Loiasis

 

Introduction

The adult Loa loa filarial worm migrates throughout the subcutaneous tissues of humans, occasionally crossing into subconjunctival tissues where it can be easily observed. This presentation led to the popular name, the African eye worm. Loa loa does not normally affect one’s vision but can be painful when moving about the eyeball or across the bridge of the nose. [16][7] The disease is, as of 2009, endemic to 11 western and central African countries, particularly in forested and swampy areas, and affects an estimated 12-13 million people, all in Africa. Geographically, the disease is limited by the location of the two tabanid vectors, Chrysops silicea and C. dimidiata, which prefer rainforest-like environments of west and central Africa. Endemicity is particularly high in Cameroon, Congo, the Democratic Republic of Congo, Central African Republic, Equitorial Guinea, Nigeria, and Gabon. [17][10]          

                                   

Image Source: [12]

 

An area of tremendous concern regarding loiasis is its co-endemicity with onchocerciasis in certain areas of west and central Africa, as mass ivermectin treatment of onchocerciasis can lead to serious adverse events (SAEs) in patients who have high Loa loa microfilarial densities, or loads. This fact necessitates the development of more specific diagnostics tests for Loa loa so that areas and individuals at a higher risk for neurologic consequences can be identified prior to microfilaricidal treatment. Additionally, the treatment of choice for loiasis, diethylcarbamazine, can lead to serious complications in and of itself when administered in standard doses to patients with high microfilarial loads. [7]

 

Agent (classification and taxonomy)

Loa loa is a filarial nematode that causes loiasis. It is part of a group of parasitic filarial nematodes that cause lymphatic filariasis (Wuchereria bancrofti and Brugia spp), onchocerciasis (Onchocerca volvulus) and mansonelliasis (Mansonella spp.). [7]

 

The taxonomic classification of Loa loa is as follows: [9]

 

Synonyms

Synonyms for the disease include Loaiasis, Loaina, Loa loa filariasis, Filaria loa, Filaria lacrimalis, Filaria subconjunctivalis, Calabar swellings, Fugitive swellings, Loaina, and Microfilaria diurnal. [10] Loa loa, the scientific name for the infectious agent, is a "Native" term itself and many other terms are used from region to region for loiasis and the relatively common angioedema (Calabar swellings) associated with the disease. [7][18]

 

History of Discovery

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 Francois 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 identification of microfilaria was made in 1890 by the ophthalmologist Stephen McKenzie. 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 Thompson Leiper. [3]

 

Clinical Presentation in Humans

Human infections with Loa loa is often asymptomatic. When symptoms do precipitate, they often take the form of one or more of the following clinical features: localized angioedema, migration of the adult worm producing urticaria and pruritus, microfilaremia, eosinophilia, and variable antibody levels.[4] Localized angioedema, or Calabar swellings (named for the coastal Nigerian town where they were first noted), most often affects the upper limbs (especially the hands) or lower limbs, and sometimes the face. They may be red and have associated pruritus (itching). Loa loa worms are not necessarily in the swellings at the time they become visible, but that is the case in the image shown here, courtesy of McGill Medicine. [12]               

 

Image Source: [12]

 

If microfilaremia manifests, it takes approximately 6-12 months to present, and the microfilariae have diurnal periodicity. They can be found in the blood, lungs, urine, spinal fluid, or sputum. Approximately one-third of loiasis cases are amicrofilaremic. [7]

 

In addition to distinct “Calabar swellings” that primarily affect the limbs, migration of adult worms can cause angioedema of the ocular region, including the eyelid. A patient presenting with swellings in this area is likely to have experienced the migration of an adult worm in the subconjunctival tissues, which at that point in time caused an allergic reaction and the visible swelling.

