# Imported loiasis: Diagnostic and therapeutic challenges

C. Elouardi, A. Lefort, L. Deconinck, N. Peiffer-Smadja, S. Houzé, N. Argy

► To cite this version:

C. Elouardi, A. Lefort, L. Deconinck, N. Peiffer-Smadja, S. Houzé, et al. Imported loiasis: Diagnostic and therapeutic challenges. *Infectious Diseases Now*, 2025, 55 (3), pp.105053. 10.1016/j.idnow.2025.105053. hal-05120157

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Submitted on 19 Jun 2025

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<figure><img src="image_1.png" /></figure>
Review

Imported loiasis: Diagnostic and therapeutic challenges

C. Elouardi<sup>a, *, c</sup>, A. Lefort<sup>b, c</sup>, L. Deconinck<sup>d, e</sup>, N. Peiffer-Smadja<sup>c, d</sup>, S. Houzé<sup>a, e</sup>, N. Argy<sup>a, e</sup>

<figure><img src="image_2.png" /></figure>

ARTICLE INFO

Keywords:

Diethylcarbamazine

Imported

Ivermectin

Loiasis

Loa loa

A B S T R A C T

Loiasis is a vector-borne parasitic disease that has long been neglected due to its benign nature and its geographical distribution, which is restricted to the forest regions of Central and West Africa. However, it is now recognized as a significant public health concern in endemic areas, where chronically infected patients face organ damage and an increased risk of mortality. Loiasis presents several challenges, from diagnosis to treatment, as inappropriate therapies can lead to severe and at times fatal side effects.

Although loiasis has low prevalence in Europe, historical connections with most endemic countries expose the continent to a high risk of imported cases, making it the most commonly imported filariasis in Europe. Population movements challenge healthcare providers, who often struggle with limited diagnostic and therapeutic tools. It is therefore essential to adopt an appropriate approach aimed at optimizing to optimize patient management and preventing severe adverse effects due to inappropriate treatment.

At present, however, there exist no specific recommendations for managing imported loiasis. The present review aims to evaluate the current state of knowledge on its management and to propose an optimal approach through a decision-making algorithm, emphasizing pathophysiology by patient category, biological diagnostic methods and perspectives, as well as therapeutic strategies adapted to the challenges of non-endemic areas. These updated data aim to help clinicians from non-endemic areas to improve management of imported loiasis through development of a decision-making algorithm.

# 1. Introduction

Loiasis is a strictly African tropical vector-borne disease caused by a blood-borne parasite: the filarial *Loa loa*.

*Loa loa* belongs to the Animal kingdom, *Nematoda* phylum, *Chromadorea* class, *Spirurida* order, *Filaria* family, *Loa* genus and *loa* species with a specific phylogenetical position, compared to other filarial species, as determined by morphological and molecular investigations [1]. It was first described in 1770 by a French surgeon, Dr. Mongin, when he attempted to extract a macrofilaria from the eye of an African slave [2].

This parasitic disease, long neglected due to its benign nature and geographical distribution restricted to the forest regions of Central and West Africa, represents a significant public health problem ultimately causing numerous complications in the absence of treatment [3]. Two retrospective studies conducted in Cameroon and Congo have shown

that chronic microfilaremia patients were exposed to an increased mortality risk estimated at 14.5 % in those over 25 years of age, with aggravating factors including age ≥ 55, male sex, and microfilaremia ≥ 30,000 mf/mL [4,5].

Loiasis raises several issues due to the complexity of its diagnosis, with a variation of the clinical and biological presentation according to the infected population, and the currently available diagnostic tools are limited. Its therapeutic management can prove problematic, and even dangerous, as the main filaricides available, diethylcarbamazine (DEC) and ivermectin, can cause severe gastrointestinal, cardiovascular, renal and respiratory disorders, and even occasional fatal neurological adverse effects (encephalopathies...), as highlighted during onchocerciasis control programs in Africa following mass treatments with ivermectin [6-8]. In addition, choice of treatment depends on several variables linked to both the infected host (age, weight, pregnancy,

<footnote><sup>a</sup> Parasitology Laboratory, Bichat-Claude Bernard Hospital, AP-HP Nord and Université Paris Cité, 46, Rue Henri Huchard 75018 Paris, France</footnote>

<footnote><sup>b</sup> Internal Medicine Department, Beaujon Hospital, AP-HP Nord and Université Paris Cité, 100, Boulevard du general Leclerc 92110 Clichy, France</footnote>

<footnote><sup>c</sup> INSERM IAME, Medicine faculty, Université Paris Cité, 16, Rue Henri Huchard, 75018 Paris, France</footnote>

<footnote><sup>d</sup> Infectious Diseases Department, Bichat-Claude Bernard Hospital, AP-HP Nord and Université Paris Cité, 46, Rue Henri Huchard 75018 Paris, France</footnote>

<footnote><sup>e</sup> IRD MERIT UMR 261, Pharmacy Faculty, Université Paris Cité, 4, Avenue de l'observatoire, 75006 Paris, France</footnote>

<footnote>* Corresponding author at: Laboratoire de parasitologie, Hôpital Bichat-Claude Bernard, 46, Rue Henri Huchard 75018 Paris, France.</footnote>

<footnote>E-mail address: familya.el-ouardi@aphp.fr (C. Elouardi).</footnote>
breastfeeding, hypersensitivity) and the parasite (filarial coinfection, microfilaremia). Lastly, numerous therapeutic failures have been described [8–14]. Clinicians from non-endemic areas need to realize that although loiasis has low prevalence in Europe, historical connections with most endemic countries expose Europe to a high risk for imported cases, making loiasis the most commonly imported filariasis in Europe (17,18). Population movements challenge healthcare providers, who often struggle with limited diagnostic and therapeutic tools. Therefore, it is essential to adopt an appropriate approach aimed at optimizing patient management and preventing severe adverse effects due to inappropriate treatment.

