Imported onchocerciasis in migrants and travelers

Abstract

Purpose of review

With increasing international travel and mass global population migration, clinicians in nonendemic countries must be familiar with imported neglected tropical diseases including onchocerciasis, which is commonly known as ‘river blindness’.

Recent findings

Imported onchocerciasis manifests differently in travelers compared with migrants from endemic areas and is likely underdiagnosed in both groups. Recent clinical studies confirm that eosinophilia is not a sensitive marker for Onchocerca volvulus, with one-third of patients having a normal eosinophil count. Novel diagnostics measuring antibodies to multiple recombinant O. volvulus antigens maintain a high sensitivity while improving specificity compared with conventional pan-filarial serologic testing. A 6-week course of doxycycline has macrofilaricidal activity through Wolbachia depletion and may be useful in nonendemic areas in addition to standard serial ivermectin.

Summary

Recent studies characterizing distinct clinical presentations in travelers and migrants may enable clinicians to better recognize imported onchocerciasis. Although novel diagnostics have improved specificity, most remain restricted to tropical disease reference laboratories and to date there is no marker of cure. Prolonged doxycycline treatment may reduce the need for serial ivermectin, though more potent short-course macrofilaricidal drugs are being developed.

INTRODUCTION

Onchocerciasis is a filarial parasitic infection that causes debilitating chronic skin and eye disease, and affects over 17 million people living in sub-Saharan Africa, foci of Brazil and Venezuela, and Yemen [1^￭]. Onchocercal skin disease may lead to chronic distressing pruritus and disfiguration, and untreated ocular involvement results in visual impairment which may progress to blindness. The 2015 Global Burden of Disease study attributed a loss of 1.1 million disability adjusted life years to Onchocerca volvulus infection, which also decreases individual economic productivity [2,3].

Of the estimated 198 million at ongoing risk of infection, over 95% live in sub-Saharan Africa [1^￭]. However, with the increasing pace of global population migration, clinicians practicing in nonendemic settings continue to encounter imported cases. In 2017 alone, there were 258 million international migrants worldwide, including 15.5 million migrants from Africa who settled in Europe, Asia, and North America [4]. Identifying and treating imported onchocerciasis is a substantial challenge for a variety of reasons, including nonspecific clinical presentation, delayed symptom onset, lack of awareness among healthcare providers in nonendemic countries, and barriers to healthcare access. We provide a comprehensive review of the epidemiology and clinical presentation of imported onchocerciasis in migrants and travelers, and highlight novel approaches to diagnosis and treatment.

TRANSMISSION AND PATHOGENESIS

Onchocerciasis is transmitted through the bite of Simulium blackflies that breed along fast-flowing rivers and streams, hence the name ‘river blindness’. Blackflies inject third-stage larvae into human skin, where they enter subcutaneous tissue and develop into adult O. volvulus worms over 6 to 12 months. Throughout their 9–15-year lifespan, mature adult females produce microfilariae which migrate to skin, eyes, and lymphatics. The intracellular endosymbiotic bacteria Wolbachia is essential to both embryogenesis and survival. It is the host immune inflammatory response to dying microfilariae and Wolbachia, rather than the parasite itself that causes chronic skin and eye disease associated with the disease.

EPIDEMIOLOGY OF IMPORTED ONCHOCERCIASIS

The majority of O. volvulus infection diagnosed outside of endemic areas occurs in immigrants, refugees, and ‘visiting friends and relatives’ (VFR) travelers, almost exclusively from sub-Saharan Africa [5–7]. Onchocerciasis was previously the most common filarial infection diagnosed outside the tropics, representing 37% of 271 imported filariases seen across the Geosentinel Surveillance Network from 1997 to 2004 [5]. The incidence of imported infection appears to be decreasing, likely reflecting the success of global control and elimination programs [6,8^￭]. A total of 9% of immigrants, 5.5% of VFR travelers, and 0.5% of expatriate travelers in a large series of 6000 patients evaluated at a tropical disease referral unit in Spain had onchocerciasis; however, the study also noted a significant temporal decline in annual cases, relative to the number of new African migrants seen in the unit [6]. In a more recent French study spanning the years 2002 to 2011, only 4 of 31 imported filarial infections were caused by O. volvulus, which suggests a decline in relative incidence [8^￭].

