Is imported onchocerciasis a truly rare entity? Case report and review of the literature

Is imported onchocerciasis a truly rare entity? Case report and review of the literature

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Travel Medicine and Infectious Disease xxx (2017) 1e7

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Is imported onchocerciasis a truly rare entity? Case report and review of the literature Spinello Antinori a, b, *, Carlo Parravicini c, Laura Galimberti b, Antonella Tosoni c, Paolo Giunta d, Massimo Galli a, b, Mario Corbellino b, Anna Lisa Ridolfo b a

Luigi Sacco Department of Biomedical and Clinical Sciences, University of Milano, Italy III Division of Infectious Diseases, Luigi Sacco Hospital, Fatebenefratelli Sacco ASST, Milano, Italy Pathology Unit, Luigi Sacco Hospital, Fatebenefratelli Sacco ASST, Milano, Italy d Pathology Unit, Melegnano and Martesana ASST, Vizzolo Predabissi, Italy b c

a r t i c l e i n f o

a b s t r a c t

Article history: Received 5 October 2016 Received in revised form 13 February 2017 Accepted 16 February 2017 Available online xxx

Background: Onchocerciasis is endemic in a number of tropical countries in Africa and South America, and it is occasionally diagnosed as an imported disease in non-endemic areas. Methods: We describe the case of an African migrant with long-lasting pruritus and a cutaneous nodule who was diagnosed with onchocerciasis after nodulectomy, and review the medical literature regarding imported cases of onchocerciasis in the period 1994e2014. Results: Twenty-nine cases of onchocerciasis diagnosed in migrants from endemic countries, and in expatriates and travellers from non-endemic areas were retrieved. They were predominantly males (73.3%), had a median age of 37 years (two were aged <15 years), and acquired the diseases in subSaharan Africa, most frequently in Cameroon (43.3%). Diagnosis of onchocercosis was proven in 73.3% of patients. The most frequent clinical manifestations in these and our own patient were pruritus (23/30, 76.7%), unilateral leg or forearm swelling (13/30, 43.3%) and rash (12/30, 40.0%), whereas only two (6.9%) complained of eye symptoms. Eosinophilia was observed in almost all of the patients (92.0%), with median counts of 2915/mL among migrants and 1960/mL among travellers/expatriates. Eighteen patients underwent a skin snip biopsy, which was positive in 10 cases (55.5%); in the other 13 patients the parasite was directly demonstrated by means of a skin or nodule biopsy (n ¼ 5), nodulectomy (n ¼ 5) or slit lamp examination (n ¼ 3). Eighteen received ivermectin, alone, and seven ivermectin combined with diethylcarbamazine or doxycycline. Outcome details were available for only 14 patients, all of whom were asymptomatic after a median follow-up of 10 months (range 1e48). Conclusions: Onchocerciasis is a neglected tropical disease whose subtle and non-specific features may lead to under-diagnosis or underreporting in non-endemic areas. Physicians should consider this tropical disease when caring for migrants and travellers/expatriates with pruritus, skin lesions and eosinophilia. © 2017 Published by Elsevier Ltd.

Keywords: Onchocerciasis River blindness Pruritus Imported infections Immigrants Travellers

1. Introduction Onchocerciasis or “river blindness” is a multisystem infestation caused by Onchocerca volvulus, a nematode worm that is transmitted to humans by the bites of infected blackflies (Simulium spp.) [1]. Microfilariae are found in peripheral blood, eye, skin and urine, and develop into adult worms in sub-dermal connective tissue. Onchocerciasis is considered a neglected tropical disease and the

* Corresponding author. Luigi Sacco Department of Biomedical and Clinical Sci degli Studi di Milano, Via GB Grassi 74, 20157, Milano, Italy. ences, Universita E-mail address: [email protected] (S. Antinori).

world's second most frequent infectious cause of blindness [2]. Typically pruritic cutaneous manifestations are very frequent during the course of the disease, and may appear several years before the ocular complications. At present, human onchocerciasis is endemic in 31 countries of sub-Saharan Africa (where 99% of infected people live), two countries of Latin America (Brazil, Venezuela) and in Yemen [3]. By 2016 the World Health Organization (WHO) verified the interruption of transmission of onchocerciasis in four countries in Latin America: Colombia (2013), Mexico (2015), Ecuador (2015), Guatemala (2016) [4,5]. Despite the great efforts of African Programme for Onchocerciasis Control (APOC) based on community-wide mass drug 1477-8939/© 2017 Published by Elsevier Ltd.