At present, however, no specific recommendations exist for the management of imported loiasis. This review aims to evaluate the current state of knowledge on its management and to propose an optimal approach through a decision-making algorithm, emphasizing pathophysiology by patient category, biological diagnostic methods and perspectives as well as therapeutic strategies adapted to the challenges of non-endemic areas [15].

## 2. Epidemiology

Due to the ecological requirements of its vector, *Chrysops* spp (Fig. 1), the geographical distribution of *Loa loa* is very limited. It thrives in the hot, humid forests of tropical Africa, spanning from Central to West Africa (Fig. 2) [16,17]. Ten countries are considered endemic for *Loa loa* filariasis: Angola (15.1 %), Cameroon (43.0 %) Central African Republic (45.5 %), Chad (10.3 %), Congo (45.3 %), Democratic Republic of Congo (21.4 %), Equatorial Guinea (65.4 %), Gabon (65.1 %), Nigeria (19.0 %), Sudan (19.0 %), with prevalence varying between grassland and forested savannahs in Cameroon and the Central African Republic, while and Equatorial Guinea have a more uniform distribution [16]. Among them, the two major hyperendemic zones, defined as areas where at least 40 % of the population report the presence of eyeworm, are located first in western Central Africa, including Gabon, Equatorial Guinea, southern Cameroon, western Central African Republic, and part of Chad, and second in the northeastern Democratic Republic of Congo, with extensions into Equatorial Province in the west, Maniema Province further south, and Sudan in the northeast [16].

An estimated 14 million people reside in these hyperendemic zones, with an additional 15 million in intermediate-risk zones (less than 40 %) [16]. Cameroon and the Democratic Republic of Congo (DRC) alone account for 80 % of the high-risk hyperendemic zones [16]. However, these figures are likely underestimated due to the documented shortcomings of the RAPLOA approach (Rapid Assessment Procedure for Loiasis) which involves questioning a sample of 80 adults per village

<figure><img src="image_3.png" /><figcaption>Fig. 1. *Chrysops* spp, *Loa loa* vector [17].</figcaption></figure>

about their history of eye worm [16]. The proportion of positive responses then serves to estimate the prevalence of loiasis in the area.

## 3. *Loa loa* life cycle

The life cycle of the *Loa loa* parasite begins when the female *Chrysops* spp. (Fig. 1), a hematophagous horsefly vector of *Loa loa*, also known as the “red fly” or “thread fly,” takes a blood meal and ingests the microfilariae of an infected host (definitive host) (Fig. 3). It belongs to the *Diptera* order (Orthorrhata) with two wings and short antennae, and the *Tabanidae* family, with *Chrysops silacea* and *Chrysops dimidiata* being the primary vector species [17]. These horseflies thrive in humid, shaded environments such as forested and plantation areas. This exophilic insectnhas a telmophage bite, predominantly targeting the ankles and lower limbs [17]. Practically noiseless and persistent daylight feeders, they are active between 10 a.m. and 4p.m., with peak activity at midday. *Chrysops* bites at all levels of the forest, crosses small clearings, and readily enters houses or attacks plantation workers [17,23]. *Loa loa* prevalence is higher in forested savannahs, where dense vegetation and favorable conditions support vector activity, while grassland savannahs, with sparser vegetation and drier climates, exhibit lower prevalence [17].

The ingested microfilariae shed their sheaths in the horsefly's stomach, developing into L1-stage larvae that cross the vector's intestinal wall and migrate into the thoracic muscles, acquiring infective power in 10-12 days through the L2 and L3 larval stages [24]. Once mature, the L3 larvae migrate towards the vector's proboscis, awaiting a new blood meal. Injected L3 larvae actively penetrate the epidermis until they reach the subcutaneous tissues, taking 6 to 12 months to mature into adult male and female filariae capable of reproduction [2]. The adult filariae, or macrofilariae, are round, transparent worms measuring 5-7 cm for females and 3-3.5 cm for males. They reside in the subcutaneous tissue, moving at a rate of 1 cm/min and can live for up to 17 years under the skin [2]. Once fertilized following sexual reproduction with adult male filariae in subcutaneous tissues, the adult viviparous female filariae periodically release larva called microfilariae into the peripheral bloodstream, only during the day, resulting in diurnal microfilaremia, coinciding with the period of activity of the female *Chrysops* spp, thereby ensuring continuity of the infection.

As loiasis in the Western world is an imported disease, the categories of patients at risk of developing imported loiasis include military personnel returning from operations in endemic zones, expatriates, migrants from endemic zones visiting their families and relatives during a long stay (from several weeks to several months), as well as farmers, loggers, hunters, fishermen, forestry workers, agricultural laborers, field researchers, hikers, and anyone engaged in outdoor activities in endemic areas [17]. Length of stay is a determining factor in the risk of exposure to and transmission of *Loa loa*. Several weeks of stay would be necessary for *Loa loa* infection, considering the parasite's lengthy development in its vector, the painful bite of *Chrysops* spp., which limits the inoculation time of L3 larvae, and the innate response, which controls the number of larvae inoculated during the vector's blood meal [25]. That is why tourists traveling to endemic areas are very rarely infected, given the type and duration of their stay, as well as the personal anti-vector protection measures that are usually well-implemented [2].

