Onchocerciasis

INTRODUCTION — Onchocerciasis is caused by the filarial nematode Onchocerca volvulus. It is also known as "river blindness" because the blackfly vector breeds near fast-flowing streams and rivers. The disease affects rural communities and is a major cause of blindness, skin disease, and onchocerciasis-associated epilepsy in endemic areas with serious socioeconomic consequences.

EPIDEMIOLOGY — In 2017, the global prevalence of infection with onchocerciasis was estimated at 20.9 million [1]. In 2017 to 2018, 205 million people were deemed at risk of onchocerciasis because they lived in areas with potential for disease transmission [2]. More than 99 percent of cases occur in 31 African countries (figure 1) whilst smaller foci of infection are found in Yemen and Central and South America.

The first confirmed elimination of an onchocerciasis focus in Africa occurred in Abu Hamed, Sudan, in 2016 [3]. Four countries in the Americas (Colombia, Ecuador, Mexico, and Guatemala) have completed the World Health Organization verification process for elimination [4]. Transmission is ongoing in the Americas region in a single large transmission zone (the "Yanomani area"), which extends across the border of Venezuela and Brazil (figure 2). (See 'Mass treatment' below.)

Onchocerciasis is the second-leading infectious cause of blindness worldwide: approximately 1.15 million people have vision loss due to onchocerciasis [1]. The epidemiologic patterns of infection differ between savanna and forest regions.

●In West African savanna areas, ocular onchocerciasis is common; it particularly affects the anterior segment of the eye, though the posterior eye segment can also be affected. The risks of visual impairment increase, in part, as the prevalence and intensity of infection in a community rises [5]. The prevalence of infection can vary between villages and was historically as high as 80 to 100 percent by the age of 20 years in some areas, with blindness peaking at 40 to 50 years of age. Prior to control activities, hyperendemic regions were frequently depopulated because of high rates of blindness.

●In African forest areas with a comparable intensity of onchocerciasis as savanna areas, onchocercal skin disease predominates, with much less blindness. Furthermore, ocular lesions, when present, usually involve the posterior eye segment. A multi-country study in highly endemic forest communities found that itching affected 42 percent of the population aged ≥20 years, and onchocercal skin lesions affected 28 percent of the population aged ≥5 years. Strong associations were found between the prevalence of skin lesions and troublesome itching and onchocercal endemicity [6]. The Global Burden of Disease Study 2017 estimated 14.7 million people had skin disease due to onchocerciasis [1].

The different savanna and forest epidemiologic patterns are thought to be due to the existence of two strains of O. volvulus. The higher propensity for ocular disease with the savanna strain has been correlated with higher quantities of Wolbachia DNA by polymerase chain reaction (PCR); Wolbachia are endosymbiotic bacteria found in O. volvulus adults and microfilariae that are essential for the filarial worm's fertility and survival [7]. Blindness from onchocerciasis is less common in Latin America; this may be related to transmission intensity, strain differences, genetic factors, or other causes.

Black flies are not efficient vectors of disease; a minimum stay of 12 months in endemic areas is generally necessary to acquire infection. Thus, short-term travelers to endemic regions are unlikely to become infected, though medical staff treating returned travelers should be aware of this possibility [8].

LIFE CYCLE — Humans are the only definitive host for O. volvulus, although there are a number of other onchocercal species that infect animals; a small number of human infections with Onchocerca lupi (a parasite known to infect cats and dogs) have been described [9,10].

Humans are infected with O. volvulus via the bite of a blackfly of the Simulium genus. The blackfly deposits infective third-stage larvae into the human skin, which mature into adult parasites (macrofilariae) over the next 6 to 12 months. The adult females measure 20 to 80 cm in length; the adult males measure 3 to 5 cm. The females live in subcutaneous or deeper intramuscular tissues and are surrounded by a fibrous capsule. The males migrate between nodules to fertilize females. The number of female worms can range from 1 to 60 or more (figure 3).

Approximately 10 to 12 months after initial infection (the prepatent period), the adult female worms begin to produce microfilariae. Offspring microfilariae, which typically measure 220 to 300 micron in length, migrate through subcutaneous tissues. Adult parasites can survive for up to 15 years, and each female can produce 1000 to 3000 microfilariae per day. The total microfilarial load in highly infected subjects is more than 100 million [11].

When an infected human is bitten by another blackfly, the vector takes up microfilariae. Over a period of one to three weeks, the filariae undergo maturation within the blackfly and develop into infective third-stage larvae, thereby completing the life cycle.

PATHOGENESIS — The adult worms (macrofilariae) become encapsulated by fibrous tissue and form subcutaneous nodules, often overlying bony prominences. The microfilariae move through subcutaneous, dermal, and ocular tissues and the lymph system. They provoke a minimal immune response while alive; when they die, they incite a clinical inflammatory response.

O. volvulus adults and microfilariae harbor endosymbiotic Wolbachia bacteria, which are essential for the filarial worm's fertility and survival. Release of Wolbachia-derived antigens from dying parasites can activate innate immune responses and are thought to play an essential role in the development of anterior segment onchocercal eye disease in an experimental murine model [12]. Wolbachia bacteria mediate corneal pathology by activating Toll-like receptors on mammalian cells, which in turn stimulate recruitment and activation of neutrophils and macrophages [11,13-16].

The pathogenesis of posterior segment eye disease is less understood. Chorioretinal disease continues to progress despite elimination of the parasite from the eye, suggesting the involvement of an autoimmune phenomenon. Cross-reactivity has been found between O. volvulus antigen Ov39 and the antigen hr44 found in the retinal pigment epithelium. Hr44, however, is also found in the optic nerve and other ocular tissues. Transfer of Ov39-derived T cell lines, which proliferate in response to stimulation with hr44, have been shown to induce inflammation of the limbus, iris, and choroid in naïve rats [17].

Corneal inflammation appears to occur in response to both Wolbachia and Onchocerca antigens, while dermatologic manifestations appear to occur in response to Onchocerca antigens alone, though the role of Wolbachia antigens has not been definitively excluded [18].