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administration (MDA) rounds with ivermectin, in 2015 an estimated 185 million people still live in African countries at risk for onchocerciasis [4]. Among the hurdles for achieving elimination it should be mentioned that in at least 20% of onchocerciasis-endemic area patients are co-infected with Loa loa and severe adverse reactions (namely encephalopathy) can be precipitated in highly parasitemic individuals under ivermectin treatment [6,7]. Onchocerciasis is rarely described in non-endemic countries, but a series of imported case published in the medical literature show that migration and population mobility may create bridges between very different health environments. We here describe the case of a Ghanaian immigrant living in Italy who presented with cutaneous nodules and pruritus, and was diagnosed as having onchocerciasis on the basis of nodulectomy findings, and review it together with other imported onchocerciasis cases published over the last 20 years. 2. Materials and methods

Fig. 1. Hematoxylin and eosin stain of a nodulectomy specimen showing multiple adult worms. The white arrow indicates a microfilaria (original magnification x 10).

The PubMed and Scopus databases were searched for English and French articles published between 1994 and 2014 using the following combination of MeSH terms: [onchocerciasis AND travel; onchocerciasis AND imported; river blindness AND imported; onchocerciasis AND immigrant; onchocerciasis AND expatriate]. Several cases were added by cross referencing the references cited in the retrieved case reports. For the purpose of this review cases of onchocerciasis retrieved in the literature were defined “proven” when microfilariae and/or adult worms (macrofilariae) were observed or a polymerase chain reaction specific for Onchocerca volvulus was positive. A diagnosis was “suspected” in the presence of epidemiologic and clinical data compatible with the disease alone or associated with positive antifilarial antibody or a positive Mazzotti test. 3. Results 3.1. Case report A 31-year-old Ghanaian immigrant who had been living in Italy since January 2011 was referred to our clinic in January 2012 after the surgical removal of a subcutaneous nodule showing the presence of worms upon histological examination. The patient had a history of generalised pruritus dating back to 1994, and a pelvic girdle nodule 2e3 cm in diameter that had been present for two years (one year before his arrival in Italy). A physical examination showed that the patient was well nourished, alert and had normal vital signs. A keratotic lesion was observed on the distal part of his right leg. A faint cardiac murmur (1/6) was audible over the mitral valve. His laboratory test results revealed a white blood cell count of 5.600/mL (with 22% eosinophils), hemoglobin 14.6 g/dL, hematocrit 44%, and a platelet count of 191.000/mL. The findings of liver function tests, a renal function panel and urinalysis were normal. Serum antibodies against human immunodeficiency virus and hepatitis C virus were negative, as was hepatitis B surface antigen. A chest-Xray was negative. Serological tests for Strongyloides stercoralis, echinococcus and Schistosoma were negative. A histological review of the removed nodule confirmed the presence of a chronic granulomatous picture, transverse and oblique sections of adult worms, and rare microfilariae, a finding that was consistent with a diagnosis of onchocerciasis (Figs. 1 and 2). The patient underwent an ophthalmological examination that was negative. He was given a single oral dose of ivermectin (150 mg/kg) followed by 100 mg of doxycycline twice a day for four weeks without any adverse effects. He reported that his pruritus had improved, but did not return to further follow-up examinations.

Fig. 2. Higher magnification of the microfilaria (original magnification x 60).

3.2. Literature search The literature search revealed articles relating to 29 patients with imported onchocerciasis. The demographic and clinical characteristics of these and our own patient are summarised in Table 1: 18 were migrants (60%), three were returned travellers (10%), and nine (30%) were expatriates. Most of them were males (22/30, 73.3%), and their median age was 37 years (range 14e77 years); all of them acquired the disease in sub-Saharan Africa, mainly in Cameroon (13/30, 43.3%) and Sierra Leone (5/30, 16.6%). The initial symptoms appeared 2e48 months (median 16.5 months) after they had left the endemic area, the most frequent being pruritus (23/30, 76.6%), unilateral (upper or lower) limb or forearm swelling (13/30, 43.3%), and rash (12/30, 40.0%). Subcutaneous nodules were observed in five cases (20.0%), skin lichenification in four, and inguinal lymphadenopathy in three. Only two patients (6.6%) presented eye complaints. Eosinophilia was present in almost all the cases (24/26, 92.3%), with a median value of 3650 cells/mL (range 296e24.000/mL). Eighteen patients underwent a skin snip test, which was positive in 10 (55.5%); in ten cases, the diagnosis was made on the basis of a skin and/or nodule biopsy (5) or histology following nodulectomy (5). A slit lamp examination documented the presence of microfilariae in the anterior chamber in 3/7 patients (42.8%), and the Mazzotti reaction test after ivermectin or

