Journal of the Egyptian Society of Parasitology, Vol.45, No.3, December 2015

J. Egypt. Soc. Parasitol. (JESP), 45(3), 2015: 639 - 654

THE ARTHROPOD-BORNE ONCHOCERCIASIS: IS IT DESERVED TO BE NEGLECTED? By MAMDOUH M. M. EL-BAHNASAWY1, AYMAN T. A. MORSY2 AND TOSSON A. MORSY3 Military Medical Academy1, Consultant of Tropical Medicine, The Ministry of Interior Hospitals2, and Faculty of Medicine, Ain Shams University, Cairo 115663, Egypt.

Abstract Onchocerciasis a filarial parasitic nematode, also known as river blindness and Robles dis- ease, is a neglected tropical disease infecting more than 18 million people mainly in sub- Saharan of Africa, the Middle East, South and Central America and many other countries. Dis- ease infectivity initiates from Onchocerca volvulus (Filarioidea: Onchocercidae) transmitted by the blackfly, Simulium sp. which introduces the infective stage larva with its saliva into the skin. Within human body, adult females (macrofilaria) produce thousands of larvae (microfilar- iae) which migrate in skin and eye. Infection results in severe visual impairment or blindness for about 2 million, as being the world’s second-leading cause of blindness after trachoma, as well as skin onchocercomata. Key words: Egypt, Onchocerciasis, blackfly, General review, Recommendations

Introduction fection rates may be as high as 80 to 100% Onchocerciasis is caused by the filarial by the age of 20 in certain areas. Clinical nematode, Onchocerca volvulus. It is a ma- manifestations become apparent later, with jor cause of both skin disease and blindness blindness peaking at 40 to 50 years of age. in endemic areas, known as "river blindness Hyperendemic regions were frequently de- and Robles disease" because the blackfly populated because of high rates of ophthal- vector for this infection breeds in areas near mic complications. Neto et al. (2009) in fast-flowing streams and rivers. Onchocerci- Brazil reported that the prevalence of ocular asis can be a major cause of morbidity for lesions strongly correlated with the cutane- individuals in endemic areas and can have ous nodules and eosinophilia, suggested that major socioeconomic consequences (Taylor, skin nodules might be an indication for an 1990). eye examination, since significant infection Epidemiology: Onchocerciasis is transmit- and onchocerciasis eye disease persisted in ted in limited areas of tropical Africa, Yem- certain regions of Northern South America. en, and Latin America. Humans are the only There are two different strains of O. volvulus definitive host for O. volvulus, although in Africa, one strain is transmitted by black there are a number of other species that in- flies that tend to breed in savannas; this fect only animals tell now. Approximately strain is more commonly associated with 18 million people are infected worldwide. ocular disease, even with only a moderate More than 99% of symptomatic cases occur parasite burden and second strain is trans- in sub-Saharan Africa, particularly in Nige- mitted by vectors that breed in forests and ria and Zaire, It where 3 to 4 million infect- generally was not associated with blindness ed individuals with skin disease, and 1 to 2 (Higazi et al, 2005). Black flies are not effi- million with blindness or visually impaired. cient vectors; as 12 months in endemic areas The disease tended to be found in rural areas is generally necessary to acquire infection, (WHO, 1995). The visual impairment in- and as most helminthes, the worms do not crease, in part, as the prevalence and intensi- replicate in humans, so an increase in adults ty of infection in a community rises. In Afri- burden requires additional exposure to a bite can endemic areas, the prevalence of infec- of an infective vector (Nguyen et al, 2005). tion can vary from village to village, but in-

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Life cycle: Humans are infected with O. hind most of its morbidity. Dying microfilar- volvulus by bite of the black fly; Simulium iae release Wolbachia surface protein that genus. The black fly transmits infective third activatedTLR2 & TLR4, triggering innate stage larvae to humans, and these larvae are immune responses and producing the in- deposited into the host skin. Over a period of flammation and its associated morbidity 6 to 12 months, the larvae mature into adult (Baldo et al, 2010). The severity of illness is worms. Females measure 20 to 80 cm in directly variable and depends upon the cir- length, live in subcutaneous or deeper intra- culating microfiliaria number and the host muscular tissues surrounded by a fibrous immune response (Burnham, 1998). Some capsule, whereas males measure 3 to 5cm patients have a minimal immune response to and migrate between nodules to fertilize fe- parasite antigens, permitting microfilariae males. The prepatent period ranges from 10 proliferation in the absence of symptoms to 12 months, the females begin to produce (Prost et al, 1979). Others have a relatively microfilariae. The Simulium female takes a robust immune response against circulating blood meal from an infected human host, microfilariae (King and Nutman, 1991). Du- and ingests microfilariae. In the Simulium, ration of infection may also play a role in the microfilaria enter the gut and thoracic degree of inflammatory response; it has been flight muscles, progressing into the first lar- suggested that individuals with early O. vol- val stage, larvae mature into the second lar- vulus infection mount a substantial cell-med- val stage, and move to proboscis and into the iated immune response, while those with the saliva in its third larval stage. Maturation chronic infection tend to have a blunted cel- takes about seven days. When the black fly lular immunity (Cooper et al, 2001). Patients takes another blood meal, it passes the lar- with a significant cellular immune response, vae into the next human’s blood. In man, polyclonal B cell activation and hypergam- larvae migrate to the subcutaneous tissue maglobulinemia are common, as are non- and undergo two more molts, and form nod- specific elevations in IgG & IgE. However, ules as they mature into adults over 6 to 12 there was minimal evidence for the acquired months. After maturing, males mate with immunity to O. volvulus in endemic areas females in subcutaneous tissue to produce (Kruppa and Burchard, 1999). Also, release from 1000 to 3000 microfilariae/day. The of Wolbachia-derived antigens from dying microfilariae migrate to the skin at daytime, adults and microfilariae can activate innate and the vectors only feed in the day, so the immune responses and may elicit inflamma- parasite is in a prime position for the female tion in the skin and eye (Johnson et al, fly to ingest it. Black flies take blood meals 2005). The heightened propensity for ocular to ingest the microfilariae to restart the cy- disease due to the Savanna strain of O. vol- cle. Adults can survive for up to 15 years, vulus relative to the milder Forest strain cor- and microfilariae can survive for one to two related with higher quantities of the Wol- years (Brattig, 2004). bachia DNA by PCR in the Savanna strain. Pathogenesis: O. volvulus adults reside in Both Wolbachia and Onchocerca antigens fibrous skin nodules where they are protect- appear to influence corneal inflammation, ed from the host immune response. The mi- although dermatologic manifestations were crofilariae, in contrast, are capable of mov- attributable to Onchocerca antigens alone ing through subcutaneous and ocular tissues. (Udall, 2007) Although they provoke a minimal immune Clinical manifestations: The onchocercia- response while alive, on dyeing incite a clin- sis manifestations include dermatologic ones ical inflammatory response. Wolbachia sp. (subcutaneous nodules and pruritic dermati- is endosymbiosis of adults and microfilariae, tis) and ocular manifestations. and are thought to be the driving force be- I- Subcutaneous nodules (onchocercomata)