There is a spectrum of immune response to infection; some infected individuals have a minimal immune response to parasite antigens, permitting proliferation of microfilariae in the absence of clinical symptoms, while others have a relatively robust and symptomatic immune response [11]. An immunogenetic basis for this clinical spectrum has been proposed [19], and differing isotypic antibody responses may play a role [20]. A single nucleotide polymorphism in the FcγRIIa gene affects the binding to the different immunoglobulin G (IgG) subclasses and may influence the clinical outcome of onchocerciasis [21]. A genome-wide search for genetic determinants of resistance to O. volvulus infection [22] detected linkage between microfilarial load and chromosome 2p21-p14, though the decisive genetic variants have not been identified.

Cellular immune responses are stronger in individuals with severe onchodermatitis than those with milder disease or uninfected individuals [23]. T-helper (Th) 2-type responses to O. volvulus antigen, rather than Th1-type responses, were more prominent in a study of Ghanians exposed to O. volvulus transmission and, in skin snip–positive individuals, the levels of interleukin (IL)-5 and IL-13 decreased with increasing microfilarial density [24]. Individuals with skin disease from this same area had more pronounced Th 2-type responses compared with individuals without skin lesions [18]. Subjects with a hyper-reactive form of skin disease (sowda) were significantly associated with a variant of the IL-13 gene, which causes a brisk Th2-type immune response with high IgE levels and a resultant low microfilarial burden [25].

A state of hyporesponsiveness or partial tolerance of cell-mediated responses exists in asymptomatic persons with high microfilarial loads. Defects in T cell responses in human filarial infections have been linked with expression of the T cell-inhibiting receptor, CTLA-4 [26]. Furthermore, a subset of CD4+ T cells, T regulatory-1 (Tr1) cells, which are known to suppress immune responses, were demonstrated for the first time in a human infectious disease in onchocerciasis [27]. Tr1 cells produce high levels of IL-10 and are thought to counteract Th2-driven effector inflammatory responses in such individuals [28]. Elevated IgG₄ also acts as blocking antibody to inhibit IgE-mediated degranulation of effector cells and thus downregulates pathogenetic responses, and Tr1 cells have been shown to induce B cells to secrete IgG₄ [29,30].

Prostaglandin (PG)E₂, which has an important role in innate and adaptive immune responses, has been shown to be generated by O. volvulus parasites themselves [31]. In addition, PGE₂ and transforming growth factor (TGF)-beta have been demonstrated histochemically in infiltrating host macrophages and plasma cells around O. volvulus in onchocercomas, and TGF-beta was preferentially observed in the skin of infected individuals with "generalized" or hyporeactive onchocerciasis and to a lesser degree in patients with the hyper-reactive form of onchocercal skin disease [32,33].

Downregulation of host immunity may be induced by O. volvulus surface molecules and by excretory-secretory products. The secretory omega-class glutathione transferase 3 from O. volvulus (OvGST3) has a protective role against intracellular and environmental reactive oxygen species. Significant IgG₁ and IgG₄ responses to recombinantly expressed OvGST3/5 were detected in sera from onchocerciasis patients, indicating exposure of this secreted protein to the host immune system [34].

Cho-Ngwa and colleagues used molecular techniques to identify and characterize O. volvulus antigens that are possibly associated with the development of concomitant immunity. They studied IgG subclass and IgE specific responses to an O. volvulus cysteine proteinase inhibitor, onchocystatin (Ov-CPI-2), in putatively immune and infected individuals in a hyperendemic region in Cameroon and found that both groups had similar IgG₃ and IgE responses, but infected persons had higher IgG₁ and IgG₄ responses. In the infected group, IgG₃ levels increased significantly with age, while IgG₁ levels were high in infected individuals regardless of age. They concluded that anti-Ov-CPI-2 IgG₁ and/or IgG₃ may be involved in protective immunity in the putative immune and infected persons and proposed Ov-CPI-2 as a possible target for an anti-L3 vaccine [35].

CLINICAL MANIFESTATIONS — The main clinical manifestations of onchocerciasis are ocular changes, pruritus, subcutaneous nodules, and onchocercal skin disease, in addition to some systemic features.

Ocular onchocerciasis — The first ocular sign of infection is the presence of microfilariae in the eye in the absence of any other pathology detected by slit-lamp examination. Presence of microfilariae in the anterior chamber is associated with the subsequent development of anterior segment lesions and also progression of posterior eye lesions [36]. Additional manifestations include:

●Punctate keratitis – Punctate keratitis is a relatively common acute, transient finding. White cell infiltrates form around dead microfilariae in the cornea, causing "snowflake opacities," especially at the three and nine o'clock positions (picture 1). Punctate keratitis is reversible.

●Sclerosing keratitis – Sclerosing keratitis is chronic full-thickness fibrovascular change of the cornea and occurs in the setting of longstanding infection, particularly in savanna regions. These changes start typically at the three and nine o'clock positions and can extend across the entire cornea (picture 2).

●Uveitis – Uveitis in the setting of onchocerciasis typically presents with flare in the absence of an accompanying cell infiltrate.

●Optic atrophy – Optic atrophy is a relatively chronic finding; optic disc pallor can occur following an episode of optic neuritis.

●Onchochorioretinitis – Onchochorioretinitis is a common chronic finding. The first layer damaged is the retinal pigment epithelium, and this is most frequently found just temporal to the macula. Subsequently, more extensive loss of the retinal pigment epithelium occurs with retinal death and atrophy and loss of the underlying choroid. The end-stage Hissette-Ridley fundus appearance is named after the authors who made the first descriptions (picture 3) [37,38]. Fluorescein angiography will detail chorioretinal lesions.

Subcutaneous nodules — Subcutaneous nodules ("onchocercomata") are typically 0.5 to 3.0 cm in diameter; they usually contain one or two adult male and two or three adult female worms. The majority of nodules are deep (not palpable), and they do not usually cause significant symptoms. They typically appear over bony prominences and have an apparent predisposition for different anatomic sites depending upon the geographic area, reflecting the different vector biting habits in different regions. Infections acquired in Africa tend to cause nodules over the iliac crests and around the pelvic girdle; infections acquired in Latin America are more commonly associated with nodules on the head, neck, and upper extremities. It is often helpful to ask the patient if they know where any nodules are located, then stand behind the patient to palpate, following a set routine checking all preferred sites (eg, head and shoulder girdle first, then ribs, iliac crests, ischial tuberosities, sacrococcygeal region, trochanters, knees, and ankles).

