Onchocerciasis (River Blindness)

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Background

Onchocerciasis is an infection caused by the nematode Onchocerca volvulus. Humans acquire onchocerciasis through the bite of Simulium blackflies (see image below).[1, 2, 3] Because the fly develops and breeds in flowing water, onchocerciasis is commonly found along rivers and is sometimes referred to as river blindness.



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Simulium fly (black fly).

In the human host, the adult nematodes live in subcutaneous nodules and produce microfilariae, which are found throughout the body but preferentially reside in the skin and eye. Repeated exposures to infected flies increase the number of adult worms and microfilariae in the host. Chronic cutaneous onchocerciasis (onchodermatitis) causes pruritus, a papular rash, scarring, and lichenification. Over time, affected skin may begin to sag, leading to terms such as "hanging groin." Patchy depigmentation on the legs leads to a condition known as leopard skin. The term sowda is used to describe severe pruritus with darkening of the skin, often confined to one limb. Chronic ocular onchocerciasis may lead to sclerosing keratitis and iridocyclitis, and finally to blindness.

Onchocerciasis is endemic in Africa, Yemen, and in small foci in Central America and South America. The burden of the disease has been reduced by prevention efforts, including control of the fly vector and periodic ivermectin therapy in at-risk individuals. More recently, attention has been focused on Wolbachia organisms, which are endosymbiotic bacteria carried by adult worms and microfilariae. Treatment of Wolbachia infection has been shown to disrupt microfilariae production by the adult female nematode. Despite these efforts, onchocerciasis remains the second leading infectious cause of blindness worldwide.[4]

Pathophysiology

O volvulus microfilariae mature into larvae in the gut of blackflies of the genus Simulium. These larvae migrate to the proboscis of the fly and are introduced to the human bloodstream when flies take blood meals. In humans, larvae migrate to various parts of the body, but most often the skin and eye, and form nodules referred to as onchocercoma, typically seen in the skin, around joints and other bony prominences.[5]



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Subcutaneous nodule on hip caused by encysted Onchocerca volvulus.

O volvulus larvae mature into their sexually competent adult forms in these nodules. Male worms may move between nodules to fertilize female worms. Fertilized female worms then produce microfilariae, which are released into the bloodstream, and picked up when new Simulium blackflies feed from infected humans. The production of microfilariae by female adult worms depends on their associated Wolbachia endosymbiont. Drugs that target Wolbachia have been shown to adversely affect microfilariae production.[6, 7]



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Simplified life cycle of Onchocerciasis volvulus.

 

Epidemiology

Frequency

United States

Onchocerciasis is not acquired in the United States. Occasional cases are found in immigrants or travelers from endemic areas.[8, 9] However, symptomatic onchocerciasis usually requires heavy infestations and repeated exposure to the vector fly. Short-term travelers are at little or no risk of the disease. Pruritus, dermatitis, and eosinophilia may occur in travelers who stay longer than 3 months in endemic areas of Africa. Symptoms may occur months to years after leaving the endemic area.

International

Currently, onchocerciasis is endemic to 31 African countries, to Yemen, and in localized foci in Brazil and Venezuela.[10, 11] Globally, at least 18 million individuals have onchocerciasis, 99% of whom reside in Africa.[12, 13] The World Health Organization (WHO) estimates that 750,000 people are blind or have reduced vision as a result of the disease.

Since 1975, the WHO, international foundations, nongovernmental organizations, and governments have worked cooperatively to reduce the burden of onchocerciasis.[14, 15, 16, 17, 18, 19, 20, 21, 22] Initial efforts focused on insecticide sprays and habitat control to reduce the numbers of black fly vectors. With the introduction of effective treatment, the program became focused on periodic treatment of at-risk persons.