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are typically 0.5 to 3 cm in diameter; they chenified dermatitis affecting one or multi- usually contain one or two adult male and ple limbs; characterized by the dramatic skin two or three adult female worms. Nodules disease and a brisk T-helper 2 (Th2)-type are not associated with inflammation and do immune response with high IgE levels not usually cause significant symptoms. (Hoerauf et al, 2002). So, patients with sow- They typically appear over bony prominenc- da have a low microfilarial burden (microfi- es and have an apparent predisposition for lariae are usually absent in skin snips) and different anatomic sites depending upon the ivermectin therapy may be less effective in region in which the infection was acquired such patients. 4- Skin atrophy manifests with (reflecting the differences in vector biting loss of skin elasticity and wrinkling of the habits in different regions). Infections ac- skin; the resulting skin has the appearance of quired in Africa tend to cause nodules over tissue paper. 5- Elephant skin or thickening the iliac crests and lower limbs, while those of human skin associated with onchocercia- acquired in Latin America are more com- sis. 6- Depigmentation manifests with loss monly associated with nodules on the head, of patches of skin with loss of pigment adja- neck, and upper extremities (Little et al, cent to areas of normally pigmented skin can 2004). II- Dermatitis due to onchocerciasis result in a "leopard skin" appearance. is an intensely pruritic inflammatory papulo- Ocular onchocerciasis: Onchocerciasis is a nodular process that may affect up to half of leading cause of blindness in the developing individuals in endemic communities. Exco- world. Individuals with blindness due to on- riation frequently leads to secondary bacteri- chocerciasis have a fourfold increase in mor- al infection. Subsequent lymphadenopathy tality and diminished life expectancy by 7 to can develop, most commonly in the inguinal 12 years. O. volvulus is the second com- region. Atrophic skin over the lymph nodes monest cause of blindness, after trachoma can become loose, leading to hanging folds (WHO, 2014). Microfilariae cause ocular of skin termed hanging groin. After pro- tissue inflammation leading to a reversible longed enlargement and inflammation, the punctate keratitis known as snowflake opaci- lymph nodes might become fibrotic, result- ty. Longstanding infection results in scle- ing in lymphatic obstruction and elephantia- rosing keratitis, characterized by an inflam- sis (Connor et al, 1985). The onchocerciasis matory infiltrate beginning at the edge of the dermatitis may be classified as follows: 1- cornea and eventually involving the anterior Acute papular dermatitis manifests as small chamber and/or the retinal epithelium. Pos- scattered pruritic papules, vesicles or pus- terior eye involvement, chorioretinitis, optic tules that may heal spontaneously in a few neuritis, optic atrophy, glaucoma and blind- months or progress to one of the following ness may ensue. The slit lamp examination categories. 2- Chronic papular dermatitis may show intraocular microfilariae, fluores- manifests with larger pruritic papules, often cein angiography may demonstrate chori- symmetrically distributed over buttocks, oretinal lesions (Egbert et al, 2005). In the ocu- waist and shoulders. Hyperpigmentation and lar findings, differential includes infection hyperkeratosis may develop in regions of with other microfilaria as M. perstans, L. chronic papular dermatitis. 3- Lichenified loa, O. gutturosa, or Dracunculus medinen- dermatitis (Sowda) manifests with hyper- sis, inflammatory lesions involving iridocy- pigmented pruritic papules and plaques with clitis includes systemic inflammatory etiolo- associated edema and lymphadenopathy. A gies as sarcoidosis, and other corneal degen- distinct form of lichenified dermatitis known erative/sclerotic diseases (Mcleod, 2008). as sowda (in Arabic, black or dark) is de- Onchocerciasis among visitors to endemic scribed in some regions, particularly Yemen areas is relatively rare; if infection does oc- and Sudan. Sowda is a localized form of li- cur it tends to manifest with pruritic dermati-