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Table 1 Demographic data, status, clinical features and treatments of patients with imported onchocerciasis, 1994e2014. Author, country, year, [reference]

Country of Age, years/ birth/ gender country of exposure/ period of exposure

Encarnacion 40/M et al., USA, 1994 [8]

Encarnacion 43/M et al., USA, 1994 [8]

Encarnacion 48/M et al., USA, 1994 [8]


Time from Clinical manifestations last stay in endemic country

Eosinophils Method(s) of diagnosis/Final diagnosis (absolute number or %)

1230 USA/Sierra Expatriate 15 months Non-pruritic rash on both arms Leone/ 4-6 weeks (in 1986 and 1987) USA/Sierra Expatriate NR Maculopapular rash on flanks, 1960 Leone/15 buttocks and back years (from 1966 to 1980) USA/Sierra Expatriate 36 months Papular lesions on upper and 750 Leone/NR lower extremities; pruritus

Expatriate 48 months Pruritic rash on shoulders and 711 dorsa of feet

Nozais et al., NR/M France, 1997 [9] Nozais et al., NR/M France, 1997 [9] Nozais et al., NR/M France, 1997 [9]

USA/Sierra Leone/6 months (1983); 3 months (1985) NR/ Cameroon/ 18 months NR/ Cameroon/4 months NR/Ivory Coast/28 years

Nozais et al., NR/M France, 1997 [9]

NR/ Cameroon/ 3 weeks

Encarnacion 34/M et al., USA, 1994 [8]

Skin snip posi-tive; slit lamp and OE: Ivermectin 150 mg/kg (SD)/NR negative/P

Skin snip nega-tive; OE nega-tive; Ivermectin 150 mg/kg (SD) antifilarial Ab positive (4000 U/mL)/S repeated after 6 and 12 months/Aymptomatic after 1 year Declined treatment Skin snip nega-tive; OE nega-tive; antifilarial Ab positive (5072 U/mL); Mazzotti reaction: negative/S

5 months


24 months Unilateral upper limb swelling; pruritus






18 months Unilateral upper limb swelling; pruritus


Skin snip posi-tive; antifilarial Ab positive (1/100); Mazzotti reaction positive/P

Nozais et al., NR/M France, 1997 [9]

Migrant NR/ Cameroon/4 years

24 months Unilateral upper limb swelling; pruritus


Skin snip posi-tive; antifilarial Ab nega-tive; Mazzotti reaction positive/P

Lazarov et al., 31/M Isreael, 1997 [10]

Ethiopia/ Migrant Ethiopia/NR


40/F Okhuysen, USA, 1997 [11] 35/M Lanternier et al., France, 1999 [12]

USA/ Cameroon/5 years France/ Gabon (2 years), Cameroon (3 years) France/ Central African Republic/3 months Africa (NS)/ Africa/NR

Le Guyadec 23/M et al., France, 1999 [13] Vernick et al., 18/F USA, 2000 [14]

 et al., 14/M Mahe France, 2001 [15]

Military NR expatriate

Unilateral upper limb swelling; pruritus


Skin snip posi-tive; slit lamp and OE Ivermectin 150 mg/kg (SD) negative; repeated after 6 and 12 Mazzotti reaction positive/P months/Aymptomatic after 4 years


Expatriate 5 months

Unilateral upper limb swelling; pruritus

Papular eruption on trunk and 30% extremities; skin lichenification; pruritus

Swelling and pruritic maculo- 5842 papular rash on right arm and forearm Swelling and pruritic papular 24000 rash on left leg

Military 36 months Swelling and pruritic rash on 4000 expatriate left leg


Cameroon/ Migrant Cameroon/8 years


NR Hypopigmented, slightly atrophic macules on anterior tibiae bilaterally

6 years (returning every year)