Ultrasonography can be useful for detection of deeper, nonpalpable nodules. (See 'Ultrasonography' below.)

Onchocercal skin disease — Generalized itching is often the first manifestation of infection, and onchocerciasis should be considered as a possible diagnosis whenever a patient from an endemic area presents with itching or has an itchy rash. Early dermatologic signs due to onchocerciasis include intensely pruritic inflammatory papules, nodules, and plaques. Subsequent lymphadenopathy can develop, most commonly in the inguinal region. After prolonged enlargement and inflammation, the lymph nodes may become fibrotic, resulting in lymphatic obstruction and sometimes genital elephantiasis.

Onchocercal skin disease may be classified as follows [39]:

●Acute papular onchodermatitis – Acute papular onchodermatitis manifests as small (1 to 3 mm diameter) scattered pruritic papules, vesicles, or pustules often across the shoulders or buttocks. It is common in children and young adults.

●Chronic papular onchodermatitis – Chronic papular onchodermatitis comprises larger (approximately 3 to 9 mm diameter), flat-topped pruritic papules, often symmetrically distributed over buttocks, waist, and shoulders. It is seen in children and adults and postinflammatory hyperpigmentation is common.

●Lichenified onchodermatitis (sowda) – Lichenified onchodermatitis is a regular feature of onchocerciasis in some regions, particularly Yemen and Sudan, although it is seen less commonly elsewhere. Teenagers and young adult males typically manifest with hyperpigmented pruritic papules and plaques limited to one limb with associated edema and soft enlargement of the draining lymph nodes. It is also known as "sowda" (Arabic for black or dark).

●Skin atrophy – Skin atrophy manifests with loss of skin elasticity and excessive wrinkling of the skin around the buttocks, waist, and upper thighs in adults; the resulting skin has the appearance of tissue paper. In order to avoid confusion with senile atrophy of the skin, the term onchocercal atrophy is reserved for individuals aged less than 50 years old.

●Hanging groin – Hanging groin is atrophy affecting the skin of the groin and anterior thigh. Inguinal lymph nodes enlarge in a sling of atrophic skin on the medial thigh, then, as the nodes shrink and become fibrotic, they leave redundant folds of loose skin.

●Depigmentation – Depigmentation (leopard skin) typically occurs on the anterior shins of older adults. The inguinal regions and external genitalia may also be affected. Patches of complete pigment loss are seen with perifollicular "spots" or islands of normally pigmented skin giving rise to the so-called "leopard skin" appearance. Atrophy and depigmentation are not usually itchy.

Systemic manifestations — In a study in Malawi, generalized musculoskeletal complaints, backache, and joint pains were more frequent in infected than uninfected individuals. In addition, infected individuals weighed significantly less than uninfected individuals [40]. Inguinal and femoral herniae are common.

Nodding syndrome, an epileptic disorder of uncertain etiology that occurs in children in East Africa, has been associated epidemiologically with O. volvulus infection; the association has been controversial. A systematic review and meta-analysis of eight studies noted that onchocerciasis is associated with epilepsy, with an average increase in epilepsy prevalence by 0.4 percent for each 10 percent increase in onchocerciasis prevalence [41]. However, a subsequent study in an endemic area of Tanzania noted no difference in microfilarial density between individuals with or without epilepsy [42]. A later systematic review and meta-analysis of 11 studies supported the hypothesis that intensity of infection with O. volvulus is involved in the etiology of epilepsy [43]. Neurotoxic autoantibodies to leiomodin-1 have been found more abundantly in patients with nodding syndrome compared with unaffected village controls and were cross-reactive with O. volvulus tropomyosin/troponin, suggesting that nodding syndrome is an autoimmune form of epilepsy caused by molecular mimicry with O. volvulus antigens [44].

A 2017 international workshop on onchocerciasis-associated epilepsy concluded that infection with O. volvulus is associated with a spectrum of epileptic seizures, mainly generalized tonic-clonic seizures, but also atonic neck seizures (nodding), myoclonic neck seizures, and absence seizures. Typically, the onset of seizures is between the ages of 3 to 18 years [45]. Two additional studies provide further evidence of a temporal relationship between onchocerciasis and epilepsy [46,47]. A minority of individuals have concomitant severe stunting with no delay or delayed puberty (the so-called Nakalanga syndrome) [48].

Data from the Onchocerciasis Control Programme in 11 countries in West Africa have shown that mortality was significantly associated with increasing microfilarial load but not with blindness per se (after controlling for other variables) [49]. The relationship between microfilarial load and mortality appears to be nonlinear [50].

Travelers — Onchocerciasis among returned travelers from endemic areas is relatively rare; a minimum stay of 12 months in endemic areas is generally necessary to acquire infection. If infection does occur, it tends to manifest with itching and/or a subtle itchy papular rash, which is often concentrated on one limb. There may be accompanying limb edema [51] and swelling may also occur without any rash. Other early manifestations include transient urticaria, arthralgia, and fever. The chronic skin changes and eye changes typically seen in long-term residents of endemic areas are generally absent. Symptoms develop in a median period of 18 months from the time of exposure (range: three months to three years) [52-54], so a detailed travel history is important. Persons who have spent many years in endemic areas (though grew up in a nonendemic area) may present with symptoms within shorter times of leaving endemic areas. Ocular signs are relatively rare in patients with imported onchocerciasis. When long-term residents of endemic areas migrate to nonendemic areas, they may manifest more chronic skin and eye pathology [55-57].

HIV coinfection — HIV may affect the clinical presentation of onchocerciasis, as well as the immune response to infection [58,59], although there does not appear to be an effect of HIV on onchocerciasis prevalence or vice versa [60] or on response to treatment [60]. Consequently, one would not expect HIV-infected individuals to be at greater risk of infection. Among six individuals with HIV in a hyperendemic area of Uganda where onchocercal skin disease is common, the burden of skin disease was higher than among patients with onchocerciasis in the absence of HIV infection [39,61]. Inclusion of HIV-infected patients in mass treatment campaigns for onchocerciasis appears to be safe [62].