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tis but without chronic skin changes or eye and from skin over each scapula, each iliac involvement. There may be an associated crest, and each calf. The biopsy specimen faint, nonspecific rash, but the chronic skin should be incubated in saline for up to 24 changes that are seen in endemic communi- hours before examination for motile microfi- ties with high intensity of infection do not lariae. Staining the specimen may be re- occur. Symptoms develop in a median peri- quired for species identification in endemic od of 18 months from exposure time with for other filarial species. The microfilariae range of three months to three years (Freed- have neither sheath nor nuclei in tails (Lip- man, 2005). ner et al, 2006). Diagnosis: diagnosis of onchocerciasis Visualization of microfilariae by skin snip depends upon a history of compatible epi- is a highly specific diagnostic tool, although demiologic exposure, clinical manifestations this technique is inadequate for detecting as described above, and supportive laborato- early infection or infection with low worm ry evidence of infection. The clinical picture burden. It takes approximately 18 months may be difficult to distinguish from loiasis for the worm to mature and release enough and from infections with Mansonella spe- microfilariae to be detectable by skin snip cies. Infection with Loa loa, occurs fre- microscopy (Winthrop et al, 2006). quently in certain endemic regions of Africa. Slit lamp examination: Diagnosis of onch- Loiasis occurred only in western and central ocerciasis can occasionally be made by vis- Africa and not commonly associated with ualizing microfilariae on slit lamp examina- severe disease in either residents or visitors tion of the eye. Lesion may manifest as mi- to endemic regions and sometimes called crofilariae visua-lized in anterior chamber or "eyeworm" as the adult may be found mi- as punctate keratitis with or without inflam- grating across the subconjunctiva of the eye. mation, inflammatory punctate keratitis It is estimated that between 3 and 13 million without visible microfilariae was insufficient people are infected. Infection appears to be for diagnosis (Enk et al, 2003). occult in a large proportion of patients and Mazzotti test: Administration of diethyl- remains undiagnosed; thus, the epidemiolo- carbamazine (DEC) to the onchocerciasis gy of loiasis in many areas has not been patients can lead to systemic reactions relat- clearly defined. The probability of infection ed to an inflammatory response to dying mi- increases with age in endemic regions, but crofilariae. A 50 mg dose of DEC or a patch the exact proportion of infected individuals test using topical DEC can be given to peo- varies from village to village depending up- ple suspected of being infected. Pruritus on vector abundance. Active infection is up would generally develop within three hours to 40% of certain populations (Bakajika et in infected individuals, although symptoms al, 2014). The significance of infections may be delayed for up to 24 hours. The test with Mansonella sp. and frequency and se- can be useful in both endemic areas and in verity of attributed symptoms are still debat- expatriates suspected of being infected, with ed (Mourembou et al, 2015). Non-specific a sensitivity of >90%. However, the test can laboratory findings in onchocerciasis patie- cause significant discomfort and can even be nts may include the Ag-specific IL-5 res- dangerous. Skin snips and ophthalmologic ponse, peripheral eosinophilia and hyper- examination should be negative prior to per- gammaglobulinemia (Hall et al, 1999). forming the Mazzotti test, and it should only A skin snip may be performed with a cor- be performed in lightly infected patients to neoscleral punch or with a small needle and avoid severe reactions. Because of the symp- disposable razor blade. It should be a blood- toms it can invoke, but not recommended as less specimen from the level of the dermal a routine diagnostic test (Kilian, 1988). papillae, taken from areas of involved skin Traditional serologic tests for antibodies

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to O. volvulus use relatively crude anti- for the longitudinal observation of patients genic extracts with significant cross- with onchocerciasis to monitor the viability reactivity between other filarial and non- of the adult worms after macrofilaricidal filarial parasites, and cannot differentiate therapy (Mand et al, 2005). between previous and active infection so are Loaisis coinfection: In patients with oncho- of limited utility in endemic areas. However, cerciasis and Loa loa coinfection, onchocer- they can be useful for evaluation of travel- ciasis treatment with ivermectin therapy can ers. Recombinant purified antigens ELISA facilitate entry of L. loa microfilariae to the and Western blot techniques improved the central nervous system, leading to encepha- specificity of serology for the active oncho- lopathy and potentially severe neurologic cerciasis diagnosis (Luz et al, 2014). Other sequelae, and in a case, noontime blood assays have been developed for detection of should be taken to evaluate L. loa microfi- antibody subclass IgG4, since this subclass lariae prior to therapy (Kamgno et al, 2004). is may be a more specific marker of active Treatment: The drug of choice for oncho- onchocercal infection than total IgG with cerciasis is ivermectin (Plaisier et al, 1995). greater sensitivity than conventional skin Ivermectin is a semisynthetic macrocyclic snip examination (Lucius et al, 1992). The lactone derivative that appears to impair re- sensitivity of the ELISA test was 92% for lease of microfilariae from gravid female serum and 86% for urine. In Cameroon, a worms. It also may have some direct an- urine and tear antigen detection dipstick test thelminthic effects on adult worms, but does for the diagnosis of onchocerciasis was not eradicate infection (Duke, 2005). It found to have sensitivity of 100% in urine should be given as a single dose 150 mcg/kg and 92% in tears and specificity of 100% orally on an empty stomach with water. (Ayong et al, 2005). Treatment may be required for 10 years or PCR: Highly sensitive tests based upon more, even for travelers without ongoing DNA amplification, in Cameroon, samples exposure in endemic areas. a single dose af- of human serum, skin, and urine for the di- ter one week post reduced skin microfilarial agnosis of onchocerciasis (Vincent et al, counts by 85 to 95%, with prolonged sup- 2000). Parasite DNA was detected in skin pression for at least a year (Alley et al, snips and urine by PCR, and results were 1994). Adverse effects following ivermectin compared with parasite antigen detection adminis-tration tend to occur as a result of and serum concentrations of IgG4 antibod- the host immune response to released On- ies. Boatin et al. (2002) found that PCR and chocerca and Wolbachia antigens rather a test based on the allergic reactions to topi- than as a result of drug toxicity (Keiser et al, cal application of diethylcar-bamazine 2002). Symptoms include fever, rash, dizzi- (DEC) patch test proved more sensitive than ness, pruritus, myalgia, arthralgia, and ten- low sensitive skin snipping. They added that der lymphadenopathy occurs within three DEC test might provide a good alternative to days of treatment. Symptoms incidence cor- skin snipping alone for surveillance in low relate with infection burden before treat- prevalence areas. ment, which could be managed by analge- Radiology: Adult onchocerciasis some- sics and antihistamines (Njoo et al, 1995). In times can be identified on ultrasound exami- patients with onchocerciasis and loiasis co- nation of subcutaneous nodules. Nodules in infection, treatment of onchocerciasis with deeper (e.g., nonpalpable) subcutaneous tis- ivermectin therapy facilitates entry of L. loa sues can be also detected by ultrasonography microfilariae to the central nervous system, (Udall, 2007). Removal and examination of leading to encephalopathy and potentially the worms confirms the species diagnosis. severe neurologic sequelae (Bockarie et al, Ultrasound may also be used as a new tool 1998).

