Loiasis (African Eye Worm)

Loiasis, commonly known as "African eye worm," is an infectious disease caused by the nematode Loa loa, which is transmitted to humans via the bite from one of two female Chrysops deerfly species: Chrysops silacea and Chrysops dimidiata. The risk of infection is highest in the rainforests of West and Central Africa and during the rainy season, when the deerfly (or mango fly or mangrove fly, as they are commonly known) are most prevalent. It is estimated that 3-13 million people have loiasis.[1] It is estimated that more than 10 million people have loiasis, with over 14 million people at risk for infection.[2]

The worm larvae that Chrysops flies deposit in human hosts mature into adults, which commonly reside in subcutaneous tissue. Most L loa infections are asymptomatic, although some progress to loiasis, which is characterized by localized painful subcutaneous joints (calabar swellings) and the migration of adult worms through the subconjuctiva of the eye.

Loiasis is commonly known as "African eye worm," since the adult form of the parasite can sometimes be found migrating across the conjunctiva of the eye. Repeated forest exposure involving repeated bites from infected flies increases the risk of infection and disease.[3]

L loa is endemic in eleven West and Central African countries, as follows (listed alphabetically):

• Angola
• Cameroon
• Central African Republic
• Chad
• Congo
• Democratic Republic of Congo
• Equatorial Guinea
• Ethiopia
• Gabon
• Nigeria
• Sudan

Ten of these countries have foci where the prevalence of infection exceeds 40%, a strong indicator of high-risk communities.[4] An estimated 14.4 million people live in these regions of high prevalence.[5] This range overlaps significantly with that of onchocerciasis and is of great epidemiological significance, since ivermectin, the major and most effective treatment for onchocerciasis, often leads to severe, and sometimes fatal, complications in individuals who are co-infected with L loa.[6]

L loa microfilariae mature into their infective third-stage larval forms in their Chrysops hosts, a process that typically takes 10-12 days to complete. These larvae make their way into humans when female flies take blood meals and migrate from the proboscis of an infected fly to the bite wound it creates.

Chrysops bites are typically quite painful, since, unlike mosquitoes, which use their probosces to puncture skin and suck blood out of their hosts, these flies use their probosces to create lacerations in the host’s skin and then lap up the blood from the wound that they create. When interrupted during a blood meal, Chrysops flies have been known to make new lacerations to continue to feed from the same host owing to the female's high blood demand for reproductive purposes.[7] In their human hosts, larvae migrate through the lymphatic system and mature into adults, residing in subcutaneous tissue for approximately 19 days.

Inside the human host, larvae migrate to the subcutaneous tissue, where they mature into adult worms in approximately 1 year, although maturation can take up to 4 years.[7] Adult worms may live up to 17 years in subcutaneous tissue.[8] The migration of adult L loa worms through subcutaneous host tissue provokes the host’s immune response to this migration, causing many of the characteristic symptoms of loiasis, such as urticaria, pruritus, and calabar swelling (painful swelling in the joints). Occasionally, adult worms migrate through the subconjunctiva of the eye and are visible therein, giving rise to the disease's common name, "African eye worm."

Once fertilized, female worms release thousands of microfilariae per day (up to 22,000). These microfilariae accumulate in the pulmonary circulation, which serves as a reservoir from which they invade peripheral blood systems. Only a fraction of the microfilariae in the lungs exit into circulation, a process that may be mediated by their age. About 17 months pass between the introduction of L loa larvae into the host and the appearance of microfilariae in the blood. Microfilariae have lifespans of approximately 6-12 months, and the cycle of infection is continued when Chrysops flies feed on the blood of humans with microfilariae in their blood.[8]

L loa has diurnal periodicity, meaning that levels of microfilariae are higher in the blood during the daytime, typically highest between 10:00 am and 3:00 pm, which coincides with the maximum activity hours of the ​Chrysops vector.[8] However, microfilariae have also been found in blood samples collected at night.[9]

Loiasis is caused by infection with L loa (tissue nematode) parasites transmitted by Chrysops flies (commonly known as the mango fly or mangrove fly). The adult L loa worm can migrate across the subconjunctiva of the human eye, giving rise to the worm's colloquial name, "African eye worm." Beyond this ocular pathology, loiasis also commonly manifests as skin findings (urticaria and pruritus), swelling (calabar swelling), and joint pain due to the immune reaction against the parasite.[10]

Frequency

United States

Loiasis is not acquired in the United States. Some cases have been reported in travellers and immigrants from endemic areas. Months to years of exposure are typically required to establish infection, although some cases have been reported after as little as four days of exposure.