SOCIOECONOMIC AND PSYCHOSOCIAL ASPECTS — High levels of blindness in African savanna regions resulted in desertion of affected villages with resettlement to less fertile areas, with serious adverse economic consequences. In a study in highly endemic areas of Guinea, blindness (and, to a lesser extent, visual impairment) were associated with substantial mobility and occupational impairments [63]. Rates of celibacy, widowhood, and divorce were higher among patients with ocular onchocerciasis than uninfected individuals.

Onchocercal skin disease is also a significant cause of stigma, disability, and diminished agricultural productivity throughout much of sub-Saharan Africa [64-66]. Even after 10 years of community treatment with ivermectin in southeast Nigeria, the most worrisome consequence of onchocerciasis for those with symptoms and signs was social seclusion or stigmatization (affecting 34 percent of individuals) [67]. Severe onchocercal skin disease in heads of households is associated with a higher school dropout rate among children, especially girls [68]. The Global Burden of Disease Study 2017 estimated a total of 1.34 million years lived with disability (YLDs) for onchocerciasis of which 96,100 YLDs were caused by onchocercal eye disease and 1.25 million YLDs were caused by onchocercal skin disease [1].

DIAGNOSIS — The diagnosis of onchocerciasis is based on a history of compatible epidemiologic exposure, clinical manifestations as described above, and supportive laboratory evidence of infection. The clinical picture may be difficult to distinguish from loiasis and from infection due to Mansonella species. Nonspecific laboratory findings in patients with onchocerciasis may include peripheral eosinophilia and hypergammaglobulinemia. However, eosinophil counts are normal in up to 30 percent of infected individuals from endemic areas. (See "Loiasis (Loa loa infection)".)

Skin snips — Skin snips are the gold standard for investigation of an individual patient. A skin snip may be performed with a corneoscleral punch or with a small needle and disposable razor blade (picture 4). It should be a bloodless specimen from the level of the dermal papillae. The site of the skin snip is selected on the basis of the site that is likely to give the highest numbers of microfilariae. In Central America, the best site is over the scapula or iliac crest; in Africa, the pelvic girdle, buttocks, and external thigh; in Yemen, the lower calf. In early infections and in localized light infections, the site selected should be that in which the dermatitis is most marked.

A minimum of two snips should be taken; the sensitivity of the test increases if more snips are taken. For investigation of a returned traveler, often a set of six snips are taken, one from over each scapula, each iliac crest, and each calf. The biopsy specimen should be incubated in saline for up to 24 hours before evaluating for presence of motile microfilariae. Hematoxylin and eosin staining of the specimen may be required for species identification, particularly in areas where other filarial species are also endemic. O. volvulus microfilariae characteristically have no sheath and no nuclei in their tails (picture 5).

It takes approximately 9 to 15 months for the worm to mature and release enough microfilariae to be detectable by skin snip. Skin snips are inadequate for detecting early or light infection, and they are often negative in expatriates and in patients with sowda. (See 'Onchocercal skin disease' above.)

In highly microfilaremic L. loa-infected individuals, L. loa microfilariae in skin snips may be misidentified as O. volvulus microfilariae. In one study including 41 skin snips from patients in Cameroon evaluated with species-specific quantitative polymerase chain reaction, 12 percent were O. volvulus microfilariae, 75 were L. loa microfilariae, 12 percent were Mansonella perstans microfilariae, and one sample had both O. volvulus and L. loa microfilariae [69].

Improved methods of diagnosis are needed for evaluation of individual patients and monitoring of onchocerciasis elimination programs. Alternative approaches based on amplification of parasitic DNA in skin snips remain research tools [70,71].

Slit-lamp examination — Slit-lamp examination can be used to look for wriggling microfilariae within the anterior chamber of the eye. Prior to slit-lamp examination, patients should be asked to sit forward (with the head between the knees) for at least two minutes to improve the likelihood of visualization. Transparent live microfilariae may also be seen coiled in the cornea. Punctate keratitis represents dead microfilariae surrounded by an inflammatory infiltrate; it is easier to see than live organisms.

Mazzotti test — The Mazzotti test should not be used as a routine diagnostic test; it may be considered if onchocerciasis is suspected in the absence of findings on skin snip or slit-lamp evaluation. It is contraindicated in heavily infected individuals (who will have positive skin snips) and individuals with optic nerve disease.

The Mazzotti test consists of a 50 mg oral dose of diethylcarbamazine (DEC), which leads to microfilarial death and associated symptoms of worsening pruritus about 20 to 90 minutes later; an acute papular rash with edema, fever, cough, and musculoskeletal symptoms may also occur. Symptoms generally reach a peak at about 24 hours and then subside over the next 48 to 72 hours. In some cases, severe systemic reactions can develop, including pulmonary edema, visual loss, collapse, and death. In the United States, DEC is not available for this indication.

Patch test — DEC can be administered as a topical preparation to a small area of the skin to assess for local skin reaction. In a study of untreated children in Cameroon, Gabon, and Central African Republic, the proportion of children who tested positive with a 10 percent DEC solution ranged from 25 to 77 percent; this finding correlated closely with the prevalence of nodules (a reflection of the level of endemicity) [72]. Sensitivity may be greater with a 20 percent DEC solution [73].

Patch testing is a useful alternative to skin snipping in low-prevalence areas, since it is noninvasive, inexpensive, and more sensitive than skin snipping. The African Program for Onchocerciasis Control recommended its widespread use as a preferred alternative to skin snip for epidemiologic evaluations [74]. The test is not available in the United States.

Serology — Serology is not uniformly reliable. In addition, the prevalence of positive serology among nonendemic adults returned from endemic areas is extremely high in the absence of active infection and can remain positive for many years [53]. Standard antifilaria enzyme-linked immunosorbent assays (ELISAs) have significant cross-reactivity between filarial parasites. Some recombinant purified antigens, ELISAs, and Western blot techniques with very good sensitivity and specificity for O. volvulus have been developed, but they are not routinely available for clinical use.

Detection of antibody subclass IgG₄ may enhance specificity. An immunochromatographic card test detecting IgG₄ against recombinant Onchocerca antigen Ov-16 (Ov-16 card test) had very good sensitivities in West Africa field trials (81 and 77 percent in two villages). Test specificity was 100 percent (using the skin snip test as the gold standard) [75].