It is clear that imported onchocerciasis remains common in migrant populations from highly endemic areas of sub-Saharan Africa and is likely underdiagnosed. Almost 400 cases of onchodermatitis in patients originating from Equatorial Guinea were identified at a single Spanish center [6,9^￭￭]. In a serosurvey conducted at five tropical disease units in Italy, 9.25% of migrants from sub-Saharan Africa had a positive pan-filarial enzyme-linked immuoassay (ELISA) though only a fraction was likely caused by O. volvulus [10^￭]. Studies employing active case finding identify a significantly higher burden of O. volvulus infection. Clinicians in Israel diagnosed onchocerciasis in 83 migrants from northwest Ethiopia through active referral and screening of patients with pruritus or rash. The diagnosis was missed in all cases during a general health examination on arrival to Israel [11]. Five years after resettlement in the United States, 21% of ‘Lost Boys’ from Sudan had positive anti-filarial immunglobulin G4 (IgG4) serologies most likely reflecting active occult infection with O. volvulus [12].

Onchocerciasis is a rare diagnosis in travelers [13,14], who, similar to migrants, acquire their infection in sub-Saharan Africa [5]. In most case series, expatriate travelers infected with O. volvulus have prolonged residence in endemic areas for a minimum of 3 months, and a with median of approximately 2 years noted in United States cohorts [6,15–17^￭￭]. However, travelers can also acquire onchocerciasis with brief, intense exposures to highly endemic areas [5,18,19]. O. volvulus infection in one member of a travel cohort should prompt further investigation of fellow travelers with similar exposures [16].

CLINICAL PRESENTATION

Imported O. volvulus infection manifests differently in immigrants from endemic areas and expatriates who acquire the infection during a temporary residence abroad. Pruritus is the most common symptom in both populations, affecting between 60% and 90% of infected individuals [9^￭￭,15,17^￭￭]. Most travelers with dermatologic involvement on physical examination have acute papular onchodermatitis, which occurs in less than 5% of migrants [9^￭￭,11,17^￭￭,20]. Chronic papular onchodermatitis, lichenified onchodermatitis (sowda or hyperreactive onchodermatitis), depigmentation, and skin atrophy were the most common forms of skin disease in immigrants from endemic areas [9^￭￭,11,20]. Interestingly, migrants with imported onchocerciasis may also present differently compared with similar populations who continue to reside in endemic areas. One Israeli study noted lichenified onchodermatitis in one-third of migrants from Ethiopia, all of whom were asymptomatic at the time of immigration and later developed dermatologic complaints a mean of 2.1 years after arrival. By contrast, sowda (or localized hyperreactive onchodermatitis) is an uncommon finding in endemic populations living in Ethiopia and was observed in only 1% of Ethiopian immigrants to Israel evaluated closer to the time of immigration [11,20]. The authors hypothesized that the increase in hyperreactive onchodermatitis could be due to immunologic changes in response to stress or changing environmental exposures, analogous to the higher burden of allergic diseases seen in migrants compared with individuals remaining in their country of origin [11,20].

Onchocercal eye disease occurs almost exclusively in migrants from endemic areas and is rarely observed in expatriates [15,17^￭￭]. The prevalence of eye disease among migrants also varies widely, likely depending on a complex interplay of O. volvulus strain as well as host genetics [21]. Approximately two-thirds of migrants report ocular symptoms, and 20–80% have ocular involvement on slit lamp examination [11,15,17^￭￭]. Old corneal scarring is the most common ocular pathology, with few cases of subepithelial infiltrates, corneal haze, active anterior segment inflammation, or ocular microfilariae. Most ocular involvement in imported cases is mild, although approximately 10% have some degree of functional vision loss. Posterior segment eye disease is rarely observed in imported cases [11]. Interestingly, historical expatriate cohorts note a prevalence of eye disease in expatriates similar to and even exceeding that in migrants [22,23]. These travelers resided in endemic areas for much longer periods, often working as missionaries in remote hyperendemic settings and had chronic untreated infection, and likely higher disease burden more closely resembling endemic populations.

Onchoceromata are often present in migrants, but are uncommon in expatriates. These subcutaneous nodules were noted in 29% of immigrants to Spain, most in the pelvic girdle and lower extremity [9^￭￭]. Acute fixed unilateral limb edema is a common manifestation unique to travelers, present in up to 12% of temporary residents [8^￭,17^￭￭]. Asymptomatic infection occurs in up to 20% of patients with imported onchocerciasis, most having been referred for screening based on elevated immunoglobulin E (IgE), eosinophil count, or similar exposure history to a known case [9^￭￭].