 

Eosinophilia is present in almost all cases of loiasis, often being very intense. Blood tests can be done to test for fraction of eosinophiles (of total white blood cell count), and this can be one basis for diagnosis. [7]

 

In very rare instances, Loa loa can infect the tunica vaginalis or spermatic cord, causing hydrocele and orchitis, the bowel wall, causing associated lesions and/or obstruction, and other systems such as the vasculature, kidneys, and nervous system. [7]

 

Transmission

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. [17]

 

Reservoir

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. Studies have indicated—but not necessarily proved—that there is no cross-over between the human and simian types of the disease. [5]

 

Vector

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. [20]

 

Image Source: [11]

 

Chrysops spp are small (5-20mm long) with a large head and downward pointing mouthparts. [17][20] 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. [17] Fly larvae are 1-6 cm long and take 1-3 years to mature from egg to adult. [20] When fully mature, C. silacea and C. dimidiata assume the day-biting tendencies of all tabanids. [17]

Image Source: [12]

 

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. [20]

 

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. [5] 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. [17]

 

A Cameroon study of Chrysops spp biting habits showed that C. silacea and C. dimidiata take human blood meals approximately 90% of the time, with hippopotamus, 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. [5]

 

Incubation Period

In the human host, Loa loa larvae migrate to the subcutaneous tissue where they mature to adult worms in approximately one year, but sometimes up to four years. Adult worms migrate in the subcutaneous tissues, mating and producing more microfilaria. The adult worms can live up to 17 years in the human host. [17]

 

Morphology

Adult Loa worms are sexual, with males considerably smaller than females at 30-34mm long and 0.35-0.42mm wide compared to 40-70mm long and 0.5mm wide. Adults live in the subcutaneous tissues of humans, where they mate and produce worm-like eggs called microfilaria. These microfilariae are 250-300mm long, 6-8mm wide, and can be distinguished morphologically from other filariae—they are sheathed and contain body nuclei that extend to the tip of the tail. [7]

 

(Above) Image Source: [7]

(Below) Image Source: [12]

 

Life Cycle

The life cycle of Loa loa is fairly simple, and involves both the fly vector (and intermediate host) and the human host. In the Chrysops fly vector, ingested Loa loa microfilaria lose their sheaths while migrating from the midgut of the mango or deerfly to the thoracic muscles via the haemocoel. Once in the midgut, they undergo development through several larval stages. Upon maturation to the third larval stage, the larvae return to the head of the fly and exit humans through the Chrysops laceration-like bite.

 

After being transmitted to the human host through the vector’s bite wound, microfilaria migrate to the subcutaneous tissues where they mature over the next 1-4 years. When they developed into adult worms, migration about the subcutaneous tissues (including the conjunctival tissues) takes place. Male and female adult worms mate and produce more microfilaria, which have diurnal periodicity and make their way into the blood, lungs, urine, spinal fluid, or sputum. [7]

 

When the Chrysops vector take a blood meal from a microfilaremic host, the vector becomes infected and the cycle begins again. (Image: the CDC’s pictographic Loa loa life cycle).

 

Diagnostic Tests

Physically, Calabar swellings (see image) are the primary tool for diagnosis. Adult worms migrating across the eye are another potential diagnostic, but the short timeframe for the worm’s passage through the conjunctiva makes this harder to achieve.

 

Image Source: [11]

 

In the past, health care providers used a provocative injection of Dirofilaria iminitis as a skin test antigen for filariasis diagnosis. If the patient was infected, the extract would cause an artificial allergic reaction and associated Calabar swelling similar to that caused, in theory, by metabolic products of the worm or dead worms. [7]

 

Blood tests to reveal microfilaremia and eosinophilia are useful in many, but not all cases, as one third of loiasis patients are amicrofilaremic. [7]

 

According to the Institute for Tropical Medicine, no serologic diagnostics are available. [11] However, serologic tests that are highly specific to Loa loa were furthered in 2008; they have not gone point-of-care yet, but show promise for highlighting high-risk areas and individuals with co-endemic loiasis and onchocerciasis. Specifically, Dr. Thomas Nutman and colleagues at the National Institutes of Health have described the luciferase immunoprecipitation assay (LIPS) and the related QLIPS (quick version). Whereas a previously described LISXP-1 ELISA test had a poor sensitivity (55%), the QLIPS test is both practical, as it requires only a 15 minutes incubation, and has high sensitivity and specificity (97% and 100%, respectively). [1] No report on the distribution status of LIPS or QLIPS testing is available, but these tests would help to limit complications derived from mass ivermectin treatment for onchocerciasis or dangerous strong doses of diethylcarbamazine for loiasis alone (as pertains to individual with high Loa loa microfilarial loads).