Since 1987, ivermectin has been provided free of charge by Merck through the Mectizan Donation Program. By 2002, most affected countries had introduced population-based programs to supply ivermectin at least annually to at-risk individuals. The drug temporarily reduces the microfilarial burden, resulting in reduced morbidity and a reduced number of flies becoming infected when they bite humans. Reports suggest that this has been highly effective in the Americas, where transmission has been interrupted entirely in several areas and ocular disease has been eliminated in most foci. In Africa, morbidity and transmission have been reduced but not eliminated. This may be due, at least in part, to migration of infected people into new areas, as well as the challenges inherent in educating and motivating large numbers of people.[23]

Despite the challenges they face, control programs have had a significant impact. In Africa alone, an estimated 600,000 cases of blindness had been prevented by 2002 and 18 million children were living in risk-free areas. In 2007, 69 million doses of ivermectin were supplied through the Mectizan Donation Program to reduce the burden of onchocerciasis. In South America, transmission has been interrupted or eliminated in 11 of 13 original foci of infection, limiting the range of the disease from six to two countries on that continent.[10, 11, 24]

Mortality/Morbidity

Onchocerciasis is the second-leading infectious cause of blindness in the world.[4]

Skin disease and subcutaneous nodules can be intensely pruritic.[25]

Long-term onchodermatitis may cause scarring, depigmentation, loss of skin elasticity, and disfigurement.

Although not directly fatal, blindness and skin disease caused by onchocerciasis affect the hosts’ ability to assimilate into their societies, perform daily tasks, and care for themselves.[26]

Affected persons often have a low body mass.

Blindness alone has been estimated to reduce life expectancy by 4-10 years.

In the West African savanna, up to 10% of villagers may be blind from the disease.

Race

Onchocerciasis does not have a racial predilection. For an unclear reason, the symptoms caused by O volvulus infection appear to differ from region to region. For example, onchodermatitis is more common in forested areas, while blindness is more common in savanna areas. Some evidence has suggested that genetic variation in the host may explain part of this geographic specificity.[27]

Sex

Onchocerciasis does not have a sexual predilection.

Age

Onchocerciasis does not have an age predilection. Children born to mothers with onchocerciasis may be immunotolerant to O volvulus infection, potentially leading to a higher microfilarial burden. Transplacental transmission of microfilariae may occur.

History

Symptoms of onchocerciasis reflect the developmental stage of the parasite and the degree of immune response by the host. Clinical manifestations are highly variable.

Symptoms of onchocerciasis do not appear until after the L3 larvae mature into adult worms. On average, symptoms appear between 9 months and 2 years after the initial infecting bite. The interval between acquisition of the parasite and onset of symptoms is sometimes referred to as the prepatent phase.

Once developed, adult worms cluster in subcutaneous nodules (onchocercomata).

Generalized pruritus may occur early in the infection and may be severe. A papular rash known as onchodermatitis may be present. Initially, the rash may be transient, but chronic infection over several years may lead to lichenification, loss of skin elasticity, atrophy, and/or depigmentation.

Itchy eyes, redness, or photophobia may be early symptoms of ocular onchocerciasis. Over years, the scarring progresses to cause visual loss and ultimately blindness. Acute optic neuritis is less common but may also cause blindness.

Weight loss and generalized myalgias may occur.

Physical

Skin examination in patients with onchocerciasis may reveal subcutaneous nodules, diffuse onchodermatitis, lymphedema, and/or atrophic changes.

Onchodermatitis consists of raised papules that are intensely pruritic. Vesicles and pustules may also be present. Scratching may cause secondary infection.

In its extreme form, skin atrophy may cause drooping of the inguinal skin, termed hanging groin.

In some cases, the skin is dry and resembles ichthyosis.



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Bleeding on skin due to scratching of itchy skin (onchodermatitis).

Sowda refers to severe pruritus and darkened skin, usually confined to one limb. It is most commonly described in Yemen but also occurs in Africa.



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Patient from Cameroon with sowdalike lesions.

Leopard skin refers to bilateral, symmetric, patchy depigmentation of the shins.



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Skin of a West African person with leopard spot depigmentation.

Lymphadenopathy may occur.

Subcutaneous nodules are firm, nontender, and mobile and are several millimeters to centimeters in size. They develop most commonly over bony prominences on the trunk and hip (Africa) or head and shoulders (Americas).