Most migrants with onchocerciasis are symptomatic at the time of immigration. However, there appears to be a subgroup with delayed symptom onset occurring months to years after moving to a nonendemic setting [11,20]. In travelers with imported onchocerciasis, median time to symptom onset after leaving the endemic area was approximately 1–1.5 years, likely reflecting the long prepatent period of O. volvulus [15]. In the absence of systematic screening, migrants experience diagnostic delays typically ranging from 1 to 2 years [9^￭￭,11]. Travelers were symptomatic for a median of 6 months before onchocerciasis was considered, with a significantly shorter time-to-diagnosis compared with migrants (Showler AJ, Nutman TB, unpublished observation).

LABORATORY INVESTIGATIONS

Eosinophilia is present in only two-thirds of travelers and migrants in larger series of imported onchocerciasis [11,15]. Smaller studies and case reports note eosinophilia in over 90% of patients, but these studies were likely influenced by selection bias [16]. Eosinophilia is generally mild to moderate, although 7% in one recent series presented with eosinophilia of more than 3000 cells/ml [9^￭￭]. McCarthy et al. noted a higher absolute eosinophil count in endemic individuals residing abroad compared with expatriate travelers [15]. However, eosinophils were similar in a related study comparing temporary residents and migrants exclusively with imported onchocerciasis (Showler AJ, Nutman TB, unpublished observation). Eosinophil granule proteins were also similar in both groups, suggesting that differences in clinical presentation between travelers and migrants are not eosinophil-mediated. Between 50% and 90% of patients have elevated serum IgE levels that may be higher in the migrant (compared to temporary residents) groups [9^￭￭,15].

Evaluation for coinfections with other neglected tropical diseases is an important part of the diagnostic evaluation. Of migrants from endemic areas, 37% had at least one additional parasitic infection, frequently with other filariae [9^￭￭].

DIAGNOSIS

Definitive diagnosis depends on finding an adult worm in an excised nodule or, more commonly, microfilariae in a skin snip. Microfilariae may also be seen in the cornea and in the anterior chamber of the eye when viewed with a slit lamp. Assays using nucleic acid amplification techniques (NAAT) to detect onchocercal DNA by targeting the O-150 repeat sequence in skin snips are now in use in research laboratories and are highly specific and sensitive, provided that organisms (or DNA) are present in the skin samples obtained [24,25].

IgG and IgG4 antibody measurement to a crude parasite extract of Brugia malayi adult antigen is the most widely used serologic tests available [26]. IgG antifilarial antibody assays, while positive in individuals with onchocerciasis as well as each of the other filarial infection, suffer from a lack of specificity and positive predictive value; however, the combined use of three groups of recombinant antigens in conventional ELISA provides sensitivity and specificities that approach 100% for the diagnosis of onchocerciasis [27]. Another platform incorporates four recombinant antigens into a rapid, high-throughput luciferase immunoprecipitation system assay that is 100% sensitive and 80–90% specific in distinguishing onchocerciasis from related filarial infections [28]. For serologic detection of O. volvulus infections, an antigen termed OV-16 has been used as an early biomarker for infection. A commercially available rapid diagnostic test (RDT) for OV-16 has been developed; this SD Bioline Onchocerciasis IgG4 RDT (Standard Diagnostics [now Abbott], Gyeonggi-do, South Korea) has a specificity that ranges from 95% to 99% and a sensitivity of approximately 80% [29,30,31,32^￭]. Although used primarily as a surveillance tool for certifying elimination, it may be useful for confirming the diagnosis in persons with suspected onchocerciasis.

TREATMENT

The current standard of care for imported onchocerciasis is serial administration of ivermectin 150 μ/kg daily every 3–6 months for the duration of symptoms, potentially in addition to the macrofilaricide doxycycline in patients without contraindications.

Ivermectin is the mainstay of treatment and rapidly eliminates microfilariae from the skin and eyes, which both alleviates symptoms and prevents long-term sequelae resulting from the host inflammatory response. Long-term cure requires annual or semiannual treatments, as ivermectin is primarily a microfilaricide. Ivermectin is safe and well tolerated in the majority of patients with onchocerciasis; serious adverse events are exceptionally rare following ivermectin administration in O. volvulus infection unless coinfected with Loa loa (and a high microfilarial burden) [33^￭]. Of 345 migrants in one Spanish series who were treated with ivermectin for onchodermatitis, only 11 had adverse reactions which consisted of pruritus, fever, or edema [9^￭￭]. One patient in this series, who was also infected with Loa loa, developed encephalitis, which highlights the importance of excluding Loa loa microfilaremia in patients from coendemic areas prior to giving ivermectin.

