Dracunculiasis is transmitted exclusively to humans via the ingestion of drinking water contaminated with D. medinensis-infected Cyclops, a copepod that is the intermediate host of this parasite. After drinking the water, the Cyclops fleas die and release D. medinensis larvae, which penetrate the human stomach and intestinal wall and then enter the abdominal cavity and retroperitoneal space. These third-stage larvae develop and mature into adults. Male worms die after copulation, whereas females grow to a length of 60 to 100 cm and migrate toward the subcutaneous skin tissue. At approximately 10 to 14 months after ingesting the contaminated water, the female worm induces a painful blister that is predominantly found on the skin of the lower extremities. When the blister ruptures, larvae are released on contact with water by emergence of the adult female worm. These immature first-stage larvae can live in the water for 3 days and can be ingested by Cyclops water fleas to become second-stage larvae. The infectious third-stage larvae develop after about two more weeks, after which the transmission cycle is perpetuated by humans drinking stagnant unfiltered water containing infected Cyclops fleas12345811.(Fig. 1)

No vaccine has yet been developed for the mass treatment of this disease1213. However, considering the life cycle of the guinea worm, various opportunities exist for prevention of GWD transmission at different points. For instance, contaminated sources of drinking water can be avoided, unsafe water can be filtered with cloth and fine-mesh strainers, sources of drinking water can be improved, and adequate measures can be taken to control the vectors of transmission.

Adult D. medinensis parasites mature only in humans over a period of 10 to 14 months, during which the infection manifests no symptoms or outward signs. After this period, a thin white female adult worm, which is up to 60 to 100 cm long and 1.5 to 2.0 mm thick, emerges slowly and painfully through a ruptured blister on the skin561415. Female worms inhabit human subcutaneous tissue and can emerge from any skin surface on the body, including the face, abdomen, arm, and lower extremities16 (Fig. 2); however, most female worms emerge from the leg, ankle, or foot. A dozen or more worms have even emerged simultaneously from a single patient.

Most of the interior body of the female worm is occupied by the uterus, which contains thousands of first-stage larvae561415. A blister is formed on the human skin around the anterior end of the worm; this blister ruptures when it is exposed to water. The female worm protrudes its anterior end and discharges first-stage larvae (650×20 µm) into the water and continues to protrude and release larvae into water for the following 2 to 6 weeks, after which the female worm dies. First-stage larvae can infect water fleas in freshwater by being swallowed. Within the water fleas, second-stage larvae develop and penetrate the gut wall of the water flea. After approximately 2 weeks, the larvae molt twice to become thirdstage larvae (450×14 µm). The vectors that harbor infectious third-stage larvae become sluggish and sink to the bottom of the water. Many species of Cyclops copepods have been found to be naturally infected with D. medinensis species in various regions of the world1718.

Cyclops copepods ingested via drinking water are dissolved by the gastric juice of the stomach, after which the infectious larvae penetrate the stomach or intestine of the human host. After a period of residence in the abdominal cavity, the larvae migrate into the connective tissues, where they develop into mature worms. Mating occurs about 3 months after the initial infection; the males (1-4 cm×0.4 mm) are much smaller than the females and die after mating. Female worms move through the connective tissues and usually reach the lower extremities by about 10 to 14 months postinfection.(Fig. 1)

Although parasites resembling D. medinensis have been observed in dogs and other animals, no other host or environmental reservoir of D. medinensis has been found outside of human beings. The immature first-stage larvae survive only a few days outside of the human body and must be ingested by a water flea for the life cycle to continue. For this reason, even though water fleas are ubiquitous in stagnant surface sources of freshwater, GWD is vulnerable to complete eradication. However, more recently the presence of other hosts (i.e., dogs) was proposed as a possible reason for why GWD has been difficult to eradicate19.