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Safety of ivermectin in young children The largest mass control program has been (<15kg) and pregnant women remains to be the Onchocerciasis Control Program, an in- established. Ivermectin has been inadvert- ternational partnership initiated in 1974 ently given to pregnant women during mass which implemented mass ivermectin treat- treatment programs; the rates of congenital ment and aerial insecticide spraying of rivers abnormalities were similar in treated and with black fly larvicidal agents in West Af- untreated women (Pacque et al, 1990). rica (Hopkins et al, 2005). The aerial spray- Diethylcarbamazine (DEC): is a potent mi- ing ended in 2002 but mass treatments are crofilaricidal agent but is associated with still needed (Osei-Atweneboana et al, 2007). numerous adverse effects including aggrava- Because the adult worms can live for 15 tion of ocular lesion, blindness, hypotension years or more, ivermectin distribution need and death. DEC was used for treatment of to be sustained for a minimum of 10 to 15 onchocerciasis prior to the introduction of years to achieve eradication (Taylor et al, ivermectin. Doxycycline has activity against 1990). Wolbachia, the endosymbiotic bacteria with- The safe ivermectin greatly reduces the in Onchocerca adults and microfilariae burden of microfilariae in skin and eye tis- (Johnston and Taylor, 2007). Although it is sues and effective for mass chemotherapy not filaricidal for either adult worms or mi- (Peters and Phillips, 2004). In control pro- crofilariae, by targeting Wolbachia species it grams, ivermectin is administered once year- can reduce the burden of microfilariae in the ly. However, the ocular microfilaria load skin. Patients with onchocerciasis, doxycy- falls at a slower rate than skin microfilaria cline (100 mg/day orally for 6 weeks) was load; ocular loads can return to 30% of pre- followed by a single oral dose of ivermectin treatment levels at one year. Administration (150mcg/kg) resulted in up to 19 months of of ivermectin every six months resulted in amicrofilaridermia and complete Wolbachia greater reductions in microfilarial loads than elimination (Hoerauf et al, 2003). Rifampin annual treatment (Awadzi et al, 1999). and Azithromycin used in vitro activity ag- It is possible that more frequent treatment ainst Wolbachia, but not effective for oncho- could provide additional benefit. In a study cerciasis management (Richards et al, 2007). of 657 patients with onchocerciasis, those Macrofilaricidal therapies: Suramin has who received treatment three times yearly activity against adult worms but has signifi- had fewer remaining female worms than cant toxicity. Amocarzine has some reported those treated once yearly (Gardon et al, macrofilaricidal activity, but with minimal 2002). clinical experience (Zea-Flores et al, 1991). In the regional countries: Removal of adult worms by nodulectomy, In Kuwait: Abdul-Salam and al-Taqui particularly in lightly infected individuals (1995) over a period of 14 months, the blood such as expatriates, but many deep embed- of 284 camels were examined, of these 32 ded worms were undetected, so nodulecto- (11%) were found infected with the microfi- my alone cannot be considered an effective laria in all months except summer, July to strategy for cure (Ottesen, 1993). September, and February. The peak (27%) Mass Control Programs: As to vaccine was in June at the end of spring. They sug- Steisslinger et al. (2015) reported that DNA gested that harsh environmental conditions vaccination with Ov-GAPDH has protective in Kuwait during summer either arrest de- potential against filarial challenge infection velopment of microfilariae or influence their in the mouse mode. Thus, to prevent oncho- diurnal distribution in camels’ tissues. Hira cerciasis relies on black fly vector control et al. (2008) described zoonotic filariasis in and mass chemotherapy programs. two patients from Kuwait; one with Oncho- cerca spp. and one with Dirofilaria spp. The

