Ophthalmologic Manifestations of Onchocerciasis

Onchocerciasis, commonly known as river blindness, is a vector-borne disease that affects millions of people in Africa, the Middle East, and South and Central America. This disease is caused by the filarial parasitic nematode Onchocerca volvulus, which is transmitted by the blackfly vector Simulium, which carries third-stage larvae.

Infection can lead to chronic skin disease, severe itching, and eye lesions that can progress to complete blindness. There are approximately 123 million people at risk for infection in 38 countries and at least 25.7 million people infected. Of infected persons, 1 million are blind or have severe visual impairments.[1]

Advances in prevention and treatment have decreased the prevalence of this disease in localized areas of Africa and Latin America. Most cases are found in Africa, south of the Sahara, in a wide zone that lies along the fifteenth parallel from Senegal to Ethiopia.

Multiple organizations have created programs whose goal is to prevent and treat onchocerciasis.[2] These include the Onchocerciasis Control Programme (OCP) in West Africa, a program created by the World Health Organization (WHO) that lasted for 28 years, ending in 2002; the program successfully eliminated onchocerciasis as a public health problem in 10 of the 11 African countries involved. The River Blindness Elimination Program, created by The Carter Center, works in Latin America and Africa to eliminate river blindness.

Although multiple programs are working extensively to eliminate this disease, onchocerciasis is still a very relevant world health problem.

A Simulium female black fly takes blood from an infected human and ingests microfilariae. The microfilariae then enter the fly’s gut and grow into the first larval stage. After approximately 7 days, the larvae mature and move to the fly’s saliva, where it is transmitted to another human during the fly’s next blood meal.

Development to the adult stage occurs in the human host. The adult worms pair and mate in the human host, and, unlike most nematodes that produce eggs, the female Onchocerca gives birth daily to thousands of microscopic larvae known as microfilariae. These larvae mature to adult worms in about 1 year. The life span of microfilariae is 6-30 months. Those adult worms that complete their life circle may survive a decade, during which time they release millions of microfilariae.

While alive, O volvulus causes little disease. The adults protect themselves in fibrous painless subcutaneous skin nodules called onchocercomas. These nodules are found predominantly on the head, face, and torso, although they can also be seen in the pelvic girdle, in the lower extremities, or near the joints. In most cases, 2-3 females and daughter microfilariae live inside the onchocercoma. Their death leads to an inflammatory cascade in the human host. Antigens released from the dead nematode cause a TH2 helper cell response, which then activates interleukins, neutrophils, eosinophils and antibodies released by plasma cells to create the inflammatory response, which, in turn, creates the manifestations of the disease.

O volvulus endosymbionts, such as the Wolbachia bacteria that are released upon its death, also cause an immunogenic response. Strains of O volvulus that carry Wolbachia DNA are associated with a higher incidence of ocular disease. It is also proposed that ocular inflammation, specifically in the posterior pole, is a consequence of antigen mimicry. There seems to be cross-reactivity between the Onchocerca antigen Ov39 and the retinal antigen hr44, which can explain the chorioretinitis seen in some humans despite proper treatment and evidence of decreased microfilariae in their blood.

Frequency

United States

No cases of onchocerciasis due to O volvulus have been reported in the United States.

International

Africa

More than 99% of African onchocerciasis cases occur in 27 sub-Saharan countries; 120 million people are at risk for infection on this continent. In West African savanna, the rate of infection has been as high as 80%-100% by age 20 years, with blindness peaking at age 40-50 years. In African forest areas, itching has affected 42% of the population older than 20 years, and skin lesions have appeared in 28% of persons aged 5 years.[3, 4]

Central and South America

Based on a report from the Centers for Disease Control and Prevention (CDC) in 2013, 231,467 people are at risk for onchocerciasis in Guatemala, making it the highest-risk country for river blindness in the Americas. Mexico is second, with 169,869 people at risk for infection. Venezuela has 119,358 people at risk. The Yanomami population in Brazil has 12,988 persons in 22 endemic areas at risk. Ecuador has 25,863 at risk. Although this is a relatively small number, they have the highest prevalence of microfilariae in the skin at baseline. Lastly, Colombia once had a single focus of infection, but, according to the WHO, the infection has been eradicated in Colombia as of 2012.[1]

Mortality/Morbidity

Microfilariae elicit the onchocerciasis syndrome that includes blindness, lymphadenitis, and dermatitis. O volvulus infection reduces immunity and resistance to other diseases. According to data published in the OCP, from 1971-2001, 1,283 (5.2%) deaths were due to onchocerciasis.[5] Mortality was significantly associated with increased microfilarial burden but not blindness. Mortality rates peaked in the 1980s and decreased afterward.