In the eye, the inflammatory response to dying microfilariae and Wolbachia antigens causes punctuate keratitis (snowflake opacities). Advanced cases may result in corneal fibrosis or opacification. Slit-lamp examination may reveal microfilariae in the cornea and anterior chamber. Other ocular manifestations include iridocyclitis, glaucoma, chorioiditis, and optic atrophy.[28]



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Man blinded by microfilariae of Onchocerca volvulus.

 

Causes

O volvulus is transmitted by the bite of infected Simulium flies. The fly bites during daylight hours. Simulium flies breed near fast-flowing rivers and streams.

Ocular symptoms are caused by the inflammatory response invoked by the release of Wolbachia antigens when microfilariae die.

Physical Examination

Physical examination in a patient with onchocerciasis should focus on the skin, with attention to the changes described above, and the eyes. Slit-lamp examination to examine the anterior chamber of the eye is needed to appreciate specific physical changes and keratitis of onchocerciasis.

Complications

High prevalences of nodding syndrome and epileptic seizures have been reported for decades in areas endemic for onchocerciasis in Africa. These neurologic disorders are termed ”river epilepsy” for their occurrence proximate to the fast-flowing rivers that are risk factors for onchocerciasis transmission. Microfilarial loads are significantly higher in individuals experiencing these seizures. A condition with similar features, but also associated with stunted growth, termed Nakalanga syndrome, was observed in Uganda in the 1950s but disappeared after the elimination of blackflies from the area. Nakalanga-like syndromes have been reported from a range of infection foci since and as distant from Uganda as Liberia and Mali. However, the pathophysiological mechanism that causes these neurological disorders is unknown.[29]

Laboratory Studies

Pathological diagnosis

Traditionally, a diagnosis of onchocerciasis requires demonstration of microfilariae in a skin-snip biopsy sample (see Procedures). This technique yields high specificity (100%) in experienced hands but low sensitivity (20%-50%) in early stages of infection.

The diagnosis may also be made by direct examination of surgical specimens obtained by excision of nodules.

Immunodiagnosis

Antibody detection does not distinguish between active and past infections. Various antibodies have been tested, as follows:

Antigen detection

Oncho-27 antigens have been studied in the diagnosis of Onchocerca infections. The advantage of this test is that it uses urine or tears for testing. In a study of 456 patients in a hyperendemic area of Cameroon, this technique yielded a sensitivity and specificity of 100%.[35]

Nucleic acid amplification tests

Polymerase chain reaction (PCR) using material from skin-snips or skin scratches provides high sensitivity and specificity, superior to older methods.[36, 3] However, the limited availability of technical expertise, as well as the high cost of the test, restricts its use in resource-limited settings.

Imaging Studies

Ultrasonography may reveal nonpalpable nodules, although this is not useful as a screening test. Ultrasonography of an adult worm in a nodule reveals a homogeneous echogenic area containing echodense particles with a lateral acoustic shadow.

Other Tests

An older technique that is more of historical interest is the test dosing with diethylcarbamazine (DEC) in oral form to observe the reaction that suggests the presence of onchocerciasis. More recently, a patch test using DEC, which decreases risk, has been used. This testing is based on the principle of the Mazzotti reaction and involves the topical application of DEC in a cream base (DEC patch). It elicits localized cutaneous reactions (pruritus, maculopapular eruptions, dermal edema) in response to dying microfilariae.[37] Earlier studies reported varying degree of sensitivity (30%-92%) in patients with positive skin-snip results. Severe cutaneous reactions may require steroid therapy or hospitalization. Higher concentrations of DEC and longer patch times increase the sensitivity.[38] However, false-positive reactions may occur in patients with other filarial diseases such as Loa loa infection.

Procedures

Skin snip

In this technique, a razor blade is used to remove tiny skin samples (3-5 mg) from multiple sites (iliac crests, shoulder blades); they are then placed in saline to observe microfilariae emerging from the skin samples. Alternatively, for the purpose of quantitation of microfilarial burden, sclerocorneal punch samples can be used to obtain a specific amount of skin (usually 5 micrograms) for each sample.