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first was a 12-year-old Kuwaiti woman who ing periodicity which could be related to a had visited Saudi Arabia, initially reported possible vector's peak of feeding activity. ocular symptoms. She later reported a nod- Siddiqui and al-Khawajah (1991) men- ule that appeared in the suprapubic area, tioned that Sowda, localized asymmetrical which was resected. This patient represented onchocerciasis lesion was endemic in Yem- the 15th reported case of zoonotic onchocer- en and Southern Saudi Arabia characterized ciasis in a country that is not endemic for by hyperpigmented lichenified papular le- human onchocerciasis. The second was a 34- sions on one leg with intense pruritus and year-old Indian woman from Kuwait City, enlargement of femoral and inguinal lymph reported a moving object in her left eye. A glands. They reported that in the long stand- live worm was extracted and identified as an ing human cases did not show elephantiasis immature female Dirofilaria (Nochtiella) of the leg or genitalia. Microfilaria appeared repens. to be scarce and adult worms could not be In Libya, only Crosskey and Ashford (1981) detected clinically or by the ultrasonography reported Simulium s. l. (except in one case). In Saudi Arabia, Cheema et al. (1984) re- Ghandour et al. (1991) reported that 192 ported that 125 of 478 (26.2%) camels were male camels young, adult and old were ex- infected with onchocerciasis and prevalence amined for O. fasciata infection. The overall rates in local and imported camels were prevalence rates were 10.9 & 33.3%, respec- 93/272 (34.2%) and 32/206 (15.5%), respec- tively. The prevalence rate was higher in tively. Infection was characterized by hard young and adult camels than in old ones. An nodules in the connective tissue around the increase in size and weight of nodules was nuchal ligaments and in the subcutis. The reported with an increase in age of the cam- nodules consisted of cavities containing live, els. Nodules varied in diameter from 2 to 36 degenerate or dead microfilariae, inflamma- mm and in weight from 0.5-5.0g. The over- tory cells, fibrosis and calcification. O. fas- all percentage of soft viable and calcified ciata microfilariae were concentrated in the nodules was 42.5 & 57.5%, respectively. skin over the head and neck regions and of- The viability of worms decreased, but calci- ten caused mild non-suppurative dermatitis. fication increased with increased age of the Nasher (1986) reported O. fasciata in subcu- camels. By SEM, four levels of degeneration taneous nodules of anterior parts of Camelus and calcification of worms were described. dromedarius (nuchal ligaments, neck, and Omar and Raoof (1996) in Abha Province shoulders) infection ranged between 2 &29, reported O. fasciata by histochemical inves- with a mean of 10.8 nodules/ camel. He tigated suggested that it lacks a classical, added that infection rate was 59%, they did mammalian-type respiratory pathway and not exhibit any apparent disease. Hussein that oxidative phosphorylation is of no im- and el Sammani (1990) found that for the portance as an energy generating pathway in release of O. raillieti microfilariae from skin this essentially anaerobic parasite. snips and for their subsequent in vitro Helmy and Al Mathal (2003) diagnosed maintenance, Tyrode's solution containing three patients referred from Dermatology 20% equine serum and antibiotics was the Out-patients Clinics, King Abdulaziz Uni- best medium tested, followed by phosphate versity Hospitals, as Sowda (chronic hyper- buffered saline proved useful. A temperature active form of O. volvulus). The patients 7-12oC lower than that of host's body fa- came from Asir Region in the Southern of vored microfilariae release from skin snips. the Kingdom. There was extensive follicular Microfilariae were best maintained at 4- hyperplasia of the regional lymph nodes in 10oC, when they remained alive for up to 5 two cases only. The skin snips taken of three days. O. raillieti microfilariae had an even- patients were positive and urine of one pa-

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tient was positive. Six months after the onset microfilariae degenerated and provoked of treatment in the Specialized Hospital, skin acute inflammation, but dermatitis decreased snips and urine samples were negative. after several days after treatment. Enlarged In Yemen, Anderson et al. (1973) report- lymph nodes from sowda showed follicular ed onchocerciasis with reference to sowda. hyperplasia, in contrast to follicular atrophy Omar et al. (1979) in a pilot study in the and perivascular fibrosis characteristic of south-western region of the Yemen Arab lymph nodes from cases of African oncho- Republic reported microfilariae in 61 per- cerciasis. Richard-Lenoble et al. (2001) stat- sons examined in eight. A single larva of S. ed that the geophysics of the north Yemen, damnosum was collected in Wadi-Barakani, associating a north-south directed mountain- and numerous larvae and pupae of S. rufi- ous fish bone (rising in more of 2,000 me- corne & S. hargreavesi were taken in fast- ters), to numerous rivers or "wadis" is con- flowing streams in four localities. By SEM venient to the development of Simulium and histochemical examination the microfi- shelters, main vectors of Onchocerca sp. lariae and adults belonged to O. volvulus, They identified as microfilaria type Oncho- which were typically as those in Liberia, cerca but not belong to species volvulus, or West Africa. al Qubati et al. (1997) reported to species ochengi. They added that the clin- that ivermectin (Mectizan) chosen as a con- ical picture of sowda be the result of devel- trol strategy plan in onchocerciasis was ac- oping onchocerciasis of animal origin and tive during 3 months for the less on clinical not identified as to day. They distinguished and histological data. After a short increase 2 kinds of answers based on the clinical of itching and oedematous skin aspects clin- origin of the snip-tests: the first one concern ical signs decrease. Some patients notice an 3 patients with numerous dermal microfilar- itching rebound after 90 days. Histological- iae but without any clinical sowda and cor- ly, localized ingratiates, presence of mono- responding to microfilaria O. volvulus type nuclear cells and melenin loaded histiocytes but different from the forest or savannah and eosinophils decreased. The rythm cure strains found in sub-Saharan Africa. The se- has to be studied on a longer period but 3 to cond one corresponds to 2 patients with less 6 months repetition between oral treatment than 5 microfilariae in their snip-test, show- with 200 micrograms/kg dose during two ing the typical clinical picture of sowda. years could be effective Büttner and, Rácz (1983) reported 14 subcu- Connor et al. (1983) reported that Sowda taneous nodules from five patients with se- is an unusual form of onchocerciasis in the vere localized onchocerciasis, one patient Yemenites that differed from African oncho- with a mild dermatitis and two men with the cerciasis. They added that Clinical and generalized form, with median worm burden pathological studies on 18 patients in North were two filariae/patient. Ten nodules con- Yemen, the most striking clinical features tained adult parasites with an average sex were swollen, darkened, pruritic, papular ratio of 1.6 for female to male worms. On- skin changes that were usually limited to one chocercomata of the two patients with se- leg, more rarely to one arm, and large soft vere localized onchocerciasis comprised one regional lymph nodes and dermal changes or two pairs of microfilariae producing were deeper and more diffuse than in Afri- worms whereas the microfilaria load in these can onchocerciasis, with many large fibro- patients’ skin was less than 100 000 microfi- blasts and plasma cells and that the microfi- lariae. One nodule contained no intact mi- lariae of O. volvulus were much rarer in skin crofilariae but more than 10 000 small gran- from Yemenites with sowda. When they ulomas with all stages of degenerating mi- treated the patients with diethylcarbamazine, crofilariae whereas the density of 0.08 live the dermatitis became suddenly worse as the microfilariae per milligram in the skin near