Race

No well-described racial differences in the incidence of onchocerciasis or susceptibility to the disease exist, although specific reports have documented higher, but not clinically significant, rates of infection in blacks.[6]

Socioeconomic differences have been clearly identified as a contributing factor.

Sex

Per OCP data, females had a risk of death approximately 7.5% less than males. Men may be affected more often than women because of farm and field occupations.[5]

Age

As many as 50% of people older than 40 years may be blind in endemic areas, particularly in Africa.

Clinicians should have high suspicion for river blindness among people living in endemic areas with the following symptoms:

• Itchy skin rashes

• Subcutaneous nodules

• Vision changes

Skin manifestations

Skin manifestations of onchocerciasis include the following:

• Subcutaneous nodules

• Diffuse onchodermatitis: Raised intensely pruritic papules, vesicles, and pustules

• Skin atrophy

• “Hanging groin”: Drooping of the inguinal skin

• Sowdah: Severe pruritus and darkened skin, usually confined to one limb

• Leopard skin: Bilateral, symmetric, patchy depigmentation of the shins

• Lymphadenopathy

Ocular manifestations

The two subtypes of ocular disease include savanna and rainforest types. The African Savanna type causes blindness 2.5-5 times more frequently and is usually caused by punctate of sclerosing keratitis. In the African rainforest subtype, ocular involvement occurs earlier but blindness is not as common. When it does happen, blindness is usually secondary to posterior segment disease such as chorioretinitis, vascular sheathing, or optic atrophy.

Via slit-lamp biomicroscopy, microfilariae can be seen within the cornea migrating freely in the anterior chamber and vitreous humor. Although live microfilariae cause minimum reaction, dead microfilariae are associated with a severe inflammatory response, believed to be secondary to the release of Wolbachia antigens when microfilariae die in the tissues of the eye. The ocular manifestations of onchocerciasis, as reported by Kayembe et al[7] , include chorioretinitis (seen in approximately 20% of infected hosts, making it the most prevalent isolated condition), punctate keratitis (13.8%), white intraretinal deposits (10.4%), and iridocyclitis (8%). Anterior segment lesions are more prevalent than posterior lesions as a whole and appear earlier in life. A correlation between the intraretinal deposits and the severity of the chorioretinitis has been found.[7]

As mentioned above, larval death induces the inflammation that results in corneal opacification and neovascularization.

Dead worms are surrounded by inflammatory infiltrates in the superficial stroma. Lymphocytes and eosinophils migrate to the peripheral cornea where the infection is more dense. Sclerosing keratitis follows, which may involve the visual axis over time. Corneal neovascularization and opacification with interstitial keratitis lead to corneal blindness.

Keratitis

The development of keratitis depends on the previous immunization and the presence of sensitized T lymphocytes. It is associated with a predominance of T-helper type 2 (Th2) response.

Eosinophils are the predominant inflammatory cells in the cornea after injection of the parasite antigen. The severity of keratitis seems to be associated with the number of eosinophils in the cornea.

Neutrophils are prominent early in the inflammatory response and mediate keratitis in the absence of eosinophils.

Iridocyclitis: Early in the disease, nongranulomatous or granulomatous inflammation may result from invasion of the iris and ciliary body by the microfilariae. Posterior synechiae may distort the pupil inferiorly, giving a classical pear-shaped iris. Seclusio pupillae and iris bombe with secondary angle-closure glaucoma may occur. The common sequelae include occlusio and seclusio pupillae, iris atrophy, iris bombe, inflammatory glaucoma, and cataract.

Chorioretinitis

Chorioretinitis is characterized by progressive inflammation associated with loss of pigment, pallor of the vessels from orange to yellow or white, and loss of choriocapillaris.

The retinal pigment epithelium is affected in the early stage of infection. Areas of hypopigmentation and hyperpigmentation, mottling, and confluent atrophy characterize it. Dark brown clumps of pigment are seen in a diffusely pale retinal pigment epithelium. Photoreceptors are initially lost, followed by loss of the inner retinal layers.

In the early stage, chorioretinitis may mimic any other diffuse chorioretinal process, such as histoplasmosis, toxoplasmosis, or retinitis pigmentosa.

Commonly involving the temporal retina, onchocerciasis tends to spare the macula; as a result, central visual acuity is maintained until late in the disease.