## 4. Clinical diagnosis

Loiasis presents with polymorphic symptoms, ranging from asymptomatic to severe. Following an asymptomatic incubation period of 6 to 12 months, during which injected microfilariae mature, three clinical signs may appear either independently or concurrently: subconjunctival passage of microfilariae or eyeworm (Fig. 4), cutaneous crawling of adult filariae, and Calabar swelling (Fig. 5) [2].

The eyeworm is the clinical sign most frequently reported by patients and is pathognomonic of *Loa loa* filariasis. It involves the *retro*-
<figure><img src="image_4.png" /><figcaption>**Fig. 2.** Geographical distribution of Loa loa inspired from [16] and [15]. Ten countries are considered endemic for Loa loa filariasis, Angola [18], Cameroon [9–14,18–21], Central African Republic [9,12,13,18,20], Chad [13], Congo [12,18,21], Democratic Republic of Congo [9–14,18,19,21], Equatorial Guinea [12,18–21], Gabon [9,10,12–14,18–21], Nigeria [10,11,13,14,18–20], Sudan [21]. Some imported cases have been reported outside RAPLOA assessment's endemic area: Guinea-Bissau [22], Guinea [22], Sierra-Leone, Liberia, Ivory coast [12,18], Ghana [10,18], Togo [9], Benin [9,12], Uganda, Rwanda [12], Zambia [18], Mali [12] and Ethiopia [18].</figcaption></figure>

conjunctival ocular passage of adult filariae visible for a few minutes to the naked eye, under the palpebral or bulbar conjunctiva. This eyeworm is often accompanied by itching, photophobia, lacrimation, or peri-orbital edema [2]. The extraction of this worm can provide relief to the patient. Skin crawling of adult filariae is characterized by the presence of a visible, palpable, mobile, and pruritic "cord," typically located on the forearms [2]. Calabar swelling, named after a locality in southern Nigeria, is a type I hypersensitivity allergic manifestation resulting from the subcutaneous passage of adult worms [2]. This histaminic angioedema, described as fleeting and migratory, lasts from a few hours to several days and clinically manifests as firm, poorly demarcated swelling, which may be erythematous and pruritic, causing a sensation of painful tension. It occurs in the upper or lower limbs, particularly in the distal extremities, but more frequently affects the upper limb, especially the wrist and hand.

However, the clinical presentation of this parasitic infection may vary among different populations, complicating the diagnosis of loiasis. Several studies have demonstrated that loiasis progresses quietly in patients native to endemic areas, with low prevalence of Calabar swelling but a more frequent eyeworm. In contrast, non-native patients (military, expatriates or tourists non-native to endemic areas) exhibit a more pronounced symptomatology with associated general signs such as asthenia, myalgias, arthralgias, and higher prevalence of Calabar swelling [11–14,26] (table S1).

This contrast in symptomology could be explained by a different immune response to the infection.

Churchill's pathophysiological hypothesis suggests that prolonged exposure to Loa loa leads to immune tolerance [10]. However, a study in the Congo found higher microfilaremia prevalence in Bantus compared to Pygmies, despite similar exposure, suggesting ethnic or genetic differences in immune response [27]. Furthermore, the first long-term study in Cameroon, which followed untreated patients for a year, found that their microfilaria levels remained stable despite high transmission risk. This suggests that genetic factors influence immune responses to *Loa loa* [25,28]. Additionally, European studies show that non-native patients (expatriates and military personnel) present different clinical and biological responses compared to native populations, even after years in endemic areas. These results support Klion's hypothesis that genetic factors, chronic polyparasitism, and prenatal sensitization play a more prominent role in immune modulation than infection or exposure duration [9].

In addition to the typical clinical manifestations, neurological (refractory headache, cerebellar syndrome, psychiatric disorders), ophthalmic (retinal hemorrhages, uveitis, chorioretinitis), renal (glomerulonephritis, nephrotic syndrome), cardiovascular (endomyocardial fibrosis, arterial thrombosis), pulmonary (pulmonary fibrosis, pleural effusion), gastrointestinal (hepatitis, splenomegaly), and dermatological (lymphangitis, vasculitis) complications have been
<figure><img src="image_5.png" /><figcaption>Fig. 3. *Loa loa* life cycle.</figcaption></figure>

<figure><img src="image_6.png" /><figcaption>Fig. 4. Subconjunctival passage of macrofilariae.</figcaption></figure>

<figure><img src="image_7.png" /><figcaption>Fig. 5. Calabar swelling.</figcaption></figure>

described, as well as damage to the reproductive, musculoskeletal (arthritis), and mammary gland systems [3].

These complications may be direct, due to the presence of the parasite, or indirect, associated with the formation of immune complexes. However, the contribution of *Loa loa* filariasis to these complications is debatable, considering the late onset of these events, the absence of microfilariae during biological and histological investigations, and chronic hypereosinophilia, which may also contribute to these complications [2]. Chronic eosinophil activation leads to massive release of granule contents, which are both cytotoxic and prothrombotic, and can induce cardiac, pulmonary, and neurological damage. A meta-analysis of 279 studies, reporting 329 cases of loiasis, including 51.4% of native patients living or not in endemic zones, and 47.4% of non-native patients (expatriates and travelers), showed that only 53.2% of patients exhibited classical clinical signs such as Calabar swelling and eyeworm, while 46.8% experienced at least one complication [3]. The latter had significantly higher microfilaremia (≥ 8000 mf/mL) but not greater eosinophilia. However, the causal relationship between loiasis and complications has not been conclusively proven for all patients, despite a strong association observed following therapeutic interventions [3].