 

Management and Therapy

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), though ivermectin is suitable. The recommend dosage of DEC is 6 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). [13]

 

In patients with high microfilarial 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. [14]

 

Image Source: [14]

 

Management of Loa loa infection in some instances can involve surgery, though the timeframe during which surgical removal of the worm must be carried out is very short. A detailed surgical strategy to remove an adult worm is as follows (from a real case in New York City). The 2007 procedure to remove an adult worm from a male Gabonian immigrant (see image above) employed proparacaine and povidone-iodine drops, a wire eyelid speculum, and 0.5ml 2% lidocaine with epinephrine 1:100,000, injected superiorly. A 2-mm incision was made and the immobile worm was removed with forceps. Gatifloxacin drops and an eye-patch over ointment were utilized post surgery and there were no complications (unfortunately, the patient did not return for DEC therapy to manage the additional worm—and microfilaria—present in his body). [14]

 

Epidemiology

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:

Š      Cameroon

Š      Congo

Š      Democratic Republic of Congo

Š      Central African Republic

Š      Nigeria

Š      Gabon

Š      Equatorial Guinea.

The rates of Loa loa infection are lower but still felt in Benin, Chad, Uganda, and Angola. The disease was once endemic to the western African countries of Ghana, Ivory Coast, Mali, Guinea, and Guinea Bissau but has since disappeared. [10]

 

Throughout Loa loa-endemic regions, infection rates vary from 9% to 70% of the population. [7] Areas at high risk of severe adverse reactions to mass treatment (with Ivermectin) are at current 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. [10]

 

Endemicity is closely linked to the habitats of the two known human loiasis vectors, Chrysops silicea and C. dimidiata.

 

Cases have been reported on occasion in the United States but are restricted to travelers who have returned from endemic regions. [6][14]

 

The Challenge of Onchocerciasis and Loiasis Co-Endemicity

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, which is a microfilaricidal drug, can 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). [8]

 

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 above images are the results of geo-mapping studies that have overlaid the endemicity of onchocerciasis with loiasis. [19] 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.

 

Public Health and Prevention Strategies/Vaccines

Diethylcarbamazine has been shown as an effective prophylaxis for Loa loa infection.

A study of Peace Corps volunteers in the highly Loa­-endemic Gabon, for example, had the following results: 6 or 20 individuals in a placebo group contracted the disease, compared to 0 of 16 in the DEC-treated group. Seropositivity for antifilarial IgG antibody was also much higher in the placebo group. The recommended prophylactic dose is 300 mg DEC given orally once per week. The only associated symptom in the Peace Corps study was nausea. [15][10]

 

Researchers believe that geo-mapping of appropriate habitat and human settlement patterns may, with the use of predictor variables such as forest, land cover, rainfall, temperature, and soil type, allow for estimation of Loa loa transmission in the absence of point-of-care diagnostic tests. [19] In addition to geo-mapping and chemoprophylaxis, the same preventative strategies used for malaria should be undertaken to avoid contraction of loiasis. Specifically, DEET-containing insect repellent, permethrin-soaked clothing, and thick, long-sleeved and long-legged clothing ought to be worm to decreased susceptibility to the bit of the mango or deerfly vector. Because the vector is day-biting, mosquito (bed) nets unfortunately do not increase protection against loiasis.

 

Vector elimination strategies are an interesting consideration. It has been shown that the Chrysops vector has a limited fly range, [2] but vector elimination efforts are not common, likely because the insects bite outdoors and have a diverse, if not long, range, living in the forest and biting in the open, as mentioned in the vector section.

 

No vaccine has been developed for loiasis and there is little report on this possibility.

 

Useful Web Links

 

 

 

References

1.    Burbelo, Peter D., Roshan Ramanathan, Amy D. Klion, Michael J. Iadarola, and Thomas B. Nutman. “Rapid, Novel, Specific, High-Throughput Assay for Diagnosis of Loa loa Infection.” 2008. J Clin Microbio 46(7): 2298-2304.