The pathogenesis of onchocercal chorioretinopathy is not well understood. The following mechanisms have been hypothesized to cause the characteristic chorioretinopathy:

• Inflammatory reaction to dead microfilariae

• Deposits of immune complexes

• Autoimmunity

• Secretory-excretory products of microfilariae

• Eosinophil-derived toxic effector molecules

Autoimmunity is supported as a mechanism for several reasons. First, the burden of microfilariae is not directly associated with the degree of chorioretinopathy. Second, the chorioretinopathy continues to progress even after effective treatment with reduction of microfilariae and vector control. Finally, retinal disease can persist throughout life unless controlled with anti-inflammatory agents.

Evidence favoring the autoreactivity theory for the development of onchocercal chorioretinopathy is derived from the detection of retina-specific autoantibodies in the human-infected sera.

Uveitis

Onchocercal human uveitis is associated with uveitopathogenic peptides, retinal S-antigen, and interphotoreceptor retinoid binding protein (IRBP). This evidence led Vingtain and Thillaye[8] to demonstrate the presence of higher levels of S-antigen antibodies in patients with onchocerciasis who also had involvement of the posterior segment. However, these findings were not replicated.

Autoantibodies may have resulted from activation of T and B cells seen in parasitic infections. About 30% of B cells produce antibodies that are able to bind to autoantigens.

Hypergammaglobulinemia is a feature of O volvulus infection. Strong evidence exists that the chorioretinopathy is an inflammatory reaction to dead microfilariae because treatment with microfilaricidal induces characteristic retinal pathology. Similar progressive pathology also is seen after antimicrobial therapy of Toxocara uveitis in children.

Microfilariae load is associated with the presence of new chorioretinal lesions. Even though the incidence of new lesions is reduced after antimicrobial chemotherapy, extension and progression of existing disease is common.

This observation suggests that although chorioretinopathy is likely to be initiated by the presence of microfilariae, persistence is a self-perpetuating autoimmune process that does not require the presence of microfilariae.

Optic atrophy

Loss of the ganglion cell axons leads to optic nerve head damage.

The optic nerve may also be involved by the infectious process or by treatment-induced inflammatory optic neuritis.

A heavy load of microfilariae may cause optic neuropathy.

Causes are discussed in Physical.

Serologic testing for antifilarial antibodies to immunoglobulin G (IgG) and IgG4 via enzyme-linked immunosorbent assay (ELISA): A positive IgG result indicates likely exposure. A positive IgG4 results indicates active filarial infection.

Mazzotti test: An oral test dose of 5 mg DEC is administered, which inhibits the neuromuscular transmission in nematodes. A positive result yields intense pruritus within 2 hours secondary to dying parasites. Although itching can be controlled with corticosteroids, severe systemic reactions can occur.

ELISA and immunochromatographic test (ICT): ELISA, the ubiquitous biological technique, uses multiple recombinant antigens. ELISA is useful to differentiate O volvulus from its cousins but requires a specialized laboratory. ICT, a rapid format antibody card test, uses an individual antigen. The sensitivity of ELISA and ICT has been estimated as 97% and 86%, respectively. Both ELISA and ICT are more sensitive than the skin snip technique and the patch test using topical diethylcarbamazine (DEC). ICT compares with ELISA and is inexpensive.

Polymerase chain reaction (PCR): An advanced molecular technique using DNA or RNA probes specific to O volvulus can be used to assay the blackfly vector and human host infection using PCR technology. These probes are sensitive very early in the disease. Although highly specific, PCR requires meticulous laboratory technique to avoid contamination and false-positive results. In addition to requiring specialized skills and being expensive, PCR-based diagnostic methods of onchocerciasis still depend on skin snips.[9]

Ultrasonography can be used to visualize subcutaneous nodules. However, it is not part of the usual workup.

Onchocerciasis is diagnosed based on clinical and laboratory data rather than imaging studies.

DEC patch test: A 10% DEC anhydrous lanolin patch is applied to the skin and later checked for local dermatitis caused by the dying microfilariae. It is safer than the Mazzotti test but not as sensitive as the skin snip test.

Skin snip test: This is the test of choice. Punch biopsies are taken from multiple skin sites and incubated at room temperature to allow for microscopic observation of microfilariae emerging from the skin samples. However, this method has low sensitivity low-transmission areas and in areas where long-term use of the microfilaricidal ivermectin has resulted in the significant reduction of individual and community microfilariae loads. Also, the procedure is painful and involves a high risk of blood-borne infections (eg, HIV).