Chronic papular dermatitis and swelling (right leg); pruritus; inguinal lymphadenopathy (6  4 cm)



Skin snip posi-tive; antifilarial Ab negative; Mazzotti reaction positive/P Skin snip posi-tive; Antifilarial Ab negative; Mazzotti reaction positive/P Skin snip posi-tive; antifilarial Ab negative; Mazzotti reaction positive/P

Skin biopsy: microfilaria with eosinophilic infiltrate; OE: pigmented lesions on conjunctivae; conjunctival biopsy: necrotising granulomatous conjunctivitis/P Skin snip nega-tive; slit lamp negative; anti-filarial Ab posi-tive/S

DEC (3 courses)/NR

Ivermectin 12 mg (SD)/ Asymptomatic after 7 months Ivermectin 12 mg þ DEC 400 mg (SD)/ Asymptomatic after 3 months Ivermectin 12 mg þ DEC 400 mg (SD)/ Asymptomatic after 3 months Ivermectin 12 mg þ DEC 400 mg (SD)/ Asymptomatic after 16 months Ivermectin 9 mg/ Improvement in pruritus

Ivermectin þ steroids/ Improvement

DEC 400 mg/day for 21 Skin biopsy nega-tive; blood test negative; Mazzotti reaction positive/ days/Full response after 1 year S

Skin snip nega-tive; Mazzotti reaction: positive; (Skin snip: positive after Mazzotti test)./P

Ivermectin 12 mg repeated 2 months later/ Asymptomatic after 8 months

Skin biopsy: perivascular inflammatory infiltrate with mononuclear cells, eosinophils, and rare microfilariae; OE negative/P Skin biopsy: eosinophil infiltrate; OE negative; Mazzotti reaction positive; antifilarial Ab positive (1/200)/S

Ivermectin 9 mg every 3 months (2 doses) then every 6 months/Lost to follow-up Ivermectin 6 mg (SD)/ Regression of symptoms

(continued on next page)

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Table 1 (continued ) Author, country, year, [reference]

Country of Age, years/ birth/ gender country of exposure/ period of exposure


Time from Clinical manifestations last stay in endemic country

Eosinophils Method(s) of diagnosis/Final diagnosis (absolute number or %)

Skin snip nega-tive (also PCR); skin biopsy: hyper-reactive onchocercal dermatitis (sowda); OE negative; anti-onchocercal Ab positive/S Slit lamp examination: microfilariae in anterior chamber; OE: optic atrophy, retinochoroiditis, uveitis; Mansonella spp in blood/P Slit lamp exami-nation: microfilariae in anterior chamber of both eyes; nodu-lectomy: adult worms of O. volvulus; skin biopsy positive for microfilariae/P Nodulectomy: adult worms of O. volvulus/P

Ivermectin 9 mg every 3 months þ steroids/ Improvement in skin symptoms after 4 months Ivermectin 150 mg/kg (SD)/Disappearance of uveitis after 1 month

Skin snip nega-tive; PCR positive for O. volvulus; OE negative; antifilarial Ab positive (359 mg/mL); anti-OV-16 Ab positive; Mazzotti reaction positive; Skin biopsy: rare microfilaria/P Skin snip posi-tive; antifilarial Ab positive (>510 mg/mL)/P

Ivermectin 15 mg biannually for a total of 7 doses þ steroids/ Asymptomatic after 36 months

Nodulectomy: O. volvulus/P

NT/Lost to follow-up

Expatriate NR missionary

Nodulectomy: O. volvulus/P

NT/Lost to follow-up


Ivermectin 150 mg/ kg þ doxycycline 200 mg/ d for 2 weeks þ steroids for 3 days/Asympto-matic after1 year Antifilarial Ab positive (1/200); blood Ivermectin 8 mg (3 doses)/ examination negative/S Asymptomatic after 1 year

Alberts et al., 14/F USA, 2001 [16]

Liberia/ Liberia/ NR



Generalised pruritic rash (for 5500 3 years); skin lichenification; inguinal lymphadenopathy

Del Rio et al., 46/M USA, 2003 [17]

Cameroon/ Cameroon/ 46 years


2 months

Bilateral vision loss (for 2 13600 years); pruritus; joint stiffness

Borup et al., 37/M USA, 2003 [18]