There are usually no symptoms during the first 10 to 14 months of parasite maturation. The first sign is normally a burning sensation and pruritus that patients experience before the worm penetrates the skin. After these sensations, the dermis of the penetrated area becomes elevated and a blister develops. Patients often place the affected area in water to relieve this pain and discomfort. Adult female worms are most frequently located in the lower extremities, including the foot or lower leg, but can also appear on the upper extremities, breasts, head, back, scrotum, or anywhere else on the bodily surface. When worms emerge close to joints, they can cause arthritis. They can also cause foot and leg joints to become stiff and painful due to inflammatory responses or worm calcification578.

Secondary infection of ulcers can lead to bacterial cellulitis; moreover, these ulcers can contain lesions that can act as points of entry for tetanus spores. Inflammation makes it difficult to extract adult worms from ulcers before the uterus of the worm has completely released its larvae. If no secondary infection is present, guinea worm ulcers can be healed spontaneously after the empty worm has been removed. However, if any part of the adult worm remains after breakage, the remainder of the worm withdraws into the host tissue and causes a severe inflammatory reaction that can result in a larger ulcer and consequent extensive fibrosis. Only a single worm usually appears in each patient per year; however, in rare instances many worms (more than 20) have emerged from a single individual. Some of these female worms die before they emerge through the skin, which is problematic because these dead or ruptured worms can cause subcutaneous abscesses. In other rare instances, worms can migrate into vital organs, where they cause serious problems. Many people in endemic areas have antibodies against the parasite because of current or recent infections. Infections do not confer immunity and thus most people in endemic areas become reinfected year after year.

Unfortunately, guinea worm infections cannot be diagnosed in the prepatent period (i.e., the first 8-10 months of infection). However, sometimes adult female worms are visible or palpable under the skin shortly before they emerge. Clinical diagnosis is made by examining the guinea worm ulcer and observing the female worm protruding from the blister. The distinctive appearance of the blister, which is accompanied by local itching and burning pain, makes diagnosis easy. Active larvae can also be obtained by immersing the protruding adult female in a small tube or container with water. The first stage larvae can be observed under a microscope and are easily identified by their characteristic pointed tails. Serologic inspection is usually of no practical use in diagnosis. Patients often have eosinophilia; dead calcified worms are easily seen in radiographs, whereas live worms are not visible5789.

Although dracunculiasis is not currently treatable, infection transmission can fortunately be prevented in several ways. Specifically, transmission can be prevented by protecting drinking water from contamination by infected humans and by protecting humans from drinking contaminated water. The most basic intervention is to teach people in endemic areas to avoid entering sources of drinking water when a worm is emerging or about to emerge from their body and to always filter any water they drink from an open pond or other stagnant source through a finely woven cloth27. Another effective intervention is to treat potentially contaminated ponds with larvicide. At the recommended concentration, the recommended larvicide is colorless, odorless, tasteless, and harmless to humans, fish, and plants, but lethal to Copepods. Unfortunately, this is the slowest and most expensive of the available preventive measures28.

Complicating prevention efforts, it is also difficult to convince conservative villagers that this disease was caused by water they drank a year ago, as opposed to a strongly held traditional belief they may have regarding its cause. This can be done, but it is not easy. To prevent contamination of water with guinea worm larvae, health education also emphasizes that people with guinea worm ulcers should have their wounds dressed and should not place infected limbs in water that is used for drinking. Focusing on effective sanitation and hygiene, in addition to reward programs for guinea worm eradication posters, are especially recommended in low-income communities.(Fig. 5)

Recently, more systematic prevention efforts targeting specific population groups252728, such as school age children, preschool children, and pregnant women have been introduced. These efforts have included school-based and maternal care programs, and were also cited as key Millennium Development Goals1415.

