections are rife tend to have fewer allergies. Nevertheless, he might have thought twice. In 1913, W. Herrick, a doctor from Columbia University in New York, noticed a very different link between parasitic worms, or helminths, and allergy. Lab workers whose duties included dissecting the gut-dwelling roundworm Ascaris often developed tenderness and swelling in their fingers, and more severe allergies after longer exposure, especially asthma.

Since the 1970s, researchers have been trying to make sense of these conflicting findings in the hope of being able to harness the power of parasites to help relieve allergies without making things worse. They know they are playing with fire - after all, helminths are responsible for some truly horrible diseases and cause great suffering around the world. Yet, as the effects of helminths on the human body become clearer, it looks as though their healing potential may be unleashed.

Not surprisingly, few researchers have been willing to take the risk of deliberately infecting themselves as Turton did. Instead, most studies are based on populations in countries where people are already infected. This research tends to focus on the three most commonly diagnosed allergic conditions: asthma, eczema and hay fever. The results have been confusing, but now researchers are beginning to understand why.

One study conducted in Taiwan, for example, showed that people infected with Enterobius vermicularis, a pinworm that is one of the most common gut parasites in the world, were less likely to have hay fever than the general population (Clinical Experimental Allergy, vol 32, p 1029). However, results from Ecuador tell a different story. Noting that hay fever was significantly more common in children living in urban than rural settings, researchers looked for a correlation between the allergy and levels of infection with the roundworm Ascaris lumbricoides. The parasite was equally common in both groups, so they concluded that something else must be responsible for the prevalence of hay fever (Clinical Experimental Allergy, vol 34, p 845).

The findings on eczema have proved just as difficult to interpret. For example, a study in Uganda found that eczema was less common among infants whose mothers had been infected with helminths while pregnant (JAMA, vol 294, p 2032). However, another study, this time in Ethiopia, discovered that children with Trichuris worms, whipworms that infest the large intestine, were more likely to have eczema than uninfected children (Journal of Allergy and Clinical Immunology, vol 115, p 370).

“Hookworms potential to protect against asthma may be related to its lung migration phase”

As for asthma, Herrick's finding that it can be triggered merely by contact with Ascaris was confirmed in the 1970s. However, hookworms reduced the severity of asthma in a group of Ethiopians (The Lancet, vol 358, p 1493) and similar benefits have been noted in Brazilian asthma sufferers infected with Schistosoma mansoni, the flatworm responsible for schistosomiasis, which damages internal organs.

What are we to make of all this? The crucial link between allergies and parasites is the human immune system. Allergies are triggered by an overactive immune response, and helminths have strategies to damp down our immune response to promote their survival; after all, they have evolved in lockstep with humans for millennia.

In people who don't have allergies, foreign material entering the body prompts the release of cytokines, molecules that sound the alarm to get the attention of other immune cells. As immune cells rally to attack the intruder, a second set of molecules is released to prevent the immune response from overreacting. One of the key molecules responsible for keeping reactions in check is interleukin-10, which inhibits the release of certain cytokines. People with allergies tend to have lower than normal levels of interleukin-10, so immune responses frequently get out of hand. Conversely, people infected with helminths have above-average levels of the molecule, and research on schistosomiasis patients indicates that this is at least partially because the worms release chemicals that stimulate the production of interleukin-10 in their host.

The mystery, then, is not so much that helminthic infections can damp down hay fever and other allergies, but that in some cases parasites do not. Clearly, different helminths interact with the immune system in different ways. "Parasitic worms are often treated as having the same effect on the body, but they probably do not," says Carsten Flohr at the University of Nottingham, UK, who recently published an article on the subject (Clinical Experimental Allergy, vol 39, p 20). What is not clear is the mechanism that sends the immune response in either direction.

One possible explanation is the helminths' lifespan. A short-lived worm, such as E. vermicularis, will not have much of a chance to tinker with the immune system and is less likely to be able to suppress the response than a hookworm, for example, a parasite that's in for the long haul. Worms responsible for chronic infections would be unlikely to survive without evolving mechanisms that allow them to strike up an immunological balance with their host.