The sensitivity is low in the prepatent disease stage of disease, in geographic areas of low prevalence, and in areas of mass ivermectin use.

Skin-snip biopsy specimens can also be used to detect microfilariae using nucleic acid amplification.



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Taking a skin snip from the hip with a 5-microgram iris scissors for quantitatively diagnosing Onchocerca volvulus infection (Rio de Micay, Colombia).....



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Taking a skin snip from the hip with a 5-microgram iris scissors for quantitatively diagnosing Onchocerca volvulus infection (Rio de Micay, Colombia).....

Nodule resection (nodulectomy, onchocercomectomy)

Although this is the most invasive method, surgical removal of nodules has both diagnostic (if adult worm is observed) and therapeutic potential (elimination of the adult worms in that nodule). It was later shown that the public health value of performing nodulectomy campaigns is of little value due to occult nodules that may enable disease transmission to persist.[39, 40]

Histologic Findings

Microscopic examination of excised onchocercomata reveals cross-sections of adult worms with eosinophils and lymphocytes at the periphery of the nodule.



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Microfilaria of Onchocera volvulus stained from skin biopsy. Courtesy of Cali Colombia, D Scott Smith, MD, and Gloria Palma, MD, PhD.

Medical Care

Because most of the pathogenesis of onchocerciasis is secondary to microfilariae, the goal of therapy is to eliminate the microfilarial stage of disease to improve symptoms, to prevent progression of eye lesions, and to interrupt disease transmission.

Ivermectin is considered to be the drug of choice as a microfilaricidal agent.[41, 42] Repeated dosing at intervals of 3–12 months is recommended for at least 10-12 years. More frequent dosing is reserved for patients who experience frequent symptomatic recurrences.

Ivermectin is usually well-tolerated. Dying microfilaria may result in pruritus and adenopathy (Mazzotti reaction), leading to angioedema in rare cases. Ocular inflammation may also be triggered by dying microfilariae. To minimize this in individuals with microfilariae observed during slit-lamp examination, some experts recommend using a short course of prednisone (2-3 d) along with ivermectin. More frequent dosing with ivermectin (every 3 mo instead of every 12 mo) may reduce inflammatory complications because it does not permit microfilarial numbers to build, thus reducing the number of dead organisms after treatment.

Concomitant infection with Loa loa should be ruled out, as ivermectin may precipitate toxic encephalopathy in these patients.

Ivermectin has little effect on adult worms. It reduces the burden of microfilaria and the risk of complications but does not cure the disease. Ivermectin may have a modest effect on infection rates with selected intestinal helminths, such as Strongyloides and Ascaris, although it is not effective against hookworm.[43]

Targeting endosymbiotic Wolbachia species has emerged as an exciting new approach in the control of onchocerciasis. Studies of doxycycline therapy (100–200 mg/d for 6 wk) have shown great promise.[6, 7, 44, 45] Doxycycline interrupts microfilarial embryogenesis, dramatically decreasing or eliminating microfilaria for at least 18 months after treatment. The drug has modest activity against adult worms, reducing numbers by approximately 50%-60%. The combination of doxycycline and ivermectin given together is more effective than either drug alone.[46] However, doxycycline has side effects and must be given daily, which limits its usefulness for large scale treatment programs.[47] . It has been suggested that minocycline may be more efficient than doxycycline in the elimination of Wolbachia.[48]

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.[49] 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.[50]

Investigators have also studied rifampin and azithromycin, but early results appear to be inferior to those of doxycycline.[51, 52, 53]

Surgical Care

Nodulectomy can result in cure only if excision eliminates all adult worms. Thus, this is not a practical choice in patients with multiple nodules or in patients in whom nodules are not clinically evident.[39]

Consultations

See the list below:

Guidelines Summary

Control and Elimination

The World Health Organization (WHO) maintains and issues guidelines for the control of onchocerciasis and the certification of its elimination from endemic regions. Historically, nodulectomy and vector control were used to decrease the frequency and intensity of filarial infections in areas endemic for onchocerciasis. Current strategy centers on the mass drug administration (MDA) of ivermectin. In Africa, this distribution is managed through community-directed treatment with ivermectin on an annual or semiannual basis. In the Americas, semi-annual ivermectin treatment is generally used, although quarterly administration has been undertaken.