A serologic test using a multi-antigen quick luciferase immunoprecipitation system and four recombinant antigens has been developed for diagnosis of O. volvulus. Sensitivity and specificity for detection of O. volvulus compared with control sera were 100 percent, though it is not widely available [76]. For distinguishing O. volvulus from Wuchereria bancrofti, Loa loa, and Strongyloides stercoralis, specificities of 76, 84, and 93 percent have been reported. The assay could be used for diagnosis of individual infections, for early detection of recrudescent infections in control areas, and for mapping new areas of transmission.

In a study including 285 patients with epilepsy in an ivermectin-naïve, onchocerciasis-endemic region in the Democratic Republic of Congo, serologic results obtained with the Ov16 rapid diagnostic test (Ov16 RDT) and the Ov16 ELISA test were compared with skin snip results [77]. The sensitivity and specificity of each test was calculated with the other assays as a reference. The Ov16 ELISA had the highest sensitivity (83 percent), followed by Ov16 RDT (74.8 percent) and the skin snip (71.4 percent). The Ov16 RDT had a higher specificity compared with the Ov16 ELISA (98.6 versus 84.8 percent).

In the United States, the National Institutes of Health and the Centers for Disease Control and Prevention may be of assistance with diagnostic testing.

Antigen testing — Antigen tests may be more useful than antibody detection assays for the diagnosis of individual infections and for monitoring the success of therapy, since they are positive only in individuals with active infection. Further research is required for additional development of antigens tests before they can be available for routine clinical use.

A study of an Onchocerca antigen detection dipstick test for urine or tears in Cameroon reported sensitivity of 100 percent and 92 percent in urine and tears, respectively; specificity for urine and tears was 100 percent [78]. Major sperm protein 2 (MSP2) has also been proposed as a potential diagnostic antigen; preliminary studies appear promising [79].

Mass spectrometry, bioinformatics, and molecular techniques have been used to characterize additional diagnostic antigens detected in the in vivo nodular fluid [80]. Liquid chromatography and mass spectrometry on blood samples from O. volvulus–infected and –uninfected individuals revealed a set of 14 biomarkers that showed excellent discrimination between infected and uninfected persons [81].

Polymerase chain reaction — Highly sensitive polymerase chain reaction (PCR) tests based upon DNA amplification have also been developed but are not yet available for general use. In a Cameroonian study comparing skin snip PCR and urine PCR with antigen detection, the skin snip PCR had higher sensitivity than the urine PCR (>90 versus 14 percent), and the PCR tests were generally equal to or more sensitive than antigen tests [82]. In a study in Guinea with low prevalence of disease after >10 years of control by the Onchocerciasis Control Programme, skin snip PCR and the DEC patch test were more sensitive than skin snip microscopic examination [83].

Ultrasonography — Ultrasonography of subcutaneous nodules may be used for identification of adult worms. Deeper, nonpalpable nodules can be also detected. Ultrasound may also be a useful tool for the longitudinal observation to monitor adult worm viability after macrofilaricidal therapy [84].

DIFFERENTIAL DIAGNOSIS — The differential diagnosis of onchocercal skin disease is summarized in the table (table 1).

Other differential diagnoses to consider in onchocerciasis include:

●Loiasis – Clinical manifestations of loiasis include transient subcutaneous Calabar swellings and migration of the adult worm across the subconjunctiva of the eye. The diagnosis is established by identifying a migrating adult worm in the subcutaneous tissue or conjunctiva or microfilariae in the blood. Coinfection with onchocerciasis can occur, which is important for decisions regarding treatment. (See "Loiasis (Loa loa infection)", section on 'Onchocerciasis coinfection'.)

●Mansonella infection – Mansonella infections are often asymptomatic, but clinical manifestations can include transient subcutaneous swellings similar to the Calabar swellings of L. loa, pruritus, papular eruptions, urticaria, and hypopigmented macules as well as ocular symptoms. Unlike O. volvulus, the Mansonella adult worms do not form subcutaneous nodules. The diagnosis is established by identifying the microfilariae in the blood or on skin snip. (See "Mansonella infections".)

TREATMENT

Clinical approach — The clinical approach varies for treatment of individuals within endemic areas, individuals outside endemic areas, and mass treatment.

Areas with high transmission

Individual treatment — Treatment of individuals within endemic areas with relatively high levels of ongoing transmission consists of ivermectin (150 mcg/kg) administered orally as a single dose, on an empty stomach with water. Treatment should be repeated every three to six months until the patient is asymptomatic (table 2) [85]. Thereafter, indications for repeat treatment include recurrence of pruritus, presence of a typical rash, or eosinophilia. Treatment with ivermectin may be required for 10 years or more [86].

Adverse effects following ivermectin administration are usually mild and are thought to occur as a result of the host immune response to released Wolbachia antigens [87]. Symptoms usually develop within three days of treatment and include fever, rash, dizziness, pruritus, myalgia, arthralgia, and tender lymphadenopathy. Severe reactions including systemic postural hypotension can also occur. The incidence of these symptoms correlates with burden of infection prior to treatment. Symptoms can usually be managed with analgesics and antihistamines.

The safety of ivermectin in young children (height <90 cm) and pregnant women is uncertain. Ivermectin has been administered inadvertently to pregnant women during mass treatment programs, and no increased rates of congenital abnormalities were observed [88]. Ivermectin may be given after the first week of lactation and no adverse effects in lactating women have been documented.

Administration of ivermectin every six months results in greater reductions in microfilarial loads than annual treatment; it is possible that even more frequent treatment could provide additional benefit. In a study of 657 patients with onchocerciasis, those who received treatment every three months had fewer remaining female worms than those treated annually [85]. In two Mexican communities, administration of treatment every three months appeared to rapidly suppress residual transmission [89].

There is considerable variability in reduction of microfilarial densities between individuals following treatment with ivermectin [90]. Development of ivermectin resistance has been suggested in Ghana [91], but it remains controversial. Suboptimal responses may be attributable to host factors, including polymorphisms in host multidrug resistance (MDR1) genes. In a Ghanian study of 42 patients treated with ivermectin, a difference in MDR1 variant allele frequency was observed between suboptimal responders and responders (21 versus 12 percent) [92]. A mathematical model has been developed for analyzing drug efficacy, which may be used to investigate atypical responses to ivermectin in onchocerciasis [93].

