Loa loa filariasis

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Kalsang Dolma, M.B.B.S.[2]

Loa loa filariasis is a skin and eye disease caused by the nematode worm, loa loa filaria. Humans contract this disease through the bite of a horsefly. The Deer fly and the Mango flyare also vectors for Loa loa. The disease can cause red itchy swellings below the skin called Calabar swellings.

The first case of Loa loa infection was noted in the Caribbean (Santo Domingo) in 1770. Localized angioedema, a common clinical presentation of loiasis, was observed in 1895 in the coastal Nigerian town of Calabar—hence the name, Calabar swellings. The association between Loa loa and Calabar swellings was not realized until 1910 (by Dr. Patrick Manson).

Loiasis is caused by the nematodes (roundworm) Loa loa that can inhabit the lymphatics and subcutaneous tissues of humans. Adult Loa worms are sexual, with males considerably smaller than females at 30–34 mm long and 0.35-0.42 mm wide compared to 40–70 mm long and 0.5 mm wide. Adults live in the subcutaneous tissues of humans, where they mate and produce worm-like eggs called microfilaria. These microfilariae are 250-300μm long, 6-8μm wide, and can be distinguished morphologically from other filariae—they are sheathed and contain body nuclei that extend to the tip of the tail.

Loa loa parasites are found in West and Central Africa. The east-west geographical distribution of the disease extends from southeastern Benin to southern Sudan and Uganda. The north-south geographical distribution extends from about 10°N to Angola. It is estimated that between 3 and 13 million people in West and Central Africa are infected.

The people most at risk for loiasis are those who live in the high-canopied rain forests of West and Central Africa. The deerflies that transmit the parasite typically bite during the day and are more common during the rainy season. They are attracted by the movement of people and by smoke from wood fires. Rubber plantations create a favorable environment for the flies, as the trees form a dense canopy.

Symptoms include itchy swellings (Calabar swellings) anywhere on the body, that are usually non painful and are often found near joints. Less common symptoms include generalized itching, muscle pain, joint pain, and fatigue. Infected persons may not have any symptoms at all

Diagnosis can be difficult in patients with low levels of larvae in the blood. The diagnostic work-up is usually begun after someone develops eye worm, Calabar swellings, or unexplained elevated levels of eosinophils on blood tests after travel to an affected area. The diagnosis can be made by identification of the adult worm by a microbiologist after its removal from under the skin or eye, identification of an adult worm in the eye by a healthcare provider in a patient with risk factors for infection,identification of the larvae on a blood smear made from blood taken from the patient between 10AM and 2PM and identification of antibodies against L. loa. Unfortunately these tests cannot distinguish between active infection and a history of exposure or past infection and they are not widely available in the United States.

Treatment of loiasis involves chemotherapy or, in some cases, surgical removal of adult worms followed by systemic treatment. The current drug of choice for therapy is diethylcarbamazine (DEC). The recommend dosage of DEC is 8 – 10 mg/kg/d taken three times daily for 12 days. The pediatric dose is the same. DEC is effective against microfilariae and somewhat effective against macrofilariae (adult worms).^[1]

In patients with high microfilaria load, however, treatment with DEC may be contraindicated, as the rapid microfilaricidal actions of the drug can provoke encephalopathy. In these cases, albendazole administration has proved helpful, and superior to ivermectin, which can also be risky despite is slower-acting microfilaricidal effects.^[1]

Surgical excision of migrating adult worms is an effective treatment for symptoms localized to the migrating worm and provides an opportunity for diagnosis. Systemic therapy would be required to cure the infection unless the patient is infected with only a single adult worm.