## 5. Biological diagnosis

To diagnose loiasis, national (French, 2015) and international (Australian, 2017, and British, 2010) guidelines consistently emphasize the importance of testing for microfilariae using diurnal blood smears and/or thick drop methods in cases of hypereosinophilia among first-time migrants from endemic regions. Serology is either systematically recommended or suggested when direct examination results are negative [29]. The incidental finding of eosinophilia upon return from an endemic area should prompt consideration of helminthiasis, including loiasis. Unlike total IgE, which may increase inconsistently, eosinophilia is present in 53-100% of *Loa loa* filariasis cases, with higher rates observed in patients non-native to endemic areas [9-14,18,29,30].

Parasitological diagnosis of loiasis is based on the detection and quantification of the parasite directly in the fresh whole blood sample collected between 10 a.m. and 4p.m. [23]. Microfilariae visualization should be performed within four hours of sample collection to prevent
degradation and a reduced parasite count [31]. *Loa loa* detection in fresh blood relies on the observation of highly motile, serpentine microfilariae but does not allow species identification. This method requires skilled technicians or microbiologists, and without proper training, the risk of false negatives is significant. As an alternative, May-Grünwald-Giemsa staining of blood smears allows both microfilariae detection and species identification through detailed microscopic examination. *Loa loa* is specifically characterized by its size (approximately 250–300 µm in length), curved tail, terminal nuclei, colorless sheath, elongated cephalic space, internal body, and overlapping somatic nuclei (Fig. 6 and Table S2) [31]. In cases of negative blood smears, more sensitive techniques, such as thick blood films or leukoconcentration, prepared from a larger volume of whole blood, may be employed. A positive result necessitates microfilariae quantification, a critical step prior to initiating treatment, typically performed using calibrated blood volumes [31]. Microfilariae may also be detectable in other samples such as urine, vaginal smears, joint fluid, or cerebrospinal fluid (CSF), depending on the clinical presentation [31].

However, conventional microscopy for the detection of *Loa loa* has
several limitations, including low sensitivity due to the use of small
sample volumes and diurnal fluctuation in microfilaremia. In addition,
infection by a single *Loa loa* adult or by unisex adults is not associated
with the presence of microfilariae necessary for the biological diagnosis
of loiasis. Microfilaremia also varies from one individual to another,
with 10–57 % of native patients being amicrofilaramic, compared with
55–90 % of non-native patients [9–14,18,20,30]. Given the limitations
of microscopic diagnosis of *Loa loa*, serology can complement direct
diagnosis, with serological techniques serving as a diagnostic tool of
exclusion due to their high negative predictive value in the absence of
other clinical or biological evidence [9–14,20]. All conventional sero-
logical assays use heterologous antigens for the detection of antifilarial
antibodies. Although techniques such as indirect immunofluorescence
(IFI) are still applied in a few diagnostic centers in non-endemic areas,
enzyme-linked immunosorbent assay (ELISA) remains the most widely
used serological screening technique in Europe for detecting pan-filarial
total IgG antibodies. ELISA offers high sensitivity (90.8 %) but variable
specificity (46.3 %) due to cross-reactivity with other parasites such as
*Mansonella perstans*, *Brugia* spp., *Schistosoma* spp., *Strongyloides* spp., and
*Ancylostoma* spp [31,32]. The lack of specificity of these serological
screening techniques may necessitate confirmation by immunoprecipi-
tation methods such as immunoelectrophoresis (IEP) or electro-
syneresis, which offer better specificity but are more time-consuming.
More advanced techniques, such as the luciferase immunoprecipita-
tion system assay (LIPS) and rapid immunochromatographic tests, pro-
vide superior analytical performance but are available primarily in the

<figure><img src="image_8.png" /><figcaption>**Fig. 6.** Picture of a microfilariae on a May-Grunwald-Giemsa-stained blood smear, magnification X1000.</figcaption></figure>

USA. LIPS technology employs a recombinant *Loa loa*-specific protein, LISXP1, fused with *Renilla* luciferase to diagnose loiasis. This technique demonstrates high sensitivity (94 %) and specificity (78 %) for total IgG detection, with reported cross-reactivity with *Wuchereria bancrofti* and *Onchocerca volvulus*, but not with *Strongyloides stercoralis* [33]. However, IgG4 detection instead of total IgG does not improve LIPS performance [33,34]. A faster version, QLIPS, incorporates protein A/G beads to enhance specificity, thereby reducing reaction time and minimizing cross-reactivity [33]. QLIPS has demonstrated nearly 100 % sensitivity and specificity, although it was evaluated on a smaller sample size compared to LIPS [33]. Additionally, the same research group has since developed improved and more generalized techniques for rapid anti-body detection based on the same principles as QLIPS. Alternatively, rapid immunochromatographic tests, employing the same antigen, demonstrate sensitivity of 86.5–94 % and specificity of 82–100 %, despite cross-reactions with *Schistosoma* spp and *Mansonella perstans* [32,35,36]. Nevertheless, IgG4 detection instead of total IgG does not improve performance of this test in terms of sensitivity since specificity was not evaluated in this study [36]. The latter offers affordability and practicality, costing approximately 4 euros per test [32]. All serological assays performances are presented in Table S3.