Tetracycline antibiotics may cause permanent tooth discoloration for children <8 years if used repeatedly. However, doxycycline binds less readily to calcium than other tetracyclines and may be used for ≤21 days in children of all ages [94].

Loa loa coinfection — In the setting of coinfection with L. loa, treatment of onchocerciasis with ivermectin can facilitate entry of L. loa microfilariae into the central nervous system, leading to encephalopathy, potentially severe neurologic sequelae, and death [95,96]. The number of people estimated to be coinfected with onchocerciasis and loiasis by 2025 is 31,000 [97].

In areas where both onchocerciasis and L. loa are endemic, blood should be obtained to evaluate for evidence of L. loa microfilariae prior to administration of ivermectin.

The optimal approach to the treatment of onchocerciasis and loiasis coinfection is uncertain; one approach consists of doxycycline (200 mg orally once daily for six weeks) plus albendazole (400 mg orally with fatty meal twice daily for three weeks) [98].

Mass treatment — Mass drug administration programs consist of ivermectin administration at 6 to 12 monthly intervals for 10 to 16 years [99]. The African Program for Onchocerciasis Control (APOC) treated hyperendemic and mesoendemic areas (hyperendemic communities have a prevalence of palpable nodules among a sample of 50 adult males of >40 percent; mesoendemic communities have a prevalence of 20 to 39 percent). The Onchocerciasis Elimination Program for the Americas administers treatment in all areas with the goal of complete elimination.

Mass treatment programs have had significant impact on the burden of disease due to ocular onchocerciasis, including reduction of ocular microfilarial loads and regression of early anterior segment lesions such as punctate keratitis and iridocyclitis [100-104]. Ivermectin also has a beneficial effect on the incidence of onchocercal optic nerve disease [105] and visual field loss [106]. These improvements have been observed to occur more rapidly with mass drug treatment than with vector control alone. In one cohort study evaluating mass treatment in eight Nigerian villages, gross visual impairment decreased from 16 to 1 percent after eight years of annual ivermectin treatment [104].

Mass treatment has also reduced the burden of onchocercal skin disease. Reductions in the prevalence of severe itching (4 to 1 percent after five years of annual treatment) [103,107], nodules (59 to 18 percent after eight years of annual treatment) [104], and papular dermatitis (15 to 2 percent after eight years of treatment) [104] have been observed. A study in Nigeria noted reduction in itching (19 percent), reduction in skin rash (17 percent), and darkening of leopard skin (7 percent) following 10 years of annual ivermectin treatment [108].

A multi-country report of the community impact after five or six years of annual ivermectin treatment noted substantial reduction in clinical symptoms and onchocercal skin disease [109]. There were significant reductions in itching, acute papular onchodermatitis, chronic papular onchodermatitis, lichenified onchodermatitis, depigmentation, and nodules (odds ratios [OR] 0.32, 0.28, 0.34, 0.54, 0.31, and 0.37 respectively). In a report including more than 1400 individuals from the Yeki district in Ethiopia treated with successive annual community-directed treatment with ivermectin for 15 years, the prevalence of infection (by skin snip) dropped from 81 percent to zero. Furthermore, papular dermatitis had reduced by 95.9 percent, palpable nodules by 90.5 percent, and atrophy by 30 percent [110]. Overall, it was estimated that APOC had cumulatively averted 8.9 million disability-adjusted life years (DALYs) due to onchocerciasis up to 2010 and would avert another 10.1 million DALYs between the period of 2011 and 2015 [111].

Elimination of onchocerciasis with ivermectin treatment in hyperendemic areas with efficient vector transmission appears to be feasible [112]. Data from Mali, Senegal, and Nigeria suggest 15 to 19 years of uninterrupted treatment may be required [112,113]. Further study is needed to establish the point at which the number of parasites or parasite density falls so low that infection cannot persist [74,114]. Studies in Burundi, Chad, and Ethiopia suggested that the foci evaluated had reached elimination thresholds; entomologic confirmation is awaited. Elimination is considered within reach for Côte d'Ivoire, Malawi, Mali, Niger, Senegal, and Uganda [115].

Loa loa coinfection — In areas where both onchocerciasis and loiasis are endemic, the rapid assessment tool for loiasis should be employed prior to mass treatment with ivermectin. This tool delineates communities at high risk of loiasis using geographic information systems to identify potential vegetation areas for vector breeding together with a history of eye-worm. (See 'Loa loa coinfection' above and "Loiasis (Loa loa infection)".)

A mobile phone–based video microscope (termed a LoaScope) has been developed that is capable of counting L. loa microfilariae in peripheral blood collected in disposable rectangular capillary tubes. In a Cameroon field trial, the device was used to identify individuals with L. loa microfilaremia levels ≥20,000/mL [116]. Among more than 16,000 individuals who underwent testing, approximately 2 percent were excluded from ivermectin distribution because of a L. loa microfilarial density above the risk threshold. More than 15,500 individuals (95 percent of those tested) received ivermectin for treatment of onchocerciasis; no serious adverse events were observed. (See "Loiasis (Loa loa infection)", section on 'Other tests'.)

Doxycycline may be effective for community-directed treatment in areas where both onchocerciasis and loiasis are endemic. In a Cameroon study evaluating the efficacy of community-directed treatment with doxycycline for six weeks among 104 individuals in communities coendemic for onchocerciasis and loiasis, doxycycline alone was effective for reducing microfilaremia and the viability of adult worms [117].

Areas with no or low transmission — For treatment of individuals outside endemic areas and for treatment of individuals in areas of relatively low transmission, we are in agreement with the United States Centers for Disease Control and Prevention, which favors treatment with ivermectin (150 mcg/kg orally single dose) one week prior to starting doxycycline (100 mg orally once daily for six weeks) (table 2) [118].

For patients with persistent symptoms, ivermectin (single dose) may be repeated every three to six months until asymptomatic (ie, resolution of signs of infection such as rash, pruritus, eosinophilia, microfilariae in skin biopsies, or microfilariae on eye examination). In addition, treatment should be repeated if there is recurrence of clinical symptoms [119,120].

Ivermectin sterilizes female adult worms. Doxycycline targets Wolbachia (the endosymbiotic bacteria within O. volvulus) but does not kill microfilaria. (See 'Targeting Wolbachia' below.)