There are no vaccines available to prevent becoming infected with Loa loa. Diethylcarbamazine (DEC) 300mg taken once a week is effective at preventing loiasis in long-term travelers to affected areas. As the deerflies breed in muddy, shaded areas along rivers and are attracted to smoke from wood fires, avoiding those areas may reduce one’s risk of infection. Other prevention efforts include personal protection measures against biting insects. This includes wearing insect repellant such as N,N-Diethyl-meta-toluamide (DEET) on exposed skin, wearing long sleeves and long pants during the day when deer flies bite, and wearing permethrin– treated clothing.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Kalsang Dolma, M.B.B.S.[2]

The first case of Loa loa infection was noted in the Caribbean (Santo Domingo) in 1770. Localized angioedema, a common clinical presentation of loiasis, was observed in 1895 in the coastal Nigerian town of Calabar—hence the name, Calabar swellings. The association between Loa loa and Calabar swellings was not realized until 1910 (by Dr. Patrick Manson).

The first case of Loa loa infection was noted in the Caribbean (Santo Domingo) in 1770. A French surgeon named Mongin tried but failed to remove a worm passing across a woman’s eye. A few years later, in 1778, the surgeon François Guyot noted worms in the eyes of West African slaves on a French ship to America; he successfully removed a worm from one man’s eye. The first case of Loa loa infection was noted in the Caribbean (Santo Domingo) in 1770. Localized angioedema, a common clinical presentation of loiasis, was observed in 1895 in the coastal Nigerian town of Calabar—hence the name, Calabar swellings. This observation was made by a Scottish ophthalmologist named Douglas Argyll-Robertson, but the association between Loa loa and Calabar swellings was not realized until 1910 (by Dr. Patrick Manson). The determination of vector—Chrysops spp.—was made in 1912 by the British parasitologist Robert Thomson Leiper.^[1]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Kalsang Dolma, M.B.B.S.[2]

The vector for Loa loa filariasis are flies from two species of the genus Chrysops, C. silacea and C. dimidiata. During a blood meal, an infected fly (genus Chrysops, day-biting flies) introduces third-stage filarial larvae onto the skin of the human host, where they penetrate into the bite wound (1). The larvae develop into adults that commonly reside in subcutaneous tissue (2). The female worms measure 40 to 70 mm in length and 0.5 mm in diameter, while the males measure 30 to 34 mm in length and 0.35 to 0.43 mm in diameter. Adults produce microfilariae measuring 250 to 300 μm by 6 to 8 μm, which are sheathed and have diurnal periodicity. Microfilariae have been recovered from spinal fluids, urine, and sputum. During the day they are found in peripheral blood, but during the noncirculation phase, they are found in the lungs (3). The fly ingests microfilariae during a blood meal (4) . After ingestion, the microfilariae lose their sheaths and migrate from the fly’s midgut through the hemocoel to the thoracic muscles of the arthropod (5). There the microfilariae develop into first-stage larvae (6) and subsequently into third-stage infective larvae (7). The third-stage infective larvae migrate to the fly’s proboscis (8) and can infect another human when the fly takes a blood meal (1).

Loa loa microfilariae are transmitted to humans by the mango (also, mangrove) or deerfly vectors, Chrysops silicea and C. dimidiata. The vectors are blood-sucking and day-biting, and they are found in rainforest-like environments in west and central Africa. Microfilaria mature to adults in the subcutaneous tissues of the human host, after which the adult worms—assuming presence of a male and female worm—mate and produce more microfilaria. The cycle of infection continues when a non-infected mango or deerfly takes a blood meal from a microfilaremic human host, and this stage of the transmission is possible due to the combination of the diurnal periodicity of microfilaria and the day-biting tendencies of the Chrysops spp.^[1]

Humans are the primary reservoir for Loa loa. Other minor potential reservoirs have been indicated in various fly biting habit studies: hippopotamus, wild ruminants (e.g., buffalo), rodents, and lizards. A simian type of loiasis exists in monkeys and apes but it is transmitted by Chrysops langi. There is no cross-over between the human and simian types of the disease.^[2]

Microfilaria of Loa loa are transmitted by several species of tabanid flies (Order: Diptera; Class: Tabanidae). Although horseflies of the Tabanus genus are often mentioned as Loa vectors, the two prominent vector are from the Chrysops genus of tabanids—C. silicea and C. dimidiata. These species exist only in Africa and are popularly known as deerflies and mango, or mangrove, flies.^[3]