As observed with the clinical presentation of imported loiasis, the biological differences observed among infected populations may also be attributed in part to variations in immune response to the infection [11–14,26]. Indeed, non-native patients typically exhibit higher levels of eosinophil polynuclear cells and positive filarial serology with elevated IgG levels, coupled with lower microfilaremia, in contrast with native patients from endemic areas. The latter group tends to display less pronounced eosinophilia, weakly positive or negative filarial serology, despite having higher microfilaremia levels [9–14,18,20,26,30] (Table S4).

To overcome the limitations of conventional direct examination, various molecular biology techniques have emerged, enabling detection of a significant number of occult loiasis cases. In 1992, Edwang et al. identified a 396-bp sequence of the 15r3 repeat region encoding a 15 kDa antigen specific to *Loa loa*, leading to the development of the initial PCR techniques [37]. Subsequently, Touré et al. devised a nested PCR assay targeting this 15r3 repeat region, achieving sensitivity of 95 % and specificity of 100 % [37]. Other PCR techniques focusing on the ITS1 (internally transcribed spacer 1) non-coding region have also been developed in recent years. In 2010, Jiménez et al. introduced and assessed a PCR-RFLP (restriction fragment length polymorphism) and a nested PCR targeting ITS1, allowing differentiation between *Loa loa*, *M. perstans*, and *W. bancrofti* infections [38]. PCR-RFLP yielded overall sensitivity of 66.6 % for *Loa loa* compared to 42.9 % for nested PCR, with both techniques demonstrating 100 % specificity. However, these methods are complex and time-consuming, making them impractical for routine use. As a result, simpler techniques such as LAMP (Loop-Mediated Isothermal Amplification) and qPCR (Quantitative Polymerase Chain Reaction) have been developed for faster, routine diagnosis [39–46]. Despite targeting different *Loa loa* sequences, whether specific (LLMF72, M34259.1, and LL2643) or non-specific (ITS1), and using distinct extraction protocols, these techniques still offer lower sensitivity and specificity comparable to conventional direct examination [39–46]. Currently, direct examination remains the gold standard for definitive diagnosis, although LAMP shows promise and warrants further refinement due to its technical simplicity, rapidity, and cost-effectiveness (Table S5).

Whole genome sequencing, such as MinION sequencing, combined with artificial intelligence (AI), could transform how *Loa loa* is diagnosed and monitored. MinION sequencing, a compact and cost-effective technology, enables accurate genetic identification of the parasite, while AI could automate and speed up the analysis of samples, reducing diagnostic time and improving public health efforts. Despite these advances, more studies are needed to confirm the effectiveness and cost of these technologies for *Loa loa* in real-world clinical settings [47,48].
In addition to molecular techniques, flow cytometry has emerged as a promising tool for improving the diagnosis and monitoring of *Loa loa*, offering an alternative approach to parasite detection. A protocol tested on a single patient from Cameroon detected *Loa loa* using dual labeling with SybrGreen and polyclonal anti-*Loa loa* antibodies, with microfilaremia results closely matching blood smear examination. While offering rapid analysis, sensitivity, and low-cost reagents, this method has been validated on only one patient. It also requires specialized infrastructure, such as cytometers, and skilled technicians, both of which are costly and time-intensive to establish. Moreover, the case report does not show clear advantages over conventional blood smear examination. Therefore, the feasibility, cost, and overall value of this approach require careful assessment [49].

## 6. Specific curative anti-*Loa loa* treatment

Therapeutic management of *Loa loa* filariasis poses a challenge due to the limited treatment options available and the high failure rate. Administration must consider various host-related factors (age, weight, pregnancy/breastfeeding, tolerance/hypersensitivity, treatment duration, compliance) and parasite-related variables (filarial coinfection, microfilaremia, localization, risk of re-exposure) [6–8].

Due to its microfilaricidal and macrofilaricidal properties, diethylcarbamazine (DEC) is the sole molecule endorsed by the WHO for the radical treatment of loiasis, but although its mode of action remains uncertain [50]. DEC, derived from piperazine, boasts nearly 100 % oral bioavailability [50]. Previous beliefs regarding DEC’s indirect parasiticidal activity, involving immune system activation leading to parasite paralysis, have been challenged in recent studies. In *W. bancrofti*, DEC has been observed to disrupt microfilarial sheaths and impede macro-molecule transport to the surface of macrofilariae. Similarly, studies on *Brugia malayi* have demonstrated concentration-dependent temporary spastic paralysis of microfilariae.

However, this therapeutic option is limited by several factors. DEC is contraindicated in pregnant and breastfeeding women, and the treatment regimen is complex, requiring strict medical supervision. The protocol involves a stepwise dosage escalation, starting with 1/32nd of the therapeutic dose on day one, with the dose doubling daily until the target of 3 mg/kg/day is reached, divided into two daily doses, without exceeding 400 mg/day. This gradual increase in dosage is intended to minimize the risk of adverse reactions, particularly the inflammatory response triggered by rapid microfilarial clearance. Close monitoring throughout treatment is crucial to ensure both safety and efficacy. It is important to note that there are no randomized controlled trials specifically assessing DEC for *Loa loa* filariasis. Current treatment recommendations are based on observational studies [8,51]. As a result, the dosing protocol may be refined, with the lack of controlled trials allowing for further optimization.