International

L loa is endemic in eleven West and Central African countries, as follows (listed alphabetically):

• Angola
• Cameroon
• Central African Republic
• Chad
• Congo
• Democratic Republic of Congo
• Equatorial Guinea
• Ethiopia
• Gabon
• Nigeria
• Sudan

Ten of these countries have foci where the prevalence of infection exceeds 40%. An estimated 14.4 million people live in these regions of high prevalence.[5] In these regions, the vast majority of infections are asymptomatic, so the range and endemicity of loiasis in many regions have not yet been determined.

The range of loiasis overlaps significantly with that of onchocerciasis and is of great epidemiological significance, since ivermectin, the major and most effective treatment for onchocerciasis, often leads to severe, and sometimes fatal, complications when administered to individuals infected with L loa.[6, 11] Furthermore, L loa infection may be misdiagnosed as onchocerciasis based on skin snip, potentially underestimating the prevalence of loiasis in co-endemic areas.[12]

The probability of infection has been found to increase with age and depends on vector abundance, which, in turn, depends on local ecology. Disease and vector infection rates are significantly higher in forested areas, the natural habitats of the Chrysops vectors, than in other ecological settings such as grassland savannas, sunlit riverbanks, forest clearings, and villages.[13]

The Chrysops vectors that carry L loa typically bite during the daytime and are most prevalent during the rainy season. They preferentially take blood meals from humans, although some nonhuman hosts have been identified (rodents and large wild animals such as buffalo and hippopotamuses).[14] They are attracted to signs of human activity, such as movement and smoke from wood fires.[7]

Morbidity/Mortality

Although L loa infections are typically described as benign and the vast majority of cases are asymptomatic, a 2017 retrospective review of 28 Cameroonian villages found heightened mortality rates (4.1%) in individuals with over 30,000 microfilariae per mL of blood, as well as significantly earlier deaths among individuals older than 25 years with over 30,000 microfilariae per mL of blood, compared to amicrofilaremic individuals, suggesting an increased mortality rate associated with high-grade L loa infection.[15]

Beyond these findings, many complications due to L loa infection have been described, albeit in a minority of cases. Worm migration through the subconjunctiva may progress to invasion of the eye itself by adult worms, causing pain, intraocular inflammation, and even blindness.[16]

In addition, encephalitis is known to occur in individuals with L loa infection, often due to administration of diethylcarbamazine (DEC) or ivermectin, drugs used in the treatment of other nematode infections, such as onchocerciasis (river blindness). This encephalitis may lead to events such as coma and may be fatal.[17]

Endomyocardial fibrosis has also been observed in cases of chronic loiasis and may progress to cardiomyopathy and, sometimes, death.[18, 19]

Renal involvement has also been reported in loiasis. Kidney failure due to loiasis-related nephropathy is uncommon but has been documented.[19]

Sex

Loiasis may be more common in males than in females,[11, 20] potentially owing to differences in outdoor exposure and occupations.[7]

Age

The prevalence of loiasis in a population increases with age,[11, 2]

Patients with L loa infection must have been exposed to the competent vector within the endemic areas in Africa. The diagnosis should be considered with such exposure in the setting of eosinophilia, urticaria, subcutaneous swellings, and joint pain. Less commonly, some patients report a history of visualizing the migrating adult worm across the conjunctiva. This transient event, which may last between 30 and 60 minutes,[8] is notable for some eye irritation described as sand in the eye with movement.