Chrysops spp are small (5–20 mm long) with a large head and downward pointing mouthparts.^[3] Their wings are clear or speckled brown. They are hematophagous and typically live in forested and muddy habitats like swamps, streams, reservoirs, and in rotting vegetation. Female mango and deerflies require a blood meal for production of a second batch of eggs. This batch is deposited near water, where the eggs hatch in 5–7 days. The larvae mature in water or soil, where they feed on organic material such as decaying animal and vegetable products. Fly larvae are 1–6 cm long and take 1–3 years to mature from egg to adult.^[3] When fully mature, C. silacea and C. dimidiata assume the day-biting tendencies of all tabanids. The bite of the mango fly can be very painful, possibly due to the laceration style employed; rather than puncturing the skin like a mosquito does, the mango (and deerfly) make a laceration in the skin and subsequently lap up blood. Female flies require a fair amount of blood for their aforementioned reproductive purposes and thus may take multiple blood meals from the same host if disturbed during the first one.

Interestingly, although Chrysops silacea and C. dimidiata are attracted to canopied rainforests, they do not do their biting there. Instead, they leave the forest and take most blood meals in open areas. The flies are attracted to smoke from wood fires and they use visual cues and sensation of carbon dioxide plumes to find their preferred host, humans. A study of Chrysops spp biting habits showed that C. silacea and C. dimidiata take human blood meals approximately 90% of the time, with hippopatomus, wild ruminant, rodent, and lizard blood meals making up the other 10%. The fact that no simian (ex: monkeys or apes) blood meals were taken suggests that there is no crossover between the human and simian types of Loa loa. A related fly, Chrysops langi, has been isolated as a vector of simian loiasis, but this variant hunts within the forest and has not as yet been associated with human infection.

Shown below is an image Chrysops callidus

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Loa loa is the filarial nematode (roundworm) species that causes Loa loa filariasis. It is commonly known as the “eye worm”. Its geographic distribution includes Africa and India.^[1]

L. loa is one of three parasitic filarial nematodes that cause subcutaneous filariasis in humans. The two other filarial nematodes are Mansonella streptocerca and Onchocerca volvulus (causes river blindness).

Maturing larvae and adults of the “eye worm” occupy the subcutaneous layer of the skin – the fat layer – of humans, causing disease. The young larvae develop in horseflies of the genus Chrysops (deer flies, yellow flies), including the species C. dimidiata and C. silacea, which infect humans by biting them.

Loa loa worms have a simple body including a head, body, and tail. Males range from 20mm to 34mm long and 350μm to 430μm wide. Females range from 20mm to 70mm long and are about 425μm wide.^[1]

Three species involved in the life cycle include the parasite Loa loa, the fly vector, and the human host:^[2]

• A vector fly bites an infected human host and ingests microfilariae.
• Microfilariae move to the fat body of the insect host.
• Microfilariae develop into first stage larvae, second stage, then third stage larvae.
• Third stage larvae (infective) travel to the proboscis of fly.
• An infected vector fly bites an uninfected human host and the third stage larvae penetrates the skin and enters human subcutaneous tissue.
• Larvae mature into adults, who produce microfilariae that have been found in spinal fluid, urine, peripheral blood, and lungs.

Loa loa parasites infect human hosts by travelling from the entry site through subcutaneous tissues and causing inflammation in the skin wherever they travel. If a parasite stops in one place for a short period of time, the human host will suffer from local inflammation known as Calabar swellings. These are localized, tense, inflammatory pruritic subcutaneous edema seen in joints of extremities, lasting for 1–3 days. They represent areas of angioedema resulting from a host response to allergens released by the maturating worm and its metabolic products.^[3] Calabar swellings often occur in the wrist and ankle joints but disappear as soon as the parasite begins to move again. Parasites can also travel through and infect the eye, causing the swelling of the eye. Common symptoms include itching, joint pain, fatigue, and death.^[1]

The main methods of diagnosis include the presence of microfilariae in the blood, the presence of a worm in the eye, and the presence of skin swellings. Surgical removal of the worm can easily be performed. The common treatment for the disease is the use of the drug Ivermectin.^[1]

Ivermectin has become the most common antiparasitic agent used worldwide but can lead to residual microfilarial load when given in the management of loiasis. High microfilarial loads should be decreased by a course of ivermectin, a prolonged administration of albendazole, or cytapheresis sessions to prevent occurrence of serious adverse events, including fatal encephalopathy induced by dying microfilariae. Cytapheresis is helpful in decreasing very high microfilarial loads up to 75%. Diethylcarbamazine kills both microfilariae and adult worms but has more severe side effects and can be fatal.