Sierra Leone/ Sierra Leone/34 years Liberia/ Liberia/24 years USA/ Cameroon/ NR


3 years

Expatriate 18 months Migratory papules on arms and trunk (for 4 months); edema of left arm; pruritus


Cameroon/ Cameroon/ 62 years Senegal/ Senegal/ NR Italy/Congo/ NR



Belgium/ Cameroon/ 10 days

Okulicz et al., 26/M USA, 2004 [19] Nguyen et al., 53/M USA, 2005 [20]

Ryan et al., USA, 2005 [21] Marchesi et al., Italy, 2005 [22] Marchesi et al., Italy, 2005 [22] Ezzedine et al., Belgium, 2006 [23]





Chakvetadze 28/M et al., France, 2006 [24] Niamba et al., 57/F France, 2007 [25]

27/F Vargas Laguna et al., Spain, 2008 [26] Bouree et al., 77/F France, 2008 [27] 51/F Bousquet et al., France, 2014 [28] 31/M Antinori et al., Italy, 2012 [PR]



NR/Several Traveller African countries/6 weeks Migrant Burkina Faso/ Burkina Faso/57 years Equatorial Migrant Guinea/ Equatorial Guinea/NR

Cameroon/ Cameroon/ NR Cameroon/ Cameroon and other African countries Ghana/ Ghana/27 years


8.6% Glaucoma (for 2 years); bilateral conjunctival injection; 2 subcutaneous nodules on left axilla, and left buttock 24 months Pruritus; subcutaneous Normal nodule on left flank

11 months Leopard skin on upper back, buttocks, and upper thighs; pruritus NR Nodule (6 cm) on dorsum of left foot (for 6 months)


NR Diffuse erythe-matous, lichen-ified skin; pruri-tus; nodule on left shoulder 24 months Swelling and pruritic maculo- 800 papular rash on right forearm

Ivermectin 150 mg/kg (SD)/NR


Skin snip posi-tive; slit lamp negative; IFA-positive for soluble O. volvu-lus antigen; anti-filarial Ab posi-tive (1/320)/P

8 months

Painful swelling of one limb


1960 Generalised pruritus (for 6 months); sub-cutaneous nodules on the trunk; bilateral inguinal mass (5  3 cm)

Skin snip posi-tive; nodule biopsy: Ivermectin 200 mg/kg (2 granulomatous inflammation, doses 1 week apart)/ numerous filariae and microfilariae/P Asymptomatic after 3 months


High (NR) Lichenoid papules on extremities and buttocks; alopecia; symmetri-cal patches of hypopigmenta-tion on lower back, buttocks and shins Generalized pruritus 1970

Skin biopsy: acanthosis, peri-vascular Ivermectin (SD) þ doxycycline lympho-histiocyte and eosinophil infil-trate; slit lamp eye examination: 200 mg for 6 weeks/NR microfilariae in anterior chamber; antifilarial Ab positive/P Skin snip positive/P

Ivermectin 12 mg/NR

Pruritic papules and oedema on right forearm


Skin biopsy nega-tive.; blood examination negative/S

Ivermectin þ doxycycline/ NR


Nodulectomy: microfilariae and adult worms of O. volvulus; blood exami-nation negative; OE negative/ P

Ivermectin 9 mg þ doxycycline 200 mg/d for 4 weeks/Lost to follow-up


6 months


2 months


12 months Generalised pruritus; subcutaneous nodule


Ivermectin 10 mg/Lost to follow-up

M: male; F: female; NS: not specified; NR: not reported; OE: ophthalmological examination; P: proven diagnosis; S: suspected diagnosis; PCR: polymerase chain reaction; IFA: immunofluorescence assay; SD: single dose; DEC: diethylcarbamazine; PR: present report.

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diethylcarbamazine administration was positive in 10/11 patients (90.9%). Globally, a diagnosis of onchocerciasis was proven in 22 patients (73.3%) and suspected in 8 patients (26.7%). For those patients coming from countries where Loa loa infection coexists a double infection was ruled out by blood microscopy examination in all cases. In one patient Mansonella species microfilariae were seen in a smear of peripheral blood. Eighteen patients were treated with ivermectin (associated with steroids in four cases); four patients received ivermectin plus doxicycline, three ivermectin plus diethylcarbamazine (DEC); two received DEC alone, and three were not treated. Outcome details were available for only 14 patients, who were all asymptomatic after a median follow-up of 10 months (range 1e48). Notably, differences in the clinical characteristics were noted between migrants and travelers/expatriates. Eye abnormalities, lymphadenopathy, and chronic dermatitis were present more frequently in migrants, whereas rash and arm swelling were more frequent in travelers and expatriates (Table 2).