After penetration from the skin, an ancient practice consisting of careful winding of the emerging worm around a small stick ("winding of the worm") has traditionally been the best way for extracting the worm. The protruding portion of the female worm must be attached to a small stick that is twisted carefully for several days until the worm is completely removed16.(Fig. 6) Since only a few centimeters of a worm can usually be pulled out per day in this fashion, the painful incapacitation associated with this infection normally lasts up to 1 to 2 months or more. Care should be taken not to break the worm. This traditional technique has been effective in many rural regions without advanced medical facilities. However, if a worm is broken while being coaxed to emerge, the remainder of the worm retracts into the body and spills larvae into the tissues, causing severe inflammation and abscess formation. This complication is very painful and requires incisions and drainage to be performed by medically trained personnel at a clinic facility.

The site of worm emergence often acquires secondary infection with various bacteria, which increases the local inflammation and pain that are the hallmarks of this disease. Infection with tetanus bacilli at the site of the ulcer, which forms at the base of the ruptured blister caused by the emerging worm, is the most dangerous secondary complication of dracunculiasis. In this case, administration of antibiotics and adequate cleaning and dressing of the ulcer are important for reducing secondary infections. In addition, tetanus vaccination is recommended. In about one percent of all cases, a worm that emerges in or near a major joint such as the elbow or knee can cause the joint to permanently freeze, with consequences very similar to those of paralytic poliomyelitis. Since infections do not confer immunity, people can be reinfected year after year.

A number of single-dose, orally administered drugs are available for the treatment and control of soil-transmitted helminth (STH) infections. Most of these drugs are broadspectrum benzimidazole anthelmintics29 that were developed in the 1970s. These drugs revolutionized the ability of communities to control geohelminths. Five drugs are currently listed on the WHO's model list of essential medicines needed in a basic health system for the medical treatment of dracunculiasis. These drugs are albendazole, mebendazole, pyrantel, levamisole, and ivermectin.(Fig. 7) Each of these drugs is recommended by the WHO for use in large-scale control program5192930.

Albendazole is a broad-spectrum antihelminthic benzimidazole used most widely for the treatment of a variety of parasitic worm infestations and for community control of multiple STH infections. It can be used to treat giardiasis, trichuriasis, filariasis, neurocysticercosis, hydatid disease, pinworm disease, and ascariasis, among others. Albendazole is taken orally and is poorly absorbed by the gastrointestinal tract. However, it is rapidly and extensively metabolized by the liver to sulphoxide and sulphone metabolites2930. Sulphoxide metabolites are active antihelminthic compounds that are believed to be responsible for most of the in vivo effects of albendazole. These compounds bind to intracellular tubulin, impairing absorption of essential nutrients by the parasite. Common side effects include nausea, abdominal pains, and headaches. Potentially serious side effects include bone marrow suppression; the risk of this effect is higher in patients with liver problems and pregnant women.

Mebendazole is another well-known broad-spectrum benzimidazole-type antihelminthic agent with activity against the adult worms and especially against the larval stages. This oral drug is effective for treating ascariasis, pinworm disease, hookworm infections, hydatid disease, giardia, and GWD. Mebendazole binds to tubulin in nematodes and prevents the formation of microtubules, thereby selectively inhibiting cell division and glucose uptake in the nematodes. In turn, the helminths use more glycogen, thus depriving the worms of their main source of energy. The adverse effects of mebendazole are mild and transient and include symptoms such as gastrointestinal discomfort, headache, and well-tolerated dizziness2930. Additional common side effects include headache, vomiting, and tinnitus. If used at large doses, mebendazole may cause bone marrow suppression. It is currently unclear whether it is safe to use mebendazole in pregnancy2. In rare instances, mebendazole stimulates Ascaris worms to emerge from the mouth and nostrils, which is an unexpected consequence about which patients should be forewarned16.(Fig. 8)

Abamectin, otherwise known as avemectin, is a natural product of the soil bacterium Streptomyces avermitilis that is fermented to insecticidal and antihelminthic compounds2930. Abamectin is a mixture of two avermectins and consists of more than 80% avermectin B1a (R=CH₂CH₃) and less than 20% avermectin B1b (R=CH₃). These two components—B1a and B1b—have similar toxicological properties and have been used as insecticides, acaricides, and nematicides. Abamectin is effective for controlling insects and mite pests that infect a range of agronomic, fruit, vegetable, and ornamental crops. Moreover, abamectin has also been used to control fire ants and as a veterinary antihelminthic. Unlike other classes of benzimidazoles, resistance against abamectin is rare.