Three phases are used to control onchocerciasis using MDA programs with ivermectin.

Phase 1 - Treatment

Features include the following:

The following recommendation are used to demonstrate the interruption of O volvulus transmission to stop MDA and to move to the Post-Treatment Surveillance phase (phase 2):

Phase 2 - Post-Treatment Surveillance

Features include the following:

The following methods are used to confirm the interruption of O volvulus transmission at the end of the post-treatment surveillance period, leading to the elimination of human onchocerciasis, and to move to the Post-Elimination Surveillance phase (phase 3):

Phase 3 - Post-Elimination Surveillance

Features include the following:

Medication Summary

Treatment involves microfilaricidal or macrofilaricidal agents. No known nontoxic macrofilaricidal agent is available to kill adult worms effectively.

Ivermectin (Mectizan, Stromectol)

Clinical Context:  Drug of choice for onchocerciasis. Derived from the soil actinomycete Streptomyces avermitilis. Metabolized in liver and excreted in feces over 12 d. Plasma half-life is 18 h. Its activity is the result of increased nerve and muscle cell permeability to chloride channels, leading to hyperpolarization and paralysis due to the drug's high affinity binding to glutamate-gated and gamma aminobutyric acid–gated chloride ion channels.

Moxidectin

Clinical Context:  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.

Diethylcarbamazine (Hetrazan)

Clinical Context:  Diethylcarbamazine (DEC) is never used in the treatment of onchocerciasis. DEC is rarely used for diagnostic purposes, when low test doses are given and patients are observed for the Mazzotti reaction, which, in mild cases, results in pruritus, dermal edema, maculopapular eruptions, lymphadenopathy, and fever and, in severe cases, results in meningismus, severe prostration, and/or death. The mechanism of action of DEC is secondary to direct effect on microfilariae by causing organelle damage and apoptosis.

Class Summary

These agents inhibit growth and proliferation of parasites.

Doxycycline (Bio-Tab, Doryx, Doxy, Periostat, Vibramycin, Vibra-Tabs)

Clinical Context:  May be used to reduce or eliminate the endosymbiotic bacteria Wolbachia. This disrupts production of microfilariae by the adult female worm.

Class Summary

Empiric antimicrobial therapy must be comprehensive and should cover all likely pathogens in the context of the clinical setting.

Inpatient & Outpatient Medications

Patients with onchocerciasis should receive ivermectin 150 mcg/kg every 3-6 months.

Deterrence/Prevention

Travelers to endemic area can avoid onchocerciasis by avoiding vector contact with protective clothing and repellants.

Population-based prevention strategies in some of the endemic areas of Africa and South America are based on elimination of blackfly vector and regular (every 6-12 mo) mass ivermectin treatment of affected individuals.

Complications

Ocular complications of onchocerciasis include blindness secondary to keratitis, pannus formation, and corneal fibrosis. Posterior segment complications include chorioretinitis, intraretinal deposits, open-angle glaucoma, and optic atrophy.

Cutaneous complications of onchocerciasis include skin atrophy, depigmentation, and sowda (chronic popular dermatitis limited to one limb). A loss of skin elasticity (hanging groin) may also occur.

Hematologic and immunologic complications of onchocerciasis include chronic lymphadenopathy.

Prognosis

Some eye manifestations and dermatitis resolve in patients undergoing ivermectin treatment every 6-12 months for the lifetime of the adult worm (approximately 12 years).

Blindness, skin atrophy, and depigmentation do not improve with treatment. The life expectancy in blind persons is decreased secondary to difficulty coping with activities of daily living, by an estimated 4 years.

Patient Education

Travelers to areas where onchocerciasis is endemic should be counseled to use protective clothing treated with permethrin and insect repellants such as DEET.