In addition, different species may have specific effects on immunity depending on the areas of the body they inhabit. Trichuris, for example, is ingested and stays in the gut, escaping the intense immune response that schistosomes encounter as they burrow their way through the skin, which is heavily monitored by cytokines and highly reactive, explains Flohr. Hookworm larvae also enter through the skin and make their way through the bloodstream to the lungs, where they pass through the thin-walled blood vessels. They then travel up from the lungs into the trachea, only to be coughed up and swallowed, allowing them to reach the small intestine where they develop into adult worms. "The potential protective effects of hookworm infections on asthma may be related to these parasites' lung migration phase," Flohr says.

Hookworm's potential to protect against asthma may be related to its lung migration phase

It is this specificity that makes parasitic worms attractive as a potential treatment for allergic conditions. "The nice thing about a worm is it does the work of entering the body and interacting with the immune system for you. It has evolved excellent techniques that allow it to get to where it wants to go and lower the ensuing immune response," says immunologist Klaus Erb from Boehringer Ingelheim Pharmaceuticals in Germany.

Could there really ever be a demand for worm therapy? With a growing understanding of which parasites have the most potential to alleviate allergies, some researchers are convinced worms have a future. That's partly because allergies are a huge and increasing problem, particularly in the developed world where they affect around 1 in 5 children, and partly because there is no treatment that resolves the underlying problem of an overreactive immune system. The choice is antihistamine tablets, which only work as long as you keep taking them, or a painful and time-consuming course of injections to desensitise you to the materials that prompt the immune system to overreact.

“Benefits occur when individuals are excreting at least 50 hookworm eggs per gram of faeces”

In an attempt to bring helminthic therapy a step closer, researchers at the University of Nottingham are testing the suitability of hookworms as a treatment for asthma. First they infected healthy people with the worms and discovered that a dose of 10 larvae resulted in a high enough level of infection to confer immune benefits; studies in Ethiopia indicate that this occurs when infected individuals are excreting at least 50 hookworm eggs per gram of faeces. Side effects included itching and sometimes minor intestinal discomfort, but they were only mild. The researchers then recruited asthma sufferers to test the effectiveness of hookworm therapy. "We monitored airway responsiveness during the period when we knew the larvae were migrating through the airways to determine if the migration made respiratory disease worse," says Johanna Feary, a member of the Nottingham team. And, most recently, they have conducted a 16-week, placebo-controlled trial on 34 people with asthma.

Benefits occur when individuals are excreting at least 50 hookworm eggs per gram of faeces

The results of these ground-breaking studies have yet to be published. Even if the treatment proves highly effective, it may well be difficult to convince people that worm therapy is the way to go. Many doctors find the idea repellant. "These things are disgusting. People are never going to allow themselves to be infected with them," says clinical immunologist Asif Rafi at the University of California, Los Angeles. "You really don't want to treat people with worms if you don't have to," adds Erb.

Aside from the yuck factor, there is another problem: helminths could ultimately make patients more susceptible to other diseases. It is an oversimplification to suggest that worms just reduce the immune response, says Rafi. What they are doing is changing the type of activity the immune system engages in. When reacting to parasites, bacteria and viruses, the immune system must balance the release of molecules that sound the alarm and increase inflammation, against those that calm things down, reducing inflammation and repairing tissue. Parasitic worms are particularly adept at shifting the balance towards an anti-inflammatory state, as it's the ability to control inflammation that allows them to survive for years in a human. That's good for them, but may make their host vulnerable to other infectious diseases.

"There may well be a downside to worm infection," admits David Pritchard from the Nottingham team. "The great challenge we face is finding the correct balance between alleviating disease and propagating it."

There may be another way to exploit the healing powers of helminths, however. "What we really need, is to find useful compounds being produced by these worms, rather than trying to use the worms themselves," says Rafi.