In 24 to 70 % of cases, a single course of treatment is not sufficient [7,9–14]. It is therefore necessary to check microfilaremia at the end of each course of treatment in order to repeat the course. Only rarely do patients fail to clear the infection after four courses of treatment [52]. DEC is poorly tolerated, with high rates of adverse effects during *Loa loa* infection management, ranging from 30 % in amicrofilaramic patients to 90 % in patients with microfilaremia exceeding 2000 mf/mL [8]. The most common adverse effects are mild and transient (fever, headache, dizziness, arthralgia, myalgia, gastrointestinal disorders, urticaria, pruritus, skin crawling of adult worms, reversible proteinuria, eosinophilia) increasing in frequency and severity when microfilaremia rises [8]. Most adverse events reported occur within the first five days of treatment. Severe side-effects are characterized by eosinophilic pleurisy, extra-membranous glomerulonephritis, Mazzotti’s reactions, Quincke’s oedema or meningoencephalitis in cases of microfilaremia > 30,000 mf/mL [7,8]. Consequently, it is strongly recommended not to use DEC if the patient has microfilaremia above 2000 mf/mL, given the increased frequency of adverse events and the risk of meningoencephalitis

occurring with very high microfilaremia [8]. When used, hospitalization during the first five days of treatment seems necessary to prevent and rapidly manage serious adverse events.

Various molecules and treatment regimens have been explored to address the drawbacks of DEC therapy, including extended treatment duration, repeated courses, and severe side effects. Among these, ivermectin and albendazole have shown significant efficacy against loiasis.

Ivermectin is a macrocyclic lactone, administered at a single dose of 150–200 µg/kg, possibly in pregnant and breast-feeding women [53]. In addition to a microfilaricide activity, ivermectin presents a macrofilariae embryostatic action and macrofilarifuge activity leading to an average microfilaremia reduction of 60 % on the first day, 75 % after three days, and 90 % after three weeks [54]. Its microfilaricidal action involves agonizing glutamate-dependent chloride channels in filarial neuromuscular cells, predominantly at the pharyngeal level, resulting in cell hyperpolarization and paralysis [50]. Side effects are mild and transient (eosinophilia, elevated transaminases, hyperbilirubinemia, hematuria, gastrointestinal disorders, arthralgia, myalgia, headache, fever, asthenia, dizziness) [6]. However, use of ivermectin presents challenges, particularly in cases of high microfilaremia, as serious adverse effects have been reported, highlighted during the Onchocerciasis mass treatment monitoring programs carried out from 1989 to 2001, in countries where *O. volvulus* and *Loa loa* are co-endemics. A total of 207 serious adverse events were recorded among the 165 million patients treated, classifying them as very rare adverse events (cumulative risk at 1/800,000). Higher incidence of these events, particularly encephalopathies, was observed in the Cameroonian population, who exhibited a distinct susceptibility to these adverse effects. More than half of the reported cases were encephalopathies related to loiasis, with 8 % resulting in death. The other half were gastrointestinal disorders, cardiovascular and respiratory disorders and anaphylactic shock, which accounted for 20 % of deaths [6]. The pathophysiological mechanisms underlying severe post-treatment adverse reactions to active amifilariae molecule (DEC and ivermectin) remain incompletely understood. Immune-mediated processes are thought to be involved, triggered by the release of massive antigens during microfilarial death as evidenced by the eosinophil level variation and interleukin-5 concentrations associated with eosinophil activation as assessed by surface CD59 expression and elevated serum concentrations of eosinophil granular proteins [6,55]. This theory is supported by the efficacy of corticosteroid therapy and antihistamines in reducing severe adverse events [6,55]. Additionally, mechanical obstruction of capillaries by paralyzed and dead microfilariae following antifilarial treatment, particularly in cases of high microfilaremia, may contribute to adverse effects [6]. Although evidence from animal studies suggests a genetic susceptibility to ivermectin-induced adverse effects, human data remain inconclusive [56,57]. Nevertheless, studies have shown that the risk of developing significant reactions, whether serious or not, increases with microfilaremia levels above 8,000 mf/mL and becomes extremely high for levels exceeding 50,000 mf/mL (relative risk > 1000) [58]. Nearly all serious adverse events occurred within the first five days of treatment, except for isolated cases, such as functional impairment on day 5 and acute diarrhea on day 7 [58].

A study assessing the individual risk of serious adverse events following ivermectin treatment for loiasis, used a predictive model to show that exclusion of patients with microfilaremia > 20,000 mf/mL would prevent 99 % of serious adverse events [59]. As a result, it would be advisable to hospitalize the patient for monitoring as soon as ivermectin is administered with microfilaremia of 8,000–20,000 mf/mL, and not to use this molecule if the patient has microfilaremia of 20,000 mf/mL.

Albendazole is a large-spectrum antiparasitic treatment, belonging to the benzimidazole family, with an anti-*Loa loa* activity at a dose of 200 mg twice a day for 21 days. Although contraindicated to pregnant and breast-feeding women, albendazole has the advantage of being better tolerated by patients. Albendazole presents microfilaricide
activity by inhibiting filarial parasite metabolism by antagonizing
mitochondrial fumarate reductase and oxidative phosphorylation [50].
However, its main target remains the cytoskeleton. Albendazole inhibits
microtubule polymerization by binding to β-tubulin molecules, thereby
preventing glucose uptake by the parasites, leading to their death. Mean
reduction in microfilaremia was observed from 60 to 80 % after six
months of oral treatment at 400 mg/day for 21 days or at 36.5 % after
10 months of oral treatment at a single dose of 600 mg [60,61]. Simi-
larly, albendazole, while better tolerated, was in one case associated
with encephalopathy [62]. Despite its effectiveness, the limited mac-
rofilaricidal action of ivermectin and albendazole underscores the need
for their use as radical pre-treatment for *Loa loa* filariasis, aimed at
reducing microfilariae numbers and minimizing the risk of serious
adverse effects associated with DEC treatment [54].