4. Discussion We describe a case of imported onchocerciasis in a young African immigrant living in Italy, who had a long history of pruritus, and was diagnosed only when a sub-cutaneous nodule was surgically removed and analysed. On the basis of the most recent estimates, onchocerciasis remains an important neglected tropical disease insofar as there are 187 million people at risk, mainly in the African countries of Nigeria (47 million), the Democratic Republic of Congo (40 million), Ethiopia (16 million), Cameroon (11 million), Guinea (8 million), United Republic of Tanzania (6 million), Mali (5 million), Ghana (4 million) [3]. Interestingly, despite the increasing human mobility due to immigration and travel, we were only able to retrieve 29 case reports of imported onchocerciasis from a search of the medical literature published during the last 20 years [8e28]. This is fewer than the number of imported cases described in previous years, such as the 100 cases (prevalently affecting Dutchmen) observed at the Amsterdam Outpatient Clinic for Tropical Diseases in the period 1959e1971 [29], or the 240 cases reported in Spain in the period 1989e2007 [30]. However, in the latter case, it needs to be noted that onchocerciasis was the most frequent tropical disease diagnosed among immigrants (9.1%), visitors to friends and relatives (VFRs, 5.4%) and travellers (0.5%), and that 88.8% of the patients


were immigrants from Equatorial Guinea, which has major geopolitical ties to Spain and is highly endemic for the disease [30]. Moreover, the authors of this study found a significant decrease in the annual number of cases (p < 0.001), which they attributed to the successful implementation of the Onchocerciasis Control Program in West Africa (OCP) and the mass distribution of ivermectin [30]. However, although the success of the OCP is undeniable and exemplary, it should be pointed out that the elimination threshold of >80% has not been yet reached in eleven of the 24 countries involved [31,32]. A study of more than 43.000 people referring to the medicine/ travel clinics of the GeoSentinel Network in various countries worldwide in the period 1997e2004 found that filarial infections were diagnosed in 271 people (0.61%), with Onchocerca volvulus being by far the most frequent causal agent [33]. Once again, the majority of these patients (80.2%) were immigrants or VFRs. A more recent study by the same group of more than 42.000 travellers returning home between 2007 and 2011 confirmed that filarial infections (including onchocerciasis) are rare in persons travelling in regions endemic for onchocerciasis for short periods (113 cases, 0.26%) [34], and two other studies have found similarly low percentages of infection in travellers returning from Africa (21/16.893, 0.1%) [35] and Central America (1/4779, 0.2%) [36]. Finally, a study regarding skin disorders among 34.000 travellers returning from tropical and non-tropical countries documented only 10 cases of O. volvulus infection among 4158 helminthic skin disorders (0.24%) [37]. The relatively small number of cases of imported onchocerciasis cases that we retrieved from the medical literature not only contrasts with the still high disease burden in endemic countries, but also the theoretically expected surge in cases due to the unprecedented recent increase in migration from Africa to Europe. The possible reasons for this discrepancy include a relative unawareness of this neglected disease among physicians practising in nonendemic countries and/or under-reporting. Another explanation may simply be that the common name of “river blindness” is misleading: only two (6.9%) of the patients included in this review presented eye complaints, and only three had microfilariae in the anterior chamber detected by means of a slit lamp. Interestingly, all of these patients were migrants, a finding that is in line with the observations of Price et al. [38] in Europe and McCarthy et al. in the USA [39]. In these two studies, ophthalmological abnormalities were present in respectively 22% and 41% of the cases of imported onchocerciasis, but were much less frequent among returning

Table 2 Differences in clinical and parasitological findings of imported onchocerciasis between travellers/expatriates and migrants. Manifestation, n (%)

Rash Pruritus Skin lichenification/atrophy Leopard skin Swelling Nodules Lymphadenopathy Eye symptoms Median eosinophil count/mL Microfilariae in the skin (skin snip/biopsy) Mazzotti test Microfilariae in the eye (slit lamp examination) a

Present review (1994e2014)