The optimal duration of ivermectin therapy for imported onchocerciasis is unknown. In the past, many experts recommended ivermectin treatment every 6–12 months throughout the usual 10-year lifespan of the adult worm. Travelers with Onchocerca may require serial treatment only for the duration of symptomatic disease [34]. Infected travelers reassessed more than 10 years after treatment had no long term sequelae of O. volvulus despite stopping ivermectin when symptoms resolved, after a median of only 3.9 doses given over 1.75 years [34]. A recent study employing mathematical modelling techniques to assess the cumulative effect of multiple doses of ivermectin may account for the apparent efficacy of so few treatments [35^￭].

Doxycycline (used ‘off label’) is a macrofilaricidal drug that targets the endosymbiotic Wolbachia bacteria that is necessary for adult worm reproduction and survival. Doxycycline administered for 4–6 weeks in combination with standard ivermectin treatment sterilizes adult worms and has a delayed gradual macrofilaricidal effect [36,37], though a recent systematic review noted high risk of bias in three major randomized controlled trials evaluating this regimen [38]. Doxycycline 200 mg daily for 6 weeks appears to have the greatest Wolbachia-depleting effect [37]. The impact of doxycycline on duration of therapy has not been studied in nonendemic settings; however, mathematical modelling of clinical trial data from endemic areas estimated a 70–80% decrease in lifespan of Wolbachia-depleted O. volvulus worms [39]. Doxycycline can be administered even in patients with high Loa loa microfilaremia as the Loa loa worms do not contain Wolbachia [40]. Novel short-course macrofilaricidal drugs and drug combinations are under development, but to date remain at the preclinical and phase I clinical trial stage. In addition, moxidectin, another macrocyclic lactone, has been shown in recently completed Phase 3 studies in West and Central Africa to have both a more prolonged plasma half-life and more sustained microfilaricidal activity than ivermectin [41^￭￭].

DIAGNOSIS AND TREATMENT OUTSIDE OF TROPICAL DISEASE REFERENCE CENTERS

From a practical standpoint, most clinicians in high-and middle-income countries evaluating patients with suspected onchocerciasis will have limited access to Ov-16 antibody testing, O. volvulus NAAT, or the equipment to perform skin snips. When higher-level diagnostic resources are not available, presumptive diagnosis is based on compatible epidemiologic exposure, characteristic signs and symptoms, and antifilarial serologic testing. The limitations of this approach include seronegativity in up to 20% of travelers, the occasional cross-reactivity with Strongyloides and difficulty in distinguishing between Onchocerca and other filarial infections or coinfections. In suspected cases, assessing treatment response to empiric ivermectin is reasonable, in particular as ivermectin is widely available and safe. In any patient with exposure to a region endemic for Loa loa, screening for high levels of Loa loa microfilariae must be performed prior to administering ivermectin. Should there be high levels of Loa loa micro-filariae, alternative treatment strategies (e.g., doxycycline) for onchocerciasis should be used.

CONCLUSION

Successful ivermectin mass drug administration (MDA) has virtually eliminated onchocerciasis in the Americas [1^￭,42]. The WHO Expanded Special Project for the Elimination of Neglected Tropical Diseases continues to work toward onchocerciasis elimination in Africa, although this poses an ongoing challenge. In 2016, only 67% of the population requiring treatment for onchocerciasis received ivermectin, a level that falls short of the threshold needed to achieve global elimination [1^￭]. Novel short-course macrofilaricidal drugs and more effective microfilaricides may facilitate more rapid elimination and lengthen the required treatment interval [41^￭￭,43^￭]. Point-of-care smartphone-based diagnostic testing for Loa loa (LoaScope) may enable reimplementation of ivermectin MDA in previously ‘off limits’ areas of West Africa [44,45^￭]. At the same time, elimination efforts remain under constant threat due to geopolitical instability, weak national public health systems, suboptimal response to ivermectin, and more fundamentally, a lack of global commitment to funding neglected tropical diseases [1^￭,46^￭]. With evolving diagnostic and therapeutic tools to promote elimination, imported onchocerciasis should become less and less an immediate medical concern and more of a historical problem, though, in the interim, both migrants and travelers remain at risk for onchocerciasis.

KEY POINTS.

• Migrants with imported onchocerciasis are likely to present with mixed chronic papular dermatitis, skin atrophy, pigment changes, hyperreactive dermatitis, and eye involvement.

• Travelers commonly have acute papular dermatitis or fixed unilateral limb edema, and rarely have ocular disease.

• Recombinant Onchocerca Ov-16 antibody testing has high specificity for O. volvulus and testing for multiple recombinant Onchocerca antigens improves sensitivity.

• Serial ivermectin treatment for the duration of symptoms is the mainstay of therapy, but an adjunctive 6-week course of doxycycline will also sterilize and kill adult worms.