Most studies on the effectiveness of doxycycline consist of treatment with ivermectin for four to six months following treatment with doxycycline, so the safety of simultaneous treatment is unknown [121].

Therapeutic approach — Potential therapeutic targets include microfilariae and adult worms (macrofilariae).

Microfilaricidal therapy

Ivermectin — Ivermectin is a semisynthetic macrocyclic lactone derivative. Itis a selective inhibitor of neurotransmission in invertebrates, is microfilaricidal, and also appears to impair release of microfilariae from gravid female worms. Within one week following a single dose, ivermectin can reduce skin microfilarial counts by 90 percent, with prolonged suppression for at least a year.

Ivermectin also may have some direct effects on adult worms, but it does not eradicate infection [122]. Multiple doses of ivermectin may have a partial macrofilaricidal effect and a modest sterilizing effect after four or more consecutive treatments, with the life expectancy of adult worm reduced by approximately 50 percent after three years of annual ivermectin treatment [123].

Addition of albendazole to ivermectin does not appear to confer treatment benefit. In a randomized trial including more than 270 patients with onchocerciasis in Ghana, combination therapy with ivermectin and albendazole was no better than ivermectin alone for sterilizing, killing adult worms, or achieving sustained microfilariae clearance [124].

Within the setting of control programs, ivermectin treatment usually has to be repeated throughout the 10- to 14-year life span of the adult worms to eradicate infection in the population. However, in general, it is not necessary to treat infected individuals for the life span of the worm if they are removed from the endemic setting [53]. Most individuals become asymptomatic after a few years of therapy.

Moxidectin — Moxidectin has a longer half-life than ivermectin (20 to 43 days versus <1 day), is more efficacious than ivermectin in reducing skin microfilarial loads, and may be capable of interrupting the transmission cycle within six rounds of annual treatment [125,126]. In a randomized trial (performed in Ghana, Liberia, and the Democratic Republic of Congo) including 1472 patients with at least 10 O. volvulus microfilariae per mg skin treated with moxidectin (978 patients treated with 8 mg single dose) or ivermectin (494 patients treated with 150 mcg/kg single dose), the skin microfilarial density was 7.5 times lower among patients treated with moxidectin (0.6 versus 4.5 microfilariae per mg skin) 12 months later [126]. Moxidectin was approved by the US Food and Drug Administration in 2018 for treatment of onchocerciasis in adults; further study is needed to delineate how it should be used in mass drug administration programs.

Macrofilaricidal therapy

Targeting Wolbachia — Wolbachia is the endosymbiotic bacteria within O. volvulus required for embryogenesis and survival [127,128]. Doxycycline has activity against Wolbachia and has been shown to induce sustained sterility of female worms with a dose-dependent macrofilaricidal effect [129-132].

In one study including 167 patients in Ghana treated with doxycycline (100 mg/day orally for six weeks), followed by ivermectin at 3 and 12 months, the percentage of living female worms containing Wolbachia was substantially reduced (from 80 to 5 percent) [130]. The greatest efficacy has been observed with administration of doxycycline 200 mg/day for six weeks [133].

Such schedules can be used for treatment of individuals in areas of relatively low transmission and for treatment of individuals outside endemic areas. However, for more rapid symptomatic relief, a pragmatic approach is to give ivermectin (single dose) first, then start doxycycline one week later. (See 'Areas with no or low transmission' above.)

Doxycycline cannot be used for treatment in areas of ongoing transmission because new infections would require repeated courses of doxycycline; in such circumstances, repeat dosing of ivermectin is the preferred approach. (See 'Areas with high transmission' above.)

Rifampin and azithromycin have in vitro activity against Wolbachia, although five-day courses do not appear to be effective for clinical management of onchocerciasis [134,135]. Rifampicin may prove to be an alternative to children who cannot be treated with doxycycline or may be used in the future in combination with other drugs; further study is needed.

The heme [136] and lipoprotein [137] biosynthetic pathways of Wolbachia have been proposed as potential candidate drug targets for future research.

Other approaches — The veterinary anthelminthic drug closantel is a potential new therapy; it is an inhibitor of filarial chitinases and inhibits molting of L3 larvae [138].

Removal of adult worms via nodulectomy is another therapeutic option, particularly in lightly infected individuals such as expatriates. However, nodulectomy alone cannot be considered an effective strategy for cure since many worms lie deep and may be undetected.

PREVENTION AND ELIMINATION — There is no vaccine to prevent onchocerciasis. A number of onchocerciasis control programs have been implemented worldwide:

●The Onchocerciasis Control Programme (OCP, 1974 to 2002) – The OCP was an international partnership that used aerial larviciding of rivers for vector control in 11 West African countries. The program was highly successful in interrupting transmission and led to economic redevelopment of fertile areas previously deserted due to high rates of blindness [139]. The OCP also distributed ivermectin to control recrudescence. In extension areas, ivermectin was used either alone or in combination with larviciding.

●Mectizan Donation Program – Merck, the manufacturer of ivermectin (Mectizan), pledged to donate all drugs necessary to overcome onchocerciasis and established the Mectizan Donation Program in 1987. Collaboration was established with the World Health Organization (WHO), health ministries, and nongovernmental organizations to distribute ivermectin using a sustainable community-directed approach [140].

●The Onchocerciasis Elimination Program in the Americas (OEPA, 1991 to the present) – The OEPA consists of partnerships between the governments of the endemic countries, the Pan American Health Organization (PAHO),the Carter Center, Lions Clubs International, the Bill and Melinda Gates Foundation, and the Mectizan Donation Program. The goal is to eliminate onchocerciasis from the region via mass ivermectin therapy every six months; it aims to reach at least 85 percent coverage of the eligible population. In 2008, a resolution adopted by the PAHO called for the regional elimination of ocular morbidity caused by onchocerciasis and interruption of transmission by 2012 [141,142].

By the end of 2012, transmission was interrupted or eliminated in 11 of the 13 foci in the Americas [143]. Colombia was the first country to achieve country-wide interruption of transmission, and ivermectin distribution was discontinued in 2008. Surveillance is required three years following cessation of treatment to achieve certification of elimination, and Colombia subsequently completed the WHO verification process. Ecuador, which has highly endemic transmission with a highly efficient vector Simulium exiguum was the second country to suspend treatment, in 2010. Post-treatment surveillance was completed in 2012, and Ecuador was the second country to be declared free of onchocerciasis in 2014. Subsequently, elimination of transmission in Mexico was confirmed in 2015 and in Guatemala in 2016 [4].