Nodulectomy: This involves removal of skin nodules to inspect for adult worms. This is a diagnostic and therapeutic technique. However, it is very invasive.

Ovolvulus can be visualized with phase-contact microscopy. It is coiled while living and straightens as it dies. Female worms live from 8-10 years, releasing millions of first-stage larvae throughout their lifetime. These microfilariae are 320-360 µm long and 5-10 µm in diameter and live from 6-30 months. In hyperendemic areas, an infected individual may have as many as 150 million microfilariae in his or her body.

Onchocerciasis is not classified according to different stages.

Traditionally, DEC was used to kill microfilariae. It is not in wide use now because of the severe reactions mentioned above in the Mazzotti test.

The standard treatment now includes ivermectin given as a single dose and repeated every 6-12 months for 10 years. Ivermectin works by paralyzing the microfilariae over 6 months. It has no effect on adult worms.[10, 11]

Ivermectin has been shown to delay the development of optic atrophy, reduce the visual field loss, and decrease the severity of keratitis. More advanced chorioretinal and keratitis lesions and angle-closure glaucoma are not treated with ivermectin. Iridocyclitis can result from ivermectin therapy and can be treated with steroids and cycloplegic drops. In addition, some ivermectin-resistant strains of O volvulus have recently appeared.[12]

Moxidectin is an antiparasitic drug that was approved by the FDA in June 2018 to treat onchocerciasis in patients aged 12 years or older. The WHO initiated clinical trials for use in onchocerciasis treatment in 2009. Moxidectin is closely related to ivermectin but yields a more sustained reduction in microfilarial levels. FDA approval was based on a double-blind, parallel group, superiority trial (n=1472) that compared moxidectin (8 mg PO once) with ivermectin (150 mcg/kg PO once). The trial took place in Ghana, Liberia, and the Democratic Republic of the Congo. Results showed skin microfilarial loads (ie, parasite transmission reservoir) were lower from month 1 to month 18 after moxidectin treatment than after ivermectin treatment, with an 86% difference at month 12. Moxidectin would therefore be expected to reduce parasite transmission between treatment rounds more than ivermectin could, thus accelerating progress toward elimination.[13]

Doxycycline has been used against Wolbachia and has been shown to decrease microfilarial loads.[14] Animal models treated with doxycycline have had a decrease in posttreatment corneal thickness and stromal haze.[14]

Other drugs currently under investigation include rifampin and azithromycin.

Surgical treatments are usually directed against preventing the loss of vision caused by Ovolvulus. These include the following:

• Cataract extraction for visually significant cataracts

• Trabeculectomy or drainage implants for glaucoma management

• Penetrating keratoplasty for corneal pathology

• Vitrectomies or laser photocoagulation for chorioretinal lesions

Infectious disease physicians and ophthalmologists should be involved in the care of all patients with onchocerciasis.

There are no dietary restrictions for affected patients.

Depending on the severity of disease, patients with severe vision loss may need assistance with activities of daily living. Otherwise, patients should have as much activity as tolerated.

The goals of pharmacotherapy are to reduce morbidity and to prevent complications.

Class Summary

These agents inhibit growth and proliferation of parasites.

Ivermectin

Semisynthetic, broad-spectrum antiparasitic agent isolated from Streptomyces avermitilis. It is a mixture of 5-O demethyl-22,23-dihydroavermectin A (90%) and 5-O demethyl-25-de (1-methylpropyl)-22,23-dihydro-25- (1-methylethyl) avermectin A1a (10%).

Selectively binds to glutamate-gated chloride ion channels in muscles and nerve cells of the invertebrate. Increased permeability of cell membrane to chloride ions leads to hyperpolarization of the nerve or muscle cell, paralysis, and death of the parasite.

Active against various life-cycle stages of many nematodes, including microfilariae of O volvulus but has no effect on adult worm.

Metabolized in liver. Plasma half-life is 16 hours, 99% excreted in feces and 1% in urine. Available as 6 mg tab for oral administration. Given as single dose of 12 mg (two 6 mg tab) or 150 mcg/kg.

Moxidectin

Moxidectin, a macrocyclic lactone, is an anthelmintic indicated for the treatment of onchocerciasis due to Onchocerca volvulus in patients aged 12 years and older. Plasma half-life is 20-43 days and thereby reduces and maintains low skin microfilarial density effectively. Moxidectin does not kill adult O volvulus. Follow-up evaluation is advised. Safety and efficacy of repeat administration has not been studied.