As such, therapeutic alternatives have been investigated, but their
efficacy and tolerability remain limited. Levamisole, a benzimidazole
family member, has proven effective albeit moderate and short-lived, on
*O. volvulus*, *W. bancrofti* and *B. malayi*. It secondarily prompted interest
in a double-blind, randomized controlled trial of levamisole versus
placebo in the treatment of loiasis [63]. With a single dose of 2.5 mg/kg,
levamisole induced a significant reduction in microfilaremia of 40 % at
2 days, 11.8 % at 7 days and 18.5 % at 30 days of treatment. Despite
moderate efficacy on *Loa loa*, levamisole is associated with gastroin-
testinal and neurological adverse effects, making it unsuitable for
routine use [63].

Wolbachia spp., Gram-negative bacilli living in the cytoplasm of ar-
thropods and filariae like *O. volvulus*, *B. malayi*, and *W. bancrofti*, are
essential to their development and reproduction. This mutualism led to
the exploration of doxycycline, a tetracycline antibiotic, which targets
*Wolbachia* spp and can kill up to 70 % of *O. volvulus* macrofilariae at 200
mg/day for 6 weeks, and 90 % of adult *W. bancrofti* after 3 months of
treatment. However, doxycycline is ineffective against *Loa loa* due to the
absence of *Wolbachia* spp in this species [64]. Several antimalarial drugs
have been evaluated for filariasis treatment, but their efficacy against
*Loa loa* remains uncertain [65]. A microfilaricidal effect of chloroquine
on *O. volvulus* and a macrofilaricidal effect of high-dose amodiaquine on
*W. bancrofti* have been observed. However, no microfilaricidal effect of
chloroquine and amodiaquine on *Loa loa* was demonstrated when
microfilaremia was monitored for 90 days after treatment [65]. The use of
quinine and artesunate in this randomized clinical trial produced no
convincing results. Additionally, apheresis has demonstrated efficacy in
reducing microfilaremia but is costly and requires specialized personnel
[2]. It should therefore be reserved for infected patients with micro-
filaremia above 20,000 mf/mL.

In conclusion, there is currently no alternative treatment equally
effective against loiasis without serious adverse effects. Management
relies primarily on preventive and adjunctive therapies, with cortico-
steroids and antihistamines being commonly used to mitigate treatment-
related adverse effects, although their efficacy remains contentious.

7. Adjuvant treatment

Corticoids and antihistaminic could be administrated as adjuvant
treatment during loiasis management, in a prophylactic or curative
manner, the objective being to avoid serious side effects during specific
curative anti-*Loa loa* treatment. The prophylactic use of corticosteroids
at a dosage of 0.5 mg/kg equivalent to prednisone is recommended
during the first 5 days of DEC treatment to prevent or alleviate adverse
effects, of which high prevalence and severity have been observed. This
recommendation is based on the findings of Awadzi et al., who
demonstrated that corticosteroid therapy administered 24-48 h before
the first DEC dose in onchocerciasis treatment reduces the severity of the
Mazzotti reaction, and needs to be continued for 4 days so as to prevent
rebound effects [66]. Corticosteroids are generally more effective than
antihistamines in managing post-DEC reactions. Carme et al. found in
their study that while antihistamines were not universally prescribed,

they did not reduce reaction frequency but helped to lessen their in-
tensity. However, their overall impact remained limited, whether used
alone or with corticosteroids. In contrast, corticosteroid therapy, when
given secondarily, showed clear efficacy in controlling these reactions
[8].

Regarding post-ivermectin reactions, adding corticosteroid therapy within 2 days of ivermectin administration seems advisable, given the rise in eosinophil count post-treatment and the short onset time for serious adverse effects (maximum time lapse of 7 days) [55]. Management of the 207 serious adverse events recorded between 1989 and 2001 by the ivermectin mass treatment monitoring program included the administration of antihistamines and corticosteroids [6]. Corticosteroids were used in 44.4 % of cases, and in 55 % of patients with loiasis encephalopathy, while antihistamines were prescribed only in 23.2 % of patients (with complete medical records available for 53 patients). These data suggest that corticosteroids and antihistamines were underutilized in both prevention and treatment of severe adverse events. Given the partial recovery or mortality observed following severe post-DEC or ivermectin adverse reactions, use of corticosteroids and antihistamines appears well-justified. In addition, in cases of significant proteinuria (30 mg/24 h) in patients on DEC, curative treatment by corticosteroids may be prescribed to protect nephrons from filarial antigen release and immune complex deposits on the glomerular capillary basement membrane [8].

More broadly, the management of DEC- or ivermectin-related adverse effects should be severity-based. Mild to moderate reactions may be adequately managed with antihistamines alone, whereas severe adverse events may require adjunctive corticosteroid therapy. To prevent the onset of severe adverse reactions, corticosteroids should be administered prophylactically during the first two days of ivermectin treatment or the first five days of DEC treatment. These findings underscore the importance of a standardized treatment strategy. Accordingly, a diagnostic and therapeutic decision-making algorithm could be developed to optimize the clinical management of imported loiasis (Figs. 7 and 8).