Symptoms of loiasis reflect the developmental stage of the parasite and the degree of immune response by the host. Clinical manifestations are highly variable between temporary residents of endemic areas and people native to these areas. Visitors and expatriates had low levels of microfilariae yet exhibited marked immunological hyperresponsiveness (symptomaticity). In contrast, people living in endemic regions were often asymptomatic despite high levels of circulating microfilariae.[19]

Symptoms of loiasis do not appear until after the L4 larvae mature into adult worms. Clinical symptoms may appear as soon as 5 months but up to 13 years (average, 17 months) after the initial infecting bite. The interval between the acquisition of the parasite and onset of symptoms is sometimes referred to as the prepatent phase.[8]

L loa is transmitted by the bite of infected Chrysops flies. The fly bites during daylight hours. Chrysops flies can be found in the tropical rainforests of West and Central Africa, are attracted to movement and smoke from wood fires, and are most abundant during the rainy season.[1, 7]

Most L loa infections are asymptomatic, and many symptoms result from adult worm migration or the host immune response to adult worms or the microfilariae they produce.[1, 8]

Physical examination may reveal skin findings such as urticaria accompanied by pruritus. The next most common finding in patients with chronic or longer-term infection is joint swelling with pain (calabar swelling), which may be seen in the wrists and elbows or lower-extremity joints. These swellings are related to angioedema (associated with immune reactions) and are nonpitting and nontender and often associated with localized pruritus. They may disappear spontaneously, typically after a few days, and then reappear on any part of the body at irregular intervals.[8]

Adult female worms are 40-70 mm in length and 0.5 mm in diameter; males are 30-34 mm in length and 0.35-0.43 mm in diameter.[7] ​ The migration of an adult worm across the conjunctiva may be felt or observed by the patient, accompanied by itching and photophobia. The worm may take between 30 to 60 minutes or up to 1 day to transit across the eye in the conjunctival space.[8]

Although L loa infections are typically described as benign and the vast majority of cases are asymptomatic, a 2017 retrospective review of 28 Cameroonian villages found heightened mortality rates (4.1%) in individuals with over 30,000 microfilariae per mL of blood, as well as significantly earlier deaths among individuals older than 25 years with over 30,000 microfilariae per mL of blood, compared to amicrofilaremic individuals, suggesting an increased mortality rate associated with high-grade L loa infection.[15]

Beyond these findings, many complications due to L loa infection have been described, albeit in a minority of cases. Worm migration through the subconjunctiva may progress to invasion of the eye itself by adult worms, causing pain, intraocular inflammation, and even blindness.[16]

In addition, encephalitis is known to occur in individuals with L loa infection, often due to administration of diethylcarbamazine (DEC) or ivermectin, drugs used in the treatment of other nematode infections, such as onchocerciasis (river blindness). This pathology is believed to result from the high microfilaricidal effects of these drugs and the immune system's response to dead microfilariae in blood. Most such cases of encephalitis have been found in individuals with over 30,000 microfilariae per mL of blood, although neurologic symptoms have been observed in patients with lower levels of microfilariae in the bloodstream.[21, 22] This encephalitis may lead to events such as coma and may be fatal.[17]

Endomyocardial fibrosis has been observed in cases of chronic loiasis and may progress to cardiomyopathy and, sometimes, death.[18, 19] ​ These cardiac manifestations of infection are associated with eosinophilia and eosinophilic infiltration of the heart and its tissue,[23] which typically results from the immune response to L loa infection.[24]

Renal involvement has also been reported in individuals with loiasis. The mechanisms that mediate this involvement are unclear, but the immune response is believed to play some role. Kidney failure due to loiasis-related nephropathy is uncommon but has been documented.[19]

While eye worms are pathognomonic for loiasis, skin and joint findings (urticaria, pruritus, swelling) may be more common than the ocular pathology for which loiasis is named ("African eye worm"). The diagnosis should be considered in individuals from endemic areas who have eosinophilia and no other findings.[25]

Definitive diagnosis can be made by visualizing L loa microfilariae in blood samples collected for Giemsa staining during peak transit times or by pathologic review of the morphology of worms recovered from tissue or the eye.[8]

Serologic testing is not readily or commercially available but can be performed at specialized centers (eg, US CDC), although these tests have some cross-reactivity with other tissue filaria (onchocerciasis and filariasis). Only one PCR test for loiasis is available in the United States,[25] although it may fail to detect infection during the prepatent period and may detect DNA from dead or dying microfilariae.[8] Owing to these persistent DNA remnants, a test of cure is not indicated after proper treatment.