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to the nodule was very low. They concluded from one geographic region to another. Enk that patients with severe localized onchocer- et al. (2003) stated that since 1992, approx- ciasis possessed the capacity naturally to kill imately 9,000 immigrants arrived from the microfilariae as many degenerating microfi- Kuwara province of northwest Ethiopia lariae were surrounded by eosinophils or where onchocerciasis was endemic. They macrophages or which lay in small abscess- examined 1,200 recent immig-rants residing es with neutrophil leucocytes or in small at the Mevasseret Zion immigration center granulomas.Abdel-Hameed et al. (1987) re- outside Jerusalem. They found that by skin ported a case of Sowda with microfilariae in examination in 83 patients, the commonest the lymph nodes.. They concluded that the was chronic papular onchodermatitis about Yemeni case contrasted with African oncho- 46 patients (55%); depigmentation and atro- cerciasis, where the lymph nodes tend to be phy in 13 (15%) and 12 (14%), respectively. atrophic and microfilariae are usually pre- In 40 patients (48%) living microfilaria were sent. detected in skin snips. Of 65 patients, 45 In Israël, Beaucournu-Saguez et al. (1976) (66%) had ocular complaints. The corneal described Simulium (W.) golani Beaucour- abnormalities were found in 55/130 eyes nu-Saguez and Braverman as n. sp. in the (42%), active anterior segment intraocular Golan region (35 degrees 42' E, 32 DE- inflammation and live microfilariae were in GREES57' N). It was related to Simulium 4 eyes (3%) and lens changes in 16 eyes (W.) paraequinum Puri 1933 but was distin- (1%), eleven eyes (9%) showed retinal or guished by the morphology of pupal respira- choroidal changes. They concluded that on- tory filaments and structure of male genita- chocerciasis skin and eye manifestations lia. Oshry et al. (1995) presented a 31-year- were prevalent among symptomatic Ethiopi- old male Ethiopian immigrant with ocular ans who immigrants. onchocerciasis. In Ethiopian population the Baum et al. (2014) carried out a retrospec- various manifestations of the disease in all tive study of 27 Ethiopian immigrants to Is- its stages can be found. Patient was treated rael were all positive skin snip test or by with oral Ivermectin, once a year, the safest IgG4 of onchocerciasis in 14 patients. The of known medications. The need for early commonest presentation was a combination detection and treatment is emphasized be- of lichenified onchodermatitis with atrophy cause of the potential for ocular destruction. and depigmenta-tion (36%), eosinophilia Pressman et al. (1998) described an 11-year- and elevated IgE were common. They con- old girl, a new immigrant from Ethiopia, cluded that Immigrants from endemic re- who had a firm mass in her left thigh, caused gions presenting with pruritic diseases, es- by O. volvulus. It was completely excised. pecially those with a clinical picture sugges- This is a very rare condition in Israel, which tive of atopic dermatitis, should be evaluated must be considered in patients coming from for possible onchocerciasis infection endemic areas. Rozenman et al. (1984) re- What about Egypt, Khalil (1939) pointed ported a 15-year-old boy with onchocercia- out that the case of Onchocerca reported as" sis had severe generalized pruritus of five filaria in the macula "by Barrada in 1935 months' duration, who emigrated to Israel and by Wilson, 1934, as "onchocerciasis of one year earlier. A biopsy specimen of an the macula" appeared in the literature as two area of depigmentation on the right thigh separate cases based on the same case. He disclosed microfilaria of O. volvulus. They reported an onchocerciasis patient from Bel- concluded that discovery of an unusual dis- beis City who never left Sharkia Governo- ease in a nonendemic area is an example of rate. Besides, one species of Simuliidae was the increased complexity of differential di- reported in Egypt (Steyskqal and el-Bahy, agnosis resulting from the ease of travel 1967). El-Massry and Derbala (2000) exam-