However, in some instances, corticosteroid therapy alone may not
suffice to prevent sequelae and deaths associated with DEC or iver-
mectin use in hyperfilaremic loiasis. This underscores the need for
research and development of new molecules and reconsideration of the
indications of existing ones such as reslizumab. Reslizumab is a hu-
manized monoclonal antibody targeting human IL-5, a cytokine
involved in eosinophil differentiation, maturation, recruitment, and
activation. Currently indicated for severe asthma refractory to inhaled
corticosteroids, reslizumab was prescribed in a prospective study of 8
patients in 2021 to evaluate its efficacy in preventing serious adverse
events associated with DEC use [67]. However, this study, comparing 2
groups of 4 patients treated with reslizumab 1 mg/kg versus placebo
administered 3 to 7 days before DEC administration, failed to demon-
strate the efficacy of reslizumab in preventing serious adverse events.
Moreover, the study's recruitment bias, including too few patients with
low microfilaremia (< 2500 mf/mL), diminishes its validity. It is known
that higher microfilaremia correlates with higher prevalence of adverse
events, particularly when exceeding 2,000 mf/mL, with meningoen-
cephalitis occurring at very high microfilaremia levels, exceeding
30,000 mf/mL.

Lastly, one author hypothesized that recombinant human erythro-
poietin (rEPO) could be a promising therapeutic approach in managing
loiasis encephalopathy, given similarities in pathophysiological pro-
cesses and lesions between cerebral malaria and loiasis encephalopathy.
In murine models of cerebral malaria, rEPO exhibited neuroprotective
effects by inhibiting pro-inflammatory cytokine synthesis and promot-
ing angiogenesis and expression of anti-apoptotic molecules (JAK2,
NFkB) [68]. However, human data on this treatment are currently un-
available [68].
<figure><img src="image_9.png" /><figcaption>Fig. 7. Diagnostic algorithm for imported loiasis.</figcaption></figure>

<figure><img src="image_10.png" /><figcaption>Fig. 8. Therapeutic algorithm for the management of imported loiasis.</figcaption></figure>

## 8. Conclusion

This comprehensive review has highlighted key advancements in the diagnosis and therapeutic management of imported loiasis, focusing on diagnostic techniques, updated therapeutic options, and strategies to mitigate the adverse effects associated with DEC and ivermectin treatment. The integration of molecular biology techniques is particularly promising, enabling more accurate detection of loiasis, especially in cases with negative microfilaremia, such as occult loiasis, and helping to correct diagnostic errors in identifying *Loa loa*. Additionally, serological tests utilizing QLIPS technology with the *Loa loa*-specific antigen LISXP1 offer a faster and more reliable alternative to traditional ELISA, with fewer cross-reactions. These tests are especially valuable as diagnostic tools in cases of negative microfilaremia, at least until molecular biology techniques are optimized for routine use. These advancements are critical for improving detection rates and reducing diagnostic ambiguity, ultimately supporting better patient outcomes.

Therapeutically, the review underscores the limitations of current treatment options, with high failure rates observed for DEC (24–70 %), ivermectin (8.8–100 %), and albendazole (50–100 %) [8–14,69,70]. These figures highlight the urgent need for more effective and reliable alternative therapies for loiasis. At the same time, the management of imported loiasis remains complicated by severe adverse effects associated with filaricides, particularly in patients with high microfilaremia. These reactions require close monitoring and may necessitate multiple treatment courses, underscoring the need to refine and improve existing treatment protocols to enhance both efficacy and safety.

Loiasis can no longer be considered a benign condition, given the serious complications highlighted in this review and the challenges associated with treatment. Managing imported loiasis involves a high risk of severe adverse effects, particularly in patients with high microfilaremia, which often manifest early in treatment. This further underscores the urgent need for a clear therapeutic protocol, including prophylactic corticosteroid therapy, which should be initiated within the first two days of ivermectin treatment or the first five days of DEC treatment to prevent severe adverse events. However, in some cases, corticosteroid therapy alone may not suffice to prevent sequelae and deaths associated with DEC or ivermectin use in hyperfilaremic loiasis. IL-5 inhibitors such as reslizumab may offer a promising alternative for managing severe adverse effects, though their efficacy must be tested in a larger cohort of patients with high microfilaremia so as to better reflect the real-world challenges of the disease.

Given the complexity of managing imported loiasis, a standardized diagnostic and therapeutic decision-making algorithm is essential. Such an algorithm would enable clinicians to tailor treatment based on the severity of the patient's condition, minimize severe adverse effects, and optimize treatment outcomes. Furthermore, it is crucial to monitor parasitemia 4–6 weeks after treatment, taking into consideration the pharmacokinetics and pharmacodynamics of each drug. If parasitemia persists or if the patient remains symptomatic, a second-line treatment may be necessary [54,60,61]. The proposed diagnostic and therapeutic strategy, as outlined in the decision-making algorithm, provides a structured approach that can significantly improve the management and outcomes of imported loiasis (Figs. 7 and 8).
Declaration of Generative AI and AI-assisted technologies in the
writing process

During the preparation of this work the author(s) used ChatGPT to correct and improve the English. After using this tool/service, the authors reviewed and edited the content as needed and take full responsibility for the content of the publication.

The life cycle of *Loa loa* and the diagrams were generated using Biorender and Lucidchart, respectively.

CRediT authorship contribution statement

C. Elouardi: Conceptualization, Resources, Writing – original draft, Writing – review & editing, Visualization. A. Lefort: Writing – original draft. L. Deconinck: Writing – original draft, Visualization. N. Peiffer-Smadja: Writing – original draft. S. Houzé: Writing – original draft. N. Argy: Conceptualization, Resources, Writing – original draft, Writing – review & editing, Visualization.

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Acknowledgments

We gratefully acknowledge the contributions of Dr Laurene Duconinck and Dr Eric d'Ortenzio, who provided photographs for this manuscript.

Appendix A. Supplementary material

Supplementary data to this article can be found online at https://doi.
org/10.1016/j.idnow.2025.105053.

Data availability

Data will be made available on request.

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