McCarthy et al., 1994 [Ref. [39]]

Pryce et al., 1992 [Ref. [38]]

Enk et al., 2003 [Ref. [40]]

Travellers/expatriates (n ¼ 12)

Migrants (n ¼ 18)a

Travellers (n ¼ 20)

Endemic subjects (n ¼ 21)

Travellers (n ¼ 22)

Immigrants (n ¼ 83)

8 (66.6) 9 (75.0) 1 (8.3) 0 (0) 6 (50.0) 1 (8.3) 0 (0) 0 (0) 1960 5/12 (41.6) 4/5 (80.0) 0/4 (0)

4 (22.2) 14 (77.7) 4 (22.2) 1 (5.5) 7 (38.8) 5 (27.7) 3 (16.6) 2 (11.1) 3970 10/14 (71.4) 6/6 (100) 3/3 (100)

12 (60.0) 17 (85.0) NR NR NR 0 (0) NR 0 (0) 1056 9 (45.0) 11/11 (100) 0 (0)

6 (28.6) 14 (66.6) NR NR NR 17 (80.9) NR 14 (66.6) 2634 21 (100) NR 17 (80.9)

15 (68.1) 17 (77.3) NR NR 9 (40.9%) NR NR 5 (22.7) NR 10 (45.4) 12/12 (100) NR

49 (59.1) NR 19 (22.9) 13 (15.6) NR 2 (2.4) NR 43/65 (66.1) NR 40 (48.2) NR 4/65 (6.1)

Including the patient described in this case report; NR: not reported.

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travellers: only one out of 22 cases (4.5%) in the study of Price et al. and none out of 20 cases in the study of McCarthy et al. It is also interesting to note that the high frequency of eye complaints (66%) and corneal abnormalities (42%) reported by Enk et al. in relation to a large series of patients with imported onchocerciasis in Israel only involved immigrants from Ethiopia [40]. Among the patients considered in our review, long-lasting pruritus with or without rash was the predominant manifestation (observed in 76.7% of cases [8e13,15e17,19e23,25,27,28]. We believe that this non-specific symptom may be another cause of an overlooked or delayed diagnosis because scabies and adult-type atopic dermatitis are also common among migrants [35]. The manifestations of onchodermatitis vary quite widely: they may include papules and a maculopapular rash during the acute stage, whereas chronic onchodermatitis is characterised by a number of progressive features that may ultimately lead to generalised atrophy or “lizard skin”, lichenification or “sowda”, or patchy depigmentation, which is known as “leopard skin” although it is actually more similar to the coat of a cheetah [41]. Unilateral limb edema, which is also referred to as “gros bras” in the French literature [9,23,24], was present in about 43% of the reviewed cases, although it is generally considered a rare presentation. It should also be noted that transient migratory angioedema involving the extremities and the face (also known as Calabar swelling) is a common manifestation of loaiasis, a disease that has many clinical similarities to onchocerciasis and an overlapping geographical distribution in West Africa. The frequency of the clinical manifestations of onchocerciasis other than the eye involvement mentioned above may be different between the native inhabitants of endemic areas and travellers/ expatriates born in non-endemic areas. In particular, lymphadenopathy and chronic dermatitis have mainly been reported in the former [10,14e18,21,25,26], whereas rash and arm swelling are more frequent in the latter [8,11e13,20,23,24]. Eosinophilia is the most frequent laboratory alteration associated with onchocerciasis, and was recorded in 92% of the reviewed cases. However, this aspecific alteration may be observed in patients with various other parasitic infestations (such as those caused by Wuchereria spp, Mansonella spp. and, especially, Loa loa) that may co-exist with onchocerciasis or should be considered in its differential diagnosis, particularly in the presence of arm or leg edema [42]. As previously reported by McCarthy et al., native inhabitants of endemic countries generally have higher eosinophil counts than travellers returning from them [39]. Only 55.5% of the reviewed cases were positive for O. volvulus as revealed by a “gold standard” skin snip biopsy (i.e., iliac crest skin tissue specimens obtained using a sclerocorneal punch), but this is consistent with the test's reported sensitivity of 45e73% [29,38]. It should be noted that in a high proportion (30%) of the cases we have reviewed, the diagnosis of onchocerciasis was not parasitologically proven. Similarly, in a recent report describing 31 cases of imported fialriasis in the metropolitan area of Paris, none of the four diagnosis of onchocerciasis was proven [43]. All together these findings highlight difficulties in obtaining a confirmed diagnosis of onchocerciasis, a fact that can also explain the low reporting rate of the disease. Most of the reviewed patients were treated with ivermectin, alone or in combination with diethylcarbamazine or doxycycline. Ivermectin is currently the drug of choice for onchocerciasis because it is effective in relieving symptoms and has some microfilaricidal activity. However, as this activity is weak, it has been suggested to repeat treatment cycles throughout the lifespan of adult Onchocerca spp. females, which may be 14 years or longer [44]. It has been shown that the administration of doxycycline for four-six weeks is effective in sterilising worms for long periods by