Pathological Diagnosis

The standard diagnostic test for loiasis is the demonstration of microfilariae on Giemsa-stained thin or thick blood smear using blood collected during the daytime (10:00 am to 2:00 pm).[25] The timing of the blood collection for smear should be adjusted to reflect the local time at the point of origin in a traveler who is still experiencing jetlag. Concentration techniques such as NucleporeTM filtration (Whatman Inc., Florham Park, NJ), Knott concentration, or saponin lysis may increase the diagnostic yield in persons with low numbers of circulating microfilariae. Identification of microfilariae on blood smear is sufficient for diagnosis of the infection. In addition, a definitive diagnosis can be made by identifying a migrating adult worm in subcutaneous tissues or the conjunctiva.

Quantification of the number of microfilariae per mL is needed to direct treatment.[25]

Immunodiagnosis

While serology tests exist to assist in the diagnosis of loiasis, they are not readily or commercially available, and these tests may cross-react with various other similar tissue nematodes such as onchocerciasis and filariasis. In addition, these serologic tests may indicate that the patient has been exposed to L loa but may not distinguish if they have active infection or prior exposure. For these reasons, they are typically less useful in endemic contexts, although negative results decrease the possibility of L loa infection.[25]

One L loa–specific Ig(G4) enzyme-linked immunoabsorbent assay (ELISA) test has been developed and deployed in some endemic contexts, revealing a sensitivity and specificity of 80% and 78%, respectively, in patients with microfilaremia, as well as significant levels of L loa–specific Ig(G4) antibodies in 55% of patients tested with no detectable microfilaria in blood, suggesting occult infection in this group. Despite the limited sensitivity and specificity of this method, it may serve as a useful tool to estimate the prevalence of loiasis in endemic regions.[26]

In addition, an Ig(G4) assay for loiasis has been developed, and it showed no reaction when used in noninfected individuals, including those with other forms of filariasis. However, the assay failed to distinguish between microfilaremia and amicrofilaremia (occult infection).[27]

Antigen Detection

Other serologic techniques and assays using recombinant L loa have been developed, including a highly sensitive and specific (96% and 100%, respectively) luciferase immunoprecipitation system (LIPS), which detects antibodies to the recombinant L loa antigen LISXP-1.[28]

Nucleic Amplification Tests

One polymerase chain reaction (PCR) test for loiasis has been approved for diagnosis in the United States. PCR-based techniques have been developed, with specificities and sensitivities as high as 100% and 95%, respectively.[29] However, these techniques yield negative results during prepatency and often return false-positive results in individuals with previous L loa infections, as they also detect DNA from dead microfilariae in blood.[8]

Real-time qPCR assays have also been developed with highly species-specific and -sensitive (96%) detection rates for L loa.[30] These have been adapted for loop-mediated isothermal amplification (LAMP), allowing the potential for point-of-care and in-field use to detect microfilariae.[31, 32]

According to the CDC, the standard diagnostic test for loiasis is the demonstration of microfilariae on Giemsa-stained thin or thick blood smear using blood collected during the daytime (10:00 am to 2:00 pm). The timing of the blood collection for smear should be adjusted to reflect the local time at the point of origin in a traveler who is still experiencing jetlag. Concentration techniques such as NucleporeTM filtration (Whatman Inc., Florham Park, NJ), Knott concentration, or saponin lysis may increase the diagnostic yield in persons with low numbers of circulating microfilariae. Identification of microfilariae on blood smear is sufficient for diagnosis of the infection. Quantification of the number of microfilariae per mL is needed to direct treatment.[25]

Currently, three drugs are used to treat loiasis: diethylcarbamazine (DEC), albendazole (ALB), and ivermectin (IVM). The treatment strategy depends on the risk of adverse events, which is related to the patient’s microfilarial (mf) density.[33]

Microfilarial density below 2000 mf/mL

DEC can be administered straightaway. DEC is the only drug of the three to have a proven macrofilaricidal (lethal to adult worms) and microfilaricidal effects.

Start with 3 or 6 mg/day if microfilaremic or 50 mg/day if amicrofilaremic, divided into 2-3 doses. The dosage is doubled every day until 400 mg/day (or 8-10 mg/kg/day) is reached, lasting 3-4 weeks.