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ined 3376 imported and 200 local Egyptian cervicalis, 3- O. dukei, 4- O. fasciata, 5- camels for O. fasciata from September 1997 O. flexuosa, 6- O. gibsoni, 7- O. gutturosa, toAugust, 1998. They found that imported 8- O. jakutensis, 9- O. linealis, 10- O. lupi, camels had the higher infection rate (2.75%) 11- O. ochengi, 12- O. ramachandrini, 13- mainly on both abdominal sides, hind limbs O. sp. 'bushbuck', 14- O. sp. 'Siisa’ and 15- (concentrated in thigh region) and fore limbs O. tubingensis. particularly on the shoulders and nuchal lig- Several Onchocerca species are agents of ament while local ones showed no palpable zoonoses. In dogs, cases of ocular onchocer- or detected nodules. This distribution varied ciasis were reported in Central Europe main- according to the degree of infection ly Germany, Hungary, Portugal, Switzerland Biswas and Yassin (2013) reported a 19- (Eckert, 1993), and in Southern Greece and year-old Egyptian male studying and living Portugal (Otranto et al, 2013). in Pittsburgh, PA, USA, for 18 months suf- Cello (1971) reported that the microfilari- fered from a month-long irritation and right ae O. cervicalis were capable of producing a eye watering without any visual loss. An variety of lesions in the equine eye, by dead, ophthalmologist prescribed topical steroids rather than living ones. He added that clini- for possible allergic conjunctivitis, which cal features are conjunctiva, cornea, uveal did not resolve his irritation. Patient’s recent tract, lens and retina. Onchocerca sp. was traveled in a trip to New Delhi, India, and normally found in Caucasian wolves (Burr et Siwa oasis (West of Egypt) more than a year al, 1998) morphologically indistinguishable prior to this presentation. He has never had from O. lienalis (Sréter-Lancz et al, 2007). any pets such as dogs and cats. Ophthalmo- As to human ocular onchocerciasis, Hira et logic examination revealed a subconjuncti- al. (1994) stated that 13 previous cases have val nodule (1.5×1 cm) only in the medial been reported from the United States, Cana- aspect of the right eye. The patient under- da, Switzerland, Hungary, Russia, and Ja- went surgical exploration of the nodule un- pan. The species involved in these infections der local anesthesia, which revealed 12 dead were tentatively identified as O. gutturosa, and living worm fragments, each about 1 cm O. cervicalis, O. reticulate, and O. dewittei in length & 0.2-0.3 mm in thickness. Serolo- japonica on the basis of morphologic fea- gy showed a positive IgG4 for filariasis, tures. Koehsler et al. (2007) reported the14th CBC was normal and the peripheral blood case identified O. jakutensis by molecular smear was negative for eosinophilia or mi- techniques in a patient from the United crofilaria. The histopathological examina- States who had traveled throughout Europe. tion showed adult Onchocerca sp. based on Fukuda et al. (2008) in Japan reported that specific morphologic features. There was no microfilariae of O. dewittei japonica (causa- evidence of microfilaria in the uteri. The tive agent of zoonotic onchocerciasis in Oi- CDC confirmed the diagnosis, and the pa- ta, Kyushu) from wild boar (Sus scrofa), O. tient was treated with ivermectin (100 mg/ skrjabini and O. eberhardi from sika deer kg) once and has had no further recurrence (Cenus nippon), O. tienalis from cattle, and of his symptoms after two years of follow- an unnamed Onchocerca sp. from wild boar, up. were injected intrathoracically into newly- The zoonotic onchocerciasis: Genus On- emerged black flies species to identify the chocerca contains one human parasite; O. potential vector(s). O. dewittei japonica mi- volvulus, which is the filaria responsible for crofilariae developed to the infective larvae the neglected onchocerciasis or the river in Simulium aokii, S. arakowae, S. bidenta- blindness (Otranto and Eberhard, 2011). tum, S. japonicum, S. quinquestriatum, and Other species affect cattle, horses, deer, pet S. rufibasis and development of infective animals…etc. are: 1- O. armillata, 2- O. larvae of O. skrjabini, O. eberhardi, and the

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unnamed Onchocerca sp. occurred in S. were not previously reported in the litera- aokii, S. arakawae, and S. bidentatum, and ture, suggesting that an in depth appraisal of O. lienalis microfilaria occurred in S. ara- the infestation in canine populations is nec- kawae. They proposed a key to identify On- essary. chocerca infective larvae found in Oita. Eberhard et al. (2013) mentioned that zo- They reconsidered the identification of three onotic onchocerciasis (O. lupi) was reported types of infective larvae from Simulium spe- from the North American continent, the cies captured at cattle sheds: the large type I West Coast of the United States and from larvae that may be an unidentified species; Europe. They added that other zoonotic spe- the small type III identified as O. lienalis cies were O. cervicalis, O. gutturosa, and O. might include O. skrjabini too; the interme- dewittei. There have been reports of cryptic diary type II that may be O. gutturosa, or O. infections with O. lupi presenting with sub- dewittei japonica, or the unnamed Oncho- conjunctival nodules from Europe as well as cerca sp. of wild boar. (Sréter et al, 2002). O. lupi seemed to be the Labelle et al. (2011) in USA by clinical, commonest zoonotic species affecting the histopathologic, and molecular diagnosis eye and aberrant infections occurred in join- reported two domestic short hair cats with ts, head soft tissues, foot, abdomen, shoul- O. lupi causing episcleritis and orbital cellu- der, and cervical spine (Hira et al, 2008). litis. Ilhan et al. (2013) in Turkey reported a 28- Eberhard et al, (2013) reported that zoono- year-old male who displayed a painless, tic onchocercosis was attributed to species immobile mass under the conjunctiva, primarily of cattle (O. gutturosa), horses (O. measured 10×12 mm in size. Pathological cervicalis), the European deer (O. jakuten- examination of the surgically excised tissue sis), and the wild boars (O. dewittei japoni- was suggestive of infection by a filarial ca), which were localized in subcutaneous nematode. The parasite was identified as O. tissues, muscular fasciae, or cervical liga- lupi through molecular analysis. They added ments, whereas in humans, O. gutturo- that all previous cases reported of O. lupi in sa and O. cervicalis caused an ocular locali- both humans and dogs were more sympto- zation. matic than that patient, Onchocerca infec- In Italy, Otranto et al. (2012) stated that tion should not be ruled out during the dif- Other Onchocerca species were sporadically ferential diagnosis of the subconjunctival reported as zoonotic agents. Cases of canine and orbital cystic mass in instances where onchocerciasis caused by O. lupi are on the there is little to no inflammation. rise in the United States and Europe. Its zo- Several Onchocerca species are agents of onotic role was ascertained in a single case zoonoses. Among the 15 clinical cases of from Turkey. They reported O. lupi infesting zoonotic onchocerciasis reported worldwide human eyes in two patients, one from Tur- (Uni et al, 2010), the species identified were key and second from Tunisia. In the first Onchocerca gutturosa and Onchocerca cer- case, diagnosed was based on O. lupi mor- vicalis (Faísca et al, 2010), affecting cattle phology at the gross examination, histologi- and horses, respectively, Onchocerca jakut- cal analysis and anatomical description, as ensis from the European deer (Koehsler et well as molecularly confirmation. They con- al, 2007) and in half of the human cases. cluded that O. lupi infestation is not an occa- O. lupi was recognized parasite causing sional finding but must be considered in the nodular lesions associated with ocular dis- differential diagnosis of other zoonotic hel- ease (i.e., conjunctivitis, ocular swelling, minths causing eye infestation as D. immitis photophobia, lacrimation, discharge, exoph- and Dirofilaria repens. Both cases came thalmia) in zoonotic potential dogs (Sréter et from the areas where canine onchocerciasis al, 2002) but only recently been reported in