• Taxonomy Browser: Loa Loa. National Center for Biotechnology Information (NCBI).

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Kalsang Dolma, M.B.B.S.[2]

Loa loa parasites are found in West and Central Africa. The east-west geographical distribution of the disease extends from southeastern Benin to southern Sudan and Uganda. The north-south geographical distribution extends from about 10°N to Angola. It is estimated that between 3 and 13 million people in West and Central Africa are infected.

As of 2009, loiasis is endemic to 11 countries, all in western or central Africa, and an estimated 12-13 million people have the disease. The highest incidence is seen in the following countries:

• Cameroon
• Republic of the Congo
• Democratic Republic of Congo
• Central African Republic
• Nigeria
• Gabon
• Equatorial Guinea

The rates of Loa loa infection are lower but it is still present in and Angola, Benin, Chad and Uganda. The disease was once endemic to the western African countries of Ghana, Guinea, Guinea Bissau, Ivory Coast and Mali but has since disappeared. Throughout Loa loa-endemic regions, infection rates vary from 9 to 70 percent of the population. Areas at high risk of severe adverse reactions to mass treatment (with Ivermectin) are at present determined by the prevalence in a population of >20% microfilaremia, which has been recently shown in eastern Cameroon (2007 study), for example, among other locales in the region. Endemicity is closely linked to the habitats of the two known human loiasis veetors, Chrysops dimidiata an C. silicea.

Cases have been reported on occasion in the United States but are restricted to travelers who have returned from endemic regions.^[1] In the 1990s, the only method of determining Loa loa intensity was with microscopic examination of standardized blood smears, which is not practical in endemic regions. Because mass diagnostic methods were not available, complications started to surface once mass ivermectin treatment programs started being carried out for Onchocerciasis, another filariasis. Ivermectin, a microfilaricidal drug, may be contraindicated in patients who are co-infection with loiasis and have associated high microfilarial loads. The theory is that the killing of massive numbers of microfilaria, some of which may be near the ocular and brain region, can lead to encephalopathy. Indeed cases of this have been documented so frequently over the last decade that a term has been given for this set of complication: neurologic serious adverse events (SAEs).^[2]

Advanced diagnostic methods have been developed since the appearance the SAEs, but more specific diagnostic tests that have been or are currently being development (see: Diagnostics) must to be supported and distributed if adequate loiasis surveillance is to be achieved. The righthand image is the result of a geo-mapping study that has overlaid the endemicity of onchocerciasis with loiasis. As one can see, there is much overlap between the endemicity of the two distinct filariases, which complicates mass treatment programs for onchocerciasis and necessitates the development of greater diagnostics for loiasis.

In Central and West Africa, initiatives to control onchocerciasis involve mass treatment with Ivermectin. However, these regions typically have high rates of co-infection with both L. loa and O. volvulus, and mass treatment with Ivermectin can have severe adverse effects (SAE). These include hemorrhage of the conjunctiva and retina, hematuria, and other encephalopathies that are all attributed to the initial L. loa microfilarial load in the patient prior to treatment. Studies have sought to delineate the sequence of events following Ivermectin treatment that lead to neurologic SAE and sometimes death, while also trying to understand the mechanisms of adverse reactions to develop more appropriate treatments. In a study looking at mass Ivermectin treatment in Cameroon, one of the greatest endemic regions for both onchocerciasis and loiasis, a sequence of events in the clinical manifestation of adverse effects was outlined.