Doxycycline

Tetracycline antibiotic who binds to the 30S ribosomal subunit in the mRNA translation complex therefore inhibiting tRNA to join the mRNA ribosome complex. In O. volvulus, it interferes with microfilarial embryogenesis. It has modes activity against adult works, decreasing them by 50%-60%. It also kills the endosymbiont Wolbachia.

Patients who are infected with larvae should receive close follow-up care with their primary care doctors, as well as their ophthalmologists and infectious disease physicians.

Once the acute stage has result, the follow-up depends on the severity of visual loss.

Inpatient care is generally unnecessary for onchocerciasis.

See Medication section.

If adequate healthcare is unavailable, patients with onchocerciasis should ideally be transferred to areas with qualified physicians who are able to promptly treat this disease. Unfortunately, many of the patients affected by onchocerciasis live in remote areas with little or no possibility of fast diagnosis and transfer.

Associations such as the African Programme for Onchocerciasis Control (APOC), OCP, River Blindness Elimination Program from the Carter Center, and organizations such as Sightsavers are working on global prevention of onchocerciasis. They administer community-wide ivermectin and focus on vector control. These measures have been very successful. Approximately 35 million people are no longer at risk for infection, 2 million infected people have been appropriately treated, and blindness has been prevented in over 200,000 people. They also target individual prevention, which includes counseling people to avoid endemic areas, using insect repellent, and wearing protective clothing.

African Programme for Onchocerciasis Control (APOC)

Launched in 1995, this programme focuses on mass distribution of ivermectin through the Ivermectin Distribution Programme. It includes 19 participating countries and empowers communities to fight onchocerciasis in their own villages and aims to treat over 90 million annually, protect 115 million people at risk, and prevent over 40,000 cases of blindness every year.[15]

Onchocerciasis Control Programme

This was launched by the WHO in 1974 in collaboration with the United Nations Development Programme, the World Bank, and the Food and Agriculture Organization to protect 30 million people from onchocerciasis in 11 countries.

Its focus was initially on spraying insecticides via helicopters and aircrafts over the endemic blackflies areas.

In 1987, Merck & Co., Inc. donated Mectizan (ivermectin) and the focus changed to treatment of the disease alone.

The OCP finished in 2002 after virtually eradicating the transmission of disease in all participating countries except Sierra Leone, where the program was interrupted by a civil war. They prevented 600,000 cases of blindness, 18 million children born in now disease-free areas were spared of the disease, and 25 million hectares of land are now safe for cultivation and settlement.[15]

River Blindness Elimination Program of the Carter Center

This aims to eliminate river blindness from 11 countries in Latin America. They focus on health education and distribution of Mectizan, donated by Merck. This program works through the Onchocerciasis Elimination Program for the Americas (OEPA) to eliminate the disease in pockets of Brazil, Colombia, Ecuador, Guatemala, Mexico, and Venezuela.[16] To date, they have distributed more than 170 million treatments of Mectizan in Africa and Latin America, interrupted transmission in 11 foci of the 13 endemic areas in Latin America, stopped transmission from 8 of 18 endemic areas in Uganda, and eradicated river blindness in Abu Hamad, Sudan. In 2013, Colombia became the first American country to eliminate onchocerciasis.[17]

Vaccination

The prospect for the development of a vaccine against onchocerciasis is hindered by the fact that antigens of O volvulus are complex and show extensive cross-reactivity with other filaria parasites of humans and animals. Challenges to development of the vaccine include development of field-usable immunodiagnostic tests to enable quantification of worm burdens in infected patients and research using immunology and molecular biology to develop a vaccine against O volvulus.[18]

Potential complications of onchocerciasis include the following:

• Dermatitis, skin atrophy, depigmentation

• Lymphadenitis and chronic lymphadenopathy

• Blindness caused by keratitis, corneal pannus or fibrosis, chorioretinitis, glaucoma, or optic atrophy

The prognosis in individuals with onchocerciasis depends on the stage of infection. If it is identified and treated early, blindness can be effectively prevented.

Globally, multiple efforts are being made for the prevention and community-based treatment of onchocerciasis (see Prevention). After parts of Uganda and Sudan were officially announced as onchocerciasis-free, there has been a surge of hope that this can continue to the remaining endemic areas. At present, however, this devastating disease has significant socioeconomic and public health effects and is still an important world health problem.

Training local experts, who would assume responsibility for human and vector population surveillance, is important.