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one patient from Turkey (Sréter and Széll, consideration the onchocerciasis blindness 2008). Zoonotic human ocular cases in are or river blindness in differential diagnosis of increasingly being reported worldwide, in- eye disease. cluding Iran and Tunisia cau-sed by O. lu- 3- The veterinarians must consider zoonotic pi (Mowlavi et al, 2014), Turkey (Otranto et onchocerciasis in the skin and eye of farm al, 2012). In addition, O. lupi infection was and pet animals. recently diagnosed near the spinal canal in a 4- The owners of pet animals must consult 22-month-old child from Arizona, USA the veterinarians if they notice eye compli- (Biswas and Yassin, 2013). cations.

Conclusion 5- Clinicians and veterinarians are request- ed to put the worm or microfilariae they The parasite Onchocerca volvulus is well- could extract in a labeled specimen tube of known in its endemic areas in South and normal saline or 70% ethanol and refer to a Central America and West Africa. It is reference parasitologist for species identifi- transmitted to man by Simulium flies and cation to pave the way for feasible control causes systemic infection with skin, lym- measures. phatic and ophthalmic manifestations and 6- Last but not least, there must be regional can cause blindness (river blindness). On- collaboration or working groups especially chocerciasis is an infectious disease caused with the African countries under the umbrel- by the filaria. Very little is known regarding la of the WHO and/or CDC to stop spread- onchocerciasis imported from the endemic ing of the risky filarial parasite. This could to non-endemic areas. Ivermectin, a relative- be by annual or semi-annual scientific meet- ly safe and low-cost treatment, should be ing to exchange the information and experi- considered even in the absence of a proven ence. disease. On the other hand, zoonotic ocular 7- On the other hand, the health education onchocerciasis due to many non-human On- cannot be neglected. Besides, promoting the chocerca species is worldwide documented behavior in the design of preventative inter- even from pet dogs and cats. ventions. Recommendations References

General onchocerciasis symptoms include severe itching, bumps under the skin, blind- Abdel-Hameed, AA, Noah, MS, Schacher, JF, ness and thus reducing the patient's ability to Taher, SA, 1987: Lymphadenitis in Sowda. work and learn. There are no vaccines or Trop. Geogr. Med. 39, 1:73-6. Abdul-Salam, J, al-Taqui, M, 1995: Seasonal medications available to prevent O. volvulus prevalence of Onchocerca-like microfilaria in infection. The best prevention efforts incl- camels in Kuwait. J. Egypt. Soc. Parasitol. 25, 1: ude the personal protection measures against 19-24. the biting of insect-vector (CDC, 2016). al Qubati, Y, Reynouard, F, Kumar, F, Gax- Consequently, to present onchocerciasis in otte, P, Richard-Lenoble, D, 1997: Onchoder- man and/or animals and its risky complica- matitis (sowda) in patients in Yémen: Clinical tions, the following is suggested. and histologic course after treatment with iver- 1- There must be urgent entomological sur- mectin. Sante 7, 6:391-9 veys for members of genus Simulium in par- Alley, ES, Plaisier, AP, Boatin, BA, et al, ticular on the Egyptian borders. It is a day- 1994: The impact of five years of annual iver- bite insect-vector. mectin treatment on skin microfilarial loads in the onchocerciasis focus of Asubende, Ghana. 2- The dermatologists should keep in mind Trans. R. Soc. Trop. Med. Hyg. 88:581-8. onchocerciasis dermatitis, sowda, particular- Anderson, J, Fuglsang, H, Al-Zubaidy, A, ly over buttocks, waist and shoulders; mean- 1973: Onchocerciasis in Yemen with special re- while the ophthalmologists should take into ference to sowda. Trans. R. Soc. Trop. Med. Hyg. 67, 1:30-1.

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