Antihistamines or corticosteroids may be useful initially to reduce the severity of adverse effects (eg, pruritus, angioedema, fever). However, a 2020 study found that, by one year following the first round of DEC treatment, L loa infection in both microfilaremic and amicrofilaremic patients had resolved to levels seen in uninfected individuals, with pretreatment corticosteroids or apheresis not affecting the efficacy of DEC.[34]

Several courses of DEC may be needed, although more than four courses is rarely indicated. In patients with DEC-refractory loiasis, a course of ALB (200 mg twice a day for 21 days) can be useful. Short courses of ALB likely have an embryotoxic effect (interrupts embryogenesis in adult female worms) and a macrofilaricidal effect.

Microfilarial densities between 2000 and 8000 mf/mL

Begin with a single dose of IVM of 150 µg/kg. Treatment with IVM can be repeated at intervals of 1-3 months to further reduce the microfilarial loads.

When the microfilaremia is less than 2000 mf/mL, a course of DEC can be started using the protocol above.

Microfilarial densities between 8000 and 30,000 mf/mL

IVM can also be given to reduce loads below 2000 mf/mL, with close surveillance/hospitalization during the first few days.

Alternatively, start with a course of ALB (200 mg twice daily for 21 days) to reduce the microfilarial load; then, continue with IVM treatment until 2000 mf/mL is reached.

Microfilarial densities above 30,000 mf/mL

ALB is probably the best option, although the effect of long courses of ALB has never been evaluated in patients with such high loads. DEC and IVM can induce potentially fatal encephalopathy in patients with loads over 30,000 mf/mL.

Apheresis, which rapidly reduces microfilarial loads by 75% after three sessions, has also been proposed but is expensive and unnecessary given the usually mild manifestations of loiasis.

DEC is not FDA-approved and is not readily available or sold in the United States but can be obtained through the CDC Drug Service after confirmed diagnosis (telephone: [404] 718-4745; email: parasites@cdc.gov).[35]

 

To be surgically removed from a patient's eye, the L loa worm should be forcibly immobilized with forceps over the conjunctiva. An incision is then made in the conjunctiva to remove the worm. Surgical removal of the L loa worm from the eye is a temporizing but not definitive treatment, as the risk of invasion by other worms in the body persists. Surgery to remove migrating worms from the eye is generally safe and relieves symptoms from the transiting adult worm and allows for a definitive diagnosis with pathologic review of the specimen. Pilocarpine should not be used, since it is a known irritant to the adult L loa worm and may cause it to disappear into deeper tissue.[36]

In patients with high microfilarial loads, the administration of rapidly microfilaricidal agents, such as ivermectin and DEC, may cause serious adverse effects, often resulting from the immune response to dead microfilariae. These adverse effects may include encephalitis,[22] cardiomyopathy,[18] renal failure, and even death.[19] To avoid adverse reactions in these patients, albendazole or apheresis is first used to reduce microfilarial loads before other agents are given.[33]

However, a 2016 study showed that even 6 doses of 800-mg albendazole every 2 months for 24 months was not sufficient to reduce microfilaricidal loads to below 8100 mf/mL in patients whose initial levels exceeded30,000 mf/mL, suggesting a need to further study pretreatment methods.[37]

Co-infection with onchocerciasis (river blindness) is notable because ivermectin, the major treatment for onchocerciasis, often leads to severe or fatal complications in patients coinfected with L loa. Conversely, DEC, the primary treatment for low-level L loa infection, can result in a severe systemic reaction (Mazzotti reaction) in individuals with onchocerciasis.[38] In areas with high co-infection rates, a test-and-not-treat (TaNT) strategy may be used to exclude those with high L loa microfilarial density from ivermectin treatment. As shown in a 2017 study in Cameroon, such exclusions of those with over 20,000 mf/mL resulted in no serious adverse events.[39] Although more costly than routine ivermectin mass drug administration (MDA) ($2.20 per person in the population versus $4), the TaNT strategy remains affordable and offers significant safety and elimination benefits.[40]

In most patients, comorbid loiasis and onchocerciasis can also be treated safely via clearance of some microfilariae with ivermectin prior to DEC treatment. Alternatively, doxycycline, which has both microfilaricidal and macrofilaricidal activity in onchocerciasis owing to its effect on the intracellular bacteria Wolbachia can be used safely in patients coinfected with low levels of L loa.[41]

The following specialists may be consulted in the management of loiasis:

• Ophthalmologist
• Infectious disease specialist
• Dermatologist

L loa infection and loiasis are prevented by avoiding the bites of daytime biting competent vector flies in endemic areas.[7] This can be done using permethrin-treated clothing or screening, as well as DEET-containing repellents.