Patients, particularly those with high microfilarial load and ocular involvement, should be cautioned on the potential complications of ivermectin therapy that may result from dying microfilaria.

Author

Darvin Scott Smith, MD, MSc, DTM&H, Adjunct Associate Clinical Professor, Department of Microbiology and Immunology, Stanford University School of Medicine; Chief of Infectious Diseases and Geographic Medicine, Department of Internal Medicine, Kaiser Permanente Medical Group

Disclosure: Nothing to disclose.

Coauthor(s)

Muzzammil Imran Muhammad Shittu, Graduate Student, CHPR, Stanford University

Disclosure: Nothing to disclose.

Specialty Editors

Francisco Talavera, PharmD, PhD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

John W King, MD, Professor of Medicine, Chief, Section of Infectious Diseases, Director, Viral Therapeutics Clinics for Hepatitis, Louisiana State University Health Sciences Center; Consultant in Infectious Diseases, Overton Brooks Veterans Affairs Medical Center

Disclosure: Nothing to disclose.

Chief Editor

Mark R Wallace, MD, FACP, FIDSA, Infectious Disease Physician, Skagit Valley Hospital, Skagit Regional Health

Disclosure: Nothing to disclose.

Additional Contributors

Apoorv Kalra, MD, Assistant Professor of Medicine, Michigan State University

Disclosure: Nothing to disclose.

Daniel R Lucey, MD, MPH, MD, MPH,

Disclosure: Nothing to disclose.

Mary D Nettleman, MD, MS, MACP, Professor and Chair, Department of Medicine, Michigan State University College of Human Medicine

Disclosure: Nothing to disclose.

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Simulium fly (black fly).

Subcutaneous nodule on hip caused by encysted Onchocerca volvulus.

Simplified life cycle of Onchocerciasis volvulus.

Bleeding on skin due to scratching of itchy skin (onchodermatitis).

Patient from Cameroon with sowdalike lesions.

Skin of a West African person with leopard spot depigmentation.

Man blinded by microfilariae of Onchocerca volvulus.

Taking a skin snip from the hip with a 5-microgram iris scissors for quantitatively diagnosing Onchocerca volvulus infection (Rio de Micay, Colombia). Courtesy of D Scott Smith, MD.

Taking a skin snip from the hip with a 5-microgram iris scissors for quantitatively diagnosing Onchocerca volvulus infection (Rio de Micay, Colombia). Courtesy of D Scott Smith, MD.

Microfilaria of Onchocera volvulus stained from skin biopsy. Courtesy of Cali Colombia, D Scott Smith, MD, and Gloria Palma, MD, PhD.

Simulium fly (black fly).

Histopathology of an Onchocerca volvulus nodule. Courtesy of the CDC and Dr. Mae Melvin.

Simplified life cycle of Onchocerciasis volvulus.

Subcutaneous nodule on hip caused by encysted Onchocerca volvulus.

Man blinded by microfilariae of Onchocerca volvulus.

Bleeding on skin due to scratching of itchy skin (onchodermatitis).

One anatomic quarter of body (leg) markedly affected by edema and papule formation of onchodermatitis.

Skin of a West African person with leopard spot depigmentation.

Patient from Cameroon with sowdalike lesions.

Microfilaria of Onchocera volvulus stained from skin biopsy. Courtesy of Cali Colombia, D Scott Smith, MD, and Gloria Palma, MD, PhD.

Taking a skin snip from the hip with a 5-microgram iris scissors for quantitatively diagnosing Onchocerca volvulus infection (Rio de Micay, Colombia). Courtesy of D Scott Smith, MD.

Taking a skin snip from the hip with a 5-microgram iris scissors for quantitatively diagnosing Onchocerca volvulus infection (Rio de Micay, Colombia). Courtesy of D Scott Smith, MD.

Adults blinded by onchocerciasis. This is the WHO/New York Times photo that inspired World Bank funding for River Blindness control programs and then the bronze statue in front of the WHO in Geneva Switzerland. Courtesy of Otis Historical Archives, National Museum of Health and Medicine.