depleting symbiotic Wolbachia spp. endobacteria in Onchocerca volvulus and enhancing the ivermectin-induced suppression of microfilariemia [45]. However, a recent Cochrane analysis of three randomised controlled trials carried out in Cameroon, Ghana and Liberia did not find any difference in vision-related outcomes between the two treatment arms, although it did confirm that the macro- and microfilaricidal activity of ivermectin plus doxycyline is greater than that of ivermectin alone [46]. A randomized open label trial evaluating five different anti-Wolbachia regimens (doxycycline given for 4 week, minocycline for 3 weeks, doxycycline for 3 weeks plus albendazole for 3 days, doxycycline for 3 weeks and albendazole for 3 days) confirmed doxycycline superiority (98.8% response) to all other treatment arms and additive effects of albendazole when used in combination with doxycycline [47]. It should be highlighted that current treatment protocols are formulated to patients who live in endemic areas and the optimal dose intervals and length of treatment to prevent disease relapse for individuals living in non-endemic areas remains to be established. In conclusion, onchocerciasis is probably under-diagnosed in migrants and travellers returning from endemic regions because of its relatively non-specific manifestations and the limited awareness of the disease among physicians practising outside endemic countries. However, the presence of pruritus, skin lesions and eosinophilia should always raise the suspicion of this disease in migrants and travellers. Conflict of interest All the Authors no conflict of interest to disclose. Funding source This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. Acknowledgement We would like to thank Mr Kevin Smart for English language review of the manuscript and Mrs Bianca Ghisi for technical assistance in the artwork. References [1] Udall DN. Recent update on onchocerciasis. Diagnosis and treatment. Clin Infect Dis 2007;44:53e60. [2] Babalola OE. Ocular onchocerciasis: current management and future prospects. Clin Ophthalmol 2011;5:1479e91. [3] World Health Organization. Progress report on the elimination of human onchocerciasis, 2015-2016. Wkly Epidem Rec 2016;91:505e14. [4] World Health Organization. Program towards eliminating onchocerciasis in the WHO Region of the Americas: verification of elimination of transmission in Guatemala. Wkly Epidem Rec 2016;91:501e5. [5] World Health Organization. Onchocerciasis. Guidelines for stopping mass drug administration and verifying elimination of human onchocerciasis. Criteria and procedures. Geneva, Switzerland: WHO; 2016.  HG, Wanji S, Noma M, Amazigo UV, Diggle PJ, Tekle AH, et al. The [6] Zoure geographic distribution of Loa loa in Africa: results of large-scale implementation of the Rapid Assessment Procedure for Loiasis (RAPLOA). Plos Negl Trop Dis 2011;5:e1210. [7] Mackenzie C, Geary T, Prichard R, Boussinesq M. Where next with Loa loa encephalopathy? Data are badly needed. Trends Parasitol 2007;23:237e8. [8] Encarnacion CF, Giordano MF, Murray HW. Onchocerciasis in New York city. The Moa-Manhattan connection. Arch Intern Med 1994;154:1749e51. [9] Nozais JP, Caumes E, Datry A, Bricaire F, Danis M, Gentilini M. A propos de cinq me onchocerquien. Bull Soc Pathol Exot 1997;90:335e8. nouveaux cas d’œde [10] Lazarov A, Amihat B, Sion-Vardy N. Pruritus and chronic papular dermatitis in an Ethiopian man. Arch Dermatol 1997;133:385e6. [11] Okhuysen PC. Onchocerciasis in an expatriate living in Cameroon. J Travel Med 1997;4:11e3. [12] Lanternier G, Maccari F, Hernandez E, Le Guyadec T. Onchocercose de

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