That is exactly what William Harnett and colleagues are doing at the University of Strathclyde in Glasgow, UK. They have shown that a complex protein called ES-62 - produced by Acanthocheilonema viteae, a parasitic filarial nematode worm that infects rodents - dramatically reduces inflammation associated with allergic conditions in mice. Intriguingly, ES-62 affects multiple aspects of the immune system simultaneously. As well as inducing production of anti-inflammatory cytokines such as interleukin-10, it also inhibits production of pro-inflammatory cytokines and proliferation of lymphocytes - the immune system's white blood cells - and blocks the activation of mast cells, which play a key role in promoting inflammation. Now Harnett and his team are attempting to create small drug-like molecules that mimic the effects of ES-62.

Treating allergies with "essence of parasite" might sound like an ambitious goal, but the ES-62 research could be just the start. Parasitologist Jan Bradley at the University of Nottingham points out that there is far more to helminths than just how they influence allergic reactions. For example, Murray Selkirk at Imperial College London has discovered that infection with parasitic worms gives animals some protection against pneumonia caused by influenza. "Things are going to get a whole lot more complicated when we start considering the effects generated by interactions between different parasites, and the interactions between parasites and certain viruses," says Bradley.■

Who's for worm therapy?

Some species of parasitic worm are better at suppressing allergies than others. Likewise, some people get greater benefits from worm infections than others. Researchers suspect that a person's age, diet and the environment in which they became infected may make a difference. In rural settings in developing countries, for example, children are often repeatedly infected from an early age. "This leads to a degree of host immunity and is probably the reason why helminths such as hookworms can survive in the same host for years, often causing only mild symptoms," says Carsten Flohr of the University of Nottingham, UK. In this case, the parasites are more likely to help alleviate allergies. Where people are infected later in life, however, exposure to helminths can actually lead to allergies.

Another factor that seems to influence the link between parasites and allergies in different individuals is genes. "Genetics are known to play a role in whether people are susceptible to both allergies and parasites," says immunologist Padraic Fallon at Trinity College in Dublin, Ireland. "Both of these susceptibilities could be under common genetic control." It may be that people who are prone to allergies have immune systems that naturally respond more aggressively towards invading parasites. Such highly reactive immune systems would have been selected for in areas where infections from parasitic worms were high. In today's developed world, where such infections are rare, these individuals will be more prone to allergies. However, they may also be more likely to respond to helminthic therapy.

Parasites

Ascaris

• EFFECTIVE AGAINST Eczema?
• INFECTION ROUTE Food contaminated with Ascaris eggs (faecal-oral spread)
• ASSOCIATED DISEASE/SYMPTOMS Often no symptoms, but can cause anaemia. Gastrointestinal symptoms increase with higher worm burden
• SITE OF INFECTION Small intestine
• DURATION OF INFECTION 1-2 years

Hookworm

• EFFECTIVE AGAINST Asthma?
• INFECTION ROUTE Usually burrows through skin of the lower legs
• ASSOCIATED DISEASE/SYMPTOMS Often no symptoms, but can cause anaemia. Gastrointestinal symptoms increase with higher worm burden
• SITE OF INFECTION Small intestine
• DURATION OF INFECTION 4-6 years

Schistosome

• EFFECTIVE AGAINST Asthma?
• INFECTION ROUTE Burrows through skin, usually from contaminated water
• ASSOCIATED DISEASE/SYMPTOMS Schistosomiasis characterised by fatigue, fever, abdominal pain, diarrhoea and damage to internal organs
• SITE OF INFECTION Liver, bladder, kidney, ureter
• DURATION OF INFECTION 4-6 years

Filarial nematodes (producing ES-62)

• EFFECTIVE AGAINST Unknown
• INFECTION ROUTE Mosquito bites
• ASSOCIATED DISEASE/SYMPTOMS Sometimes asymptomatic. In the worst case elephantiasis - severe leg swelling due to blockage of the lymphatic system
• SITE OF INFECTION Skin (adult worms)
• DURATION OF INFECTION Unknown

Matt Kaplan is a writer based in California and the UK

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