2.    Chippaux, J.P., B. Bouchité, M. Demanou, I. Morlais, and G. LeGoff. “Density and dispersal of the loaiasis vector Chrysops dimidiata in southern Cameroon.” 2000. Med Vet Entomol 14: 339-344.

3.    Cox, F. E. G. “History of Human Parasitology.” 2002. Clin Microbiol Rev 15(4): 595-612.

4.    Franco-Paredes, Carlos. “Filariasis Caused by Loa loa Is Also a Cause of Angioedema.” 2008. Amer J Med 34(4).

5.    Gouteux, J. P. and F. Noireau. “The host preferences of Chrysops silacea and C. dimidiata (Diptera: Tabanidae) in an endemic area of Loa loa in the Congo.” 1989. Annals Trop Med Parasitol 83(2): 167-172.

6.    Grigsby, Margaret E. and Donald H. Keller. “Loa-loa in the District of Columbia.” 1971. J Natl Med Assoc 63(3): 198-201.

7.    John, David T. and William A. Petri, Jr. Markell and Voge’s Medical Parasitology. 2006. 9th ed.

8.    Kamgno, Joseph, Michel Boussinesq, Francois Labrousse, Blaise Nkegoum, Bjorn I. Thylefors, and Charles D. Mackenzie. “Case Report: Encephalopathy after Ivermectin Treatment in a Patient Infected with Loa loa and Plasmodium spp.” 2008. Am J Trop Med Hyg 78(4): 546-551.

9.    Loa loa.” 2009. NCBI Taxonomy Browser. Available online at: http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?lvl=0&id=7209.

10. “Loiasis.” 2009. The Gideon Online. Available online at: http://web.gideononline.com/web/epidemiology/index.php?disease=11340&country=&view=General.

11. “Loiasis.” 2009. The Institute of Tropical Medicine. Available online at: http://www.itg.be/itg/distancelearning/lecturenotesvandenendene/41_Filariasisp5.htm.

12. McLean, J.D. “Nematodes.” McGill Medicine – Tropical Medicine Lecture 5. Available online at: http://www.medicine.mcgill.ca/tropmed/txt/.

13. “The Medical Letter – Filariasis.” Available online at: http://www.dpd.cdc.gov/dpdx/HTML/PDF_Files/MedLetter/Filariasis.pdf.

14. Nam, Julie N., Shanian Reddy, and Norman C. Charles. “Surgical Management of Conjunctival Loiasis.” 2008. Ophthal Plastic Reconstr Surg  24(4): 316-317.

15. Nutman, TB, KD Miller, M Mulligan, GN Reinhardt, BJ Currie, C Steel, and EA Ottesen. “Diethylcarbamazine prophylaxis for human loiasis. Results of a double-blind study.” 1988. New Eng J Med 319: 752-756.

16. Osuntokun, Olabopo and Oyin Olurin. “Filarial worm (Loa loa) in the anterior chamber.” Brit J Ophthal. (1975) 59: 166.

17. Padgett, Jeannie J. and Kathryn H. Jacobsen. “Loiasis: African eye worm.” 2008. Trans R Soc Trop Med Hyg 102, 983-989.

18. Takougang, I., J. Meli, S. Lamlenn, P.N. Tatah, and M. Ntep. “Loiasis—a neglected and under-estimated afflication: endemicity, morbidity and perceptions in eastern Cameroon.” 2007. Annals Trop Med Parasitol 101(2): 151-160.

19. Thomson, MC, V Obsomer, M Dunne, S J Conner, D H Molyneux. “Satellite mapping of Loa loa prevalence in relation to ivermectin use in west and central Africa.” 2000. The Lancet 356: 1077-1078.

20. World Health Organization (WHO). “Vector Control – Horseflies and deerflies (tabanids).” 1997. Available online at: http://www.who.int/docstore/water_sanitation_health/vectcontrol/ch06.htm#b6-Horseflies%20and%20deerflies%20%28tabanids%29.

21. World Health Organization - TDR. “Eliminating River Blindness.” A 2007 selection from Making A Difference, 30 Years of Research and Capacity Building in Tropical Diseases.