It was noted that the patients used in this study had a L. loa microfilarial load of greater than 3,000 per ml of blood.

Within 12–24 hours post-Ivermectin treatment (D1), individuals complained of fatigue, anorexia, and headache, joint and lumbar pain a bent forward walk was characteristic during this initial stage accompanied by fever. Stomach pain and diarrhea were also reported in several individuals.

By day 2 (D2), many patients experienced confusion, agitation, dysarthria, mutism and incontinence. Some cases of coma were reported as early as D2. The severity of adverse effects increased with higher microfilarial loads. Hemorrhaging of the eye, particularly the retinal and conjunctiva regions, is another common sign associated with SAE of Ivermectin treatment in patients with L. loa infections and is observed between D2 and D5 post-treatment. This can be visible for up to 5 weeks following treatment and has increased severity with higher microfilarial loads.

Haematuria and proteinuria have also been observed following Ivermectin treatment, but this is common when using Ivermectin to treat onchocerciasis. The effect is exacerbated when there are high L. loa microfilarial loads however, and microfilaria can be observed in the urine occasionally. Generally, patients recovered from SAE within 6–7 months post-Ivermectin treatment; however, when their complications were unmanaged and patients were left bed-ridden, death resulted due to gastrointestinal bleeding, septic shock, and large abscesses.^[3]

Mechanisms for SAE have been proposed. Though microfilarial load is a major risk factor to post-Ivermectin SAE, three main hypotheses have been proposed for the mechanisms.

The first mechanism suggests that Ivermectin causes immobility in microfilariae, which then obstructs microcirculation in cerebral regions. This is supported by the retinal hemorrhages seen in some patients, and is possibly responsible for the neurologic SAE reported. The second hypothesis suggests that microfilaria may try to escape drug treatment by migrating to brain capillaries and further into brain tissue; this is supported by pathology reports demonstrating a microfilarial presence in brain tissue post-Ivermectin treatment. Lastly, the third hypothesis attributes hypersensitivity and inflammation at the cerebral level to post-Ivermectin treatment complications, and perhaps the release of bacteria from L. loa after treatment to SAE. This has been observed with the bacteria Wolbachia that live with O. volvulus.

More research into the mechanisms of post-Ivermectin treatment SAE is needed to develop drugs that are appropriate to individuals suffering from multiple parasitic infections.^[3]

One drug that has been proposed for the treatment of onchocerciasis is doxycycline. This drug has been shown to be effective in killing both the adult worm of O. volvulus and Wolbachia, the bacteria believed to play a major role in the onset of onchocerciasis, while having no effect on the microfilaria of L. loa. In a study done at 5 different co-endemic regions for onchocerciasis and loiasis, doxycycline was shown to be effective in treating over 12,000 individuals infected with both parasites with minimal complications. Drawbacks to using Doxycycline include bacterial resistance and patient compliance because of a longer treatment regimen and emergence of doxycycline-resistant Wolbachia. However, in the study over 97% of the patients complied with treatment, so it does pose as a promising treatment for onchocerciasis, while avoiding complications associated with L. loa co-infections.^[4]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Kalsang Dolma, M.B.B.S.[2]

The people most at risk for loiasis are those who live in the high-canopied rain forests of West and Central Africa. The deerflies that transmit the parasite typically bite during the day and are more common during the rainy season. They are attracted by the movement of people and by smoke from wood fires. Rubber plantations create a favorable environment for the flies, as the trees form a dense canopy.

The people most at risk for loiasis are those who live in the high-canopied rain forests of West and Central Africa. The deerflies that transmit the parasite typically bite during the day and are more common during the rainy season. They are attracted by the movement of people and by smoke from wood fires. Rubber plantations create a favorable environment for the deerflies, as the trees form a dense canopy. The flies do not typically enter homes, but might be attracted to homes that are well lit.

Travelers to at-risk areas who stay for long periods of time are more likely to become infected than short-term travelers, though a few cases have been documented in persons who were in at-risk areas for less than one month. A traveler’s risk for infection likely will depend on the number of bites received and the number of infected deerflies in the area visited.

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