Chemoprophylaxis strategies have also been described, using diethylcarbamazine (DEC) 300 mg PO once weekly or DEC 200 mg twice daily for 3 days each month while in an endemic area for long periods.[42] Mass drug administration (MDA) of DEC may reduce transmission in these areas but is complicated by the high rate of coinfection with onchocerciasis and, in some cases, lymphatic filariasis, which introduces the risk of severe adverse effects.[7] However, MDA of ivermectin to treat onchocerciasis has also been shown to substantially reduce microfilarial density for L loa for at least one year with no risk of severe adverse effects in patients with a microfilarial density of less than 20,000 mf/mL.[43]

Prevalence Estimation

RAPLOA (Rapid Assessment Procedure for L loa) is a WHO procedure to assess the endemicity and prevalence of L loa in communities with suspected L loa infection. It consists of a questionnaire designed to take advantage of the observation that, in communities with high prevalence of L loa infection, the characteristic symptoms of loiasis are well-known and often have local names, whereas this is often not the case where the prevalence of infection is low or nonexistent. The proportion of interviewees reporting a history of eye worm has also been shown to correlate with parasitological indicators of disease prevalence. A threshold of 40% of respondents reporting a history of eye worm adequately identifies communities where the prevalence of L loa and the risk of severe adverse reactions is predicted to be too high for routine ivermectin treatment.

The steps of the RAPLOA procedure are as follows:

• Step 1: Identification of local names for eye worm and the typical symptoms of L loa infection
• Step 2: A survey of 80 adults on the history of eye worm
• Step 3: Calculation of percentage of adults reporting a history of eye worm; used to predict infection prevalence ^[44]

The goals of pharmacotherapy are to eradicate the infection, to reduce morbidity, and to prevent complications. Treatment involves microfilaricidal and/or macrofilaricidal agents, as follows:[33]

• If the microfilarial density is below 2000 mf/mL, DEC should be administered straightaway.
• If the microfilarial density is between 2000 and 8000 mf/mL, ivermectin should be used to reduce microfilaremia to less than 2000 mf/mL for DEC treatment.
• If the microfilarial density is between 8000 and 30,000 mf/mL, ivermectin or albendazole should be used to reduce microfilaremia to less than 2000 mf/mL for DEC treatment.
• If the microfilarial density is above 30,000 mf/mL, albendazole or apheresis should be used to reduce microfilaremia to less than 2000 mf/mL for DEC treatment.

Individuals treated with ivermectin do not need to be retested for microfilarial density before the next treatment, as over 99.9% remain below the level associated with severe complications.[45]

Diethylcarbamazine

Not commercially available in the United States (available only through the CDC). Has both microfilaricidal and macrofilaricidal effects. For use in cases of symptomatic loiasis parasitemia of less than 8000 L loa microfilariae/mL. Serves as an inhibitor of arachidonic acid metabolism in microfilaria.

CDC guidelines (adult and pediatric dose): 8-10 mg/kg/day orally in 3 divided doses daily for 21 days

Alternatively: 3 or 6 mg/day if microfilaremic or 50 mg/day if amicrofilaremic, divided into 2-3 doses; dosage doubled every day until 400 mg/day (or 8-10 mg/kg/day) is reached, lasting 3-4 weeks

Albendazole (Albenza)

Has microfilaricidal effects. For treatment of symptomatic loiasis with parasitemia of over 30,000 mf/mL to reduce level to less than 2000 microfilariae/mL prior to treatment with DEC.

Dose: 200 mg orally twice daily for 21 days.

Ivermectin (Stromectol)

Has microfilaricidal effects. For treatment of symptomatic loiasis with parasitemia between 2000 and 30,000 mf/mL to reduce level to less than 2000 microfilariae/mL prior to treatment with DEC.

Dose: 150 µg/kg, repeated at intervals of 1-3 months, as needed