Outside of the benzimidazole derivatives, pyrantel is an antinematodal thiophene and a nicotinic receptor agonist that is also used against the parasites. Like levamisole and the related pyrimidine morantel, it binds to parasite acetylcholine receptors and acts on the neuromuscular system of the worms2930. Spastic muscle paralysis results from prolonged activation of the excitatory nicotinic acetylcholine receptors on the body wall muscle. Pyrantel was often prescribed by veterinarians to treat and prevent the occurrence of intestinal parasites in small animal pets; however, this drug is poorly absorbed by the gastrointestinal tract. Specifically, less than 15% is excreted in the urine in its original form or as metabolites, whereas 70% is excreted in its original form in feces. Common adverse effects include mild and transient gastrointestinal discomfort, headache, dizziness, drowsiness, insomnia, and skin rash. It has not been established whether it is safe to use during pregnancy. Pyrantel and piperazine are antagonistic and should not be administered concurrently.

Levamisole, also known as ergamisol, has a similar mode of action as pyrantel and causes spastic paralysis followed by passive elimination of parasites2930. This drug is rapidly absorbed by the gastrointestinal tract, achieves peak plasma levels within 2 hours, and is eliminated within 3 days. Since much of the absorbed drug is metabolized in the liver, levamisole has also been studied as a chemotherapeutic agent. Levamisole is a synthetic imidazothiazole derivative. Common adverse effects include abdominal pain, nausea, vomiting, dizziness, and headache; the most serious side effect of levamisole is low white blood cells, which makes patients highly vulnerable to infection.

Ivermectin is classified in the avermectin family. This drug causes the cell wall of invertebrates to become more permeable, which results in their death. Ivermectin is broadly effective against many types of parasites, including the causative agents of onchocerciasis, lymphatic filariasis, head lice, scabies, river blindness, and strongyloidiasis2930. In addition, ivermectin is on the WHO's List of Essential Medicines, which contains the most important medications needed in a basic health system31. Although ivermectin has therapeutic properties against Ascaris lumbricoides, it shows only limited effectiveness against Trichuris trichiura and hookworm. Ivermectin can be used topically or orally; common side effects include red eyes, dry skin, and burning skin.

Piperazine is a broad class organic compound with a core piperazine functional group that consists of a six-membered ring containing two nitrogen atoms at opposite positions in the ring.(Fig. 7) Piperazine has many important pharmacological properties and takes the form of small alkaline deliquescent crystals that have a saline taste. This drug is used to treat A. lumbricoides and Enterobius vermicularis infections, especially in the presence of intestinal or biliary obstruction2930.

Nitazoxanide is a broad-spectrum antiparasitic and antiviral drug that is used to treat various helminthic, protozoan, and viral infections. It is the prototype member of the thiazolides, a class of drugs that are synthetic nitrothiazolyl-salicylamide derivatives with antiparasitic and antiviral activity. Tizoxanide, an active nitazoxanide metabolite found in humans, is also a thiazolide antiparasitic drug. The associated adverse effects are generally mild and transient and include abdominal pain, nausea, vomiting, and diarrhea.

In addition to these drugs, a number of new candidates are in development for human use. The first of these, tribendimindine, was initially synthesized in China in the 1980s. Early trials in humans demonstrated that single-dose tribendimidine is effective against all STH species32. However, before tribendimidine can be made available outside China, additional preclinical and clinical studies are required. Additional candidates believed to have promising antihelminthic properties are PF1022A (and its derivative emodepside) and monepantel32.