Active transmission is ongoing in two foci, the Venezuelan South Focus and the Brazilian Amazonas Focus, where Yanomani people live deep in the rain forest. Communities with the highest infection prevalence are being targeted with quarterly treatment to try to expedite elimination of onchocerciasis in the Americas.

●The African Program for Onchocerciasis Control (APOC, 1995 to 2015) – APOC initially aimed to control onchocerciasis as a public health and socioeconomic problem. After 2009, however, the treatment goal shifted from control toward elimination. The program covered 19 African countries using annual ivermectin treatment delivered by community distributors chosen by the communities themselves. The communities also controlled the timing of the intervention, taking into consideration issues like weather, religious events, and cultural events. By 2009, more than 68 million people were treated in 15 endemic countries; the average therapeutic coverage was 77 percent in countries with a stable security situation and 64 percent in post-conflict countries [144]. During 2013, seven countries (Burkina Faso, Burundi, Cameroon, Liberia, Malawi, Mali, and Sierra Leone) achieved the minimum requirement of 80 percent therapeutic coverage deemed necessary for eventual onchocerciasis elimination.

Local vector eradication was used in combination with ivermectin treatment in a small number of APOC projects [145,146]. The APOC Trust Fund was supported by a range of partners from the public and private sectors; the program was executed through the WHO, with the World Bank as the fiscal agent. Elimination of onchocerciasis transmission has been reported for the Wambabya-Rwamarongo focus in western Uganda using twice-yearly treatment with ivermectin combined with vector control [147].

Further prevalence of infection surveys were conducted in 2014 with the aim of re-evaluation of villages previously classified as hypoendemic (with precontrol nodule prevalence ranging from 5 to 19 percent) and therefore not previously included in APOC treatment programs. The surveys identified the need to extend areas of treatment in the Democratic Republic of Congo and the need to initiate mass treatment in Gabon [115].

The community-directed intervention approach has been integrated successfully with other primary health care interventions, such as management of malaria, distribution of insecticide-treated bednets, and vitamin A supplementation, with the support of community-directed distributors [148]. African universities and nursing schools are including the community-based strategy in their curricula to broaden use of this effective technique for health care interventions. In 2013, a total of 15 countries coimplemented treatment of onchocerciasis with ivermectin with treatment of lymphatic filariasis with albendazole. Other coimplemented activities include treatment of soil-transmitted helminthiasis, schistosomiasis control, sensitization on HIV/AIDS, and primary eye-care activities.

●The Expanded Special Project for Elimination of Neglected Tropical Diseases is a program established in 2016 to coimplement control activities of onchocerciasis alongside other neglected tropical diseases; specific aims include elimination of lymphatic filariasis by 2020 and onchocerciasis by 2025. Elimination of onchocerciasis requires hypoendemic areas not previously considered for treatment to be mapped by onchocerciasis elimination mapping (OEM), but the prevalence thresholds of positive Ov16 serology and sampling strategies for OEM await confirmation.

SUMMARY AND RECOMMENDATIONS

●Onchocerciasis is caused by the filarial nematode Onchocerca volvulus. It is also known as "river blindness" because the blackfly vector breeds near fast-flowing streams and rivers. The disease affects rural communities and is a major cause of blindness and skin disease in endemic areas, as well as onchocerciasis-associated epilepsy. (See 'Introduction' above.)

●Humans are infected with O. volvulus via the bite of a blackfly of the Simulium genus (figure 3). The blackfly deposits infective third-stage larvae into the human skin, which mature into adult parasites (macrofilariae) over the next 6 to 12 months. The females live in subcutaneous or deeper intramuscular tissues and are surrounded by a fibrous capsule. The males migrate between nodules to fertilize females. Approximately 12 months after initial infection, the adult female worms begin to produce microfilariae, which migrate through subcutaneous tissues, dermal, and ocular tissues. When an infected human is bitten by another blackfly, the fly takes up dermal microfilariae. (See 'Life cycle' above.)

●Clinical manifestations of onchocerciasis include eye involvement, subcutaneous nodules, skin involvement, and systemic manifestations, including onchocerciasis-associated epilepsy. Manifestations of ocular onchocerciasis include punctate and sclerosing keratitis, uveitis, optic atrophy, and chorioretinitis. Manifestations of onchocercal skin disease include acute and chronic papular onchodermatitis, lichenified onchodermatitis, skin atrophy, hanging groin, and depigmentation. (See 'Clinical manifestations' above.)

●The diagnosis of onchocerciasis is based on a history of compatible epidemiologic exposure, clinical manifestations, and supportive laboratory evidence of infection. A skin snip biopsy is the gold standard for investigation of a patient. Slit-lamp examination can be used to look for wriggling microfilariae within the anterior chamber of the eye. Mazzotti testing should be performed only in certain clinical circumstances. Serology, antigen testing, and polymerase chain reaction are useful tools though are not routinely available in endemic areas. Ultrasonography of subcutaneous nodules may be useful for identification of adult worms. (See 'Diagnosis' above.)

●For individuals with onchocerciasis in endemic areas with high levels of ongoing transmission, we suggest treatment with ivermectin (150 mcg/kg) administered orally as a single dose (table 2) (Grade 2C). Treatment should be repeated every three to six months until the patient is asymptomatic; treatment may be required for 10 years or more. In areas where both onchocerciasis and Loa loa are endemic, blood should be obtained to evaluate for evidence of L. loa microfilariae prior to administration of ivermectin. (See 'Individual treatment' above and 'Loa loa coinfection' above.)

●For treatment of individuals outside endemic areas and for treatment of individuals in areas of relatively low transmission, we suggest treatment with ivermectin (single dose) one week prior to starting doxycycline (daily for six weeks) (table 2) (Grade 2C). (See 'Areas with no or low transmission' above.)

●Mass drug administration programs consist of ivermectin administration at 6 to 12 monthly intervals for 10 to 16 years. In areas where both onchocerciasis and loiasis may be endemic, assessment for loiasis should be made prior to mass treatment with ivermectin. (See 'Mass treatment' above.)