Treatment of loiasis: a review of clinical management recommendations

Abstract

Background

Loiasis affects more than 20 million residents of endemic regions in Central and West Africa causing chronic and often lifelong disease. Antifilarial treatment options for loiasis include diethylcarbamazine, ivermectin, and albendazole. Safe and effective management requires classifying patients into occult, microfilaremia, and hypermicrofilaremia categories. Treatment is complicated by the risk of severe adverse events, particularly encephalitis. Clear guidance on the appropriate use of antifilarial therapy is therefore of utmost importance. The aim of this review is to evaluate current treatment recommendations and assess their quality and consistency.

Methods

A scoping review was conducted to evaluate treatment recommendations for loiasis. The literature search encompassed multiple databases, including PubMed and specialized medical repositories, without restrictions on publication date or language. The approach included a systematic search with specific loiasis-related keywords and an unstructured search of guidelines from health ministries in endemic countries, along with grey literature and professional recommendations. Renowned tropical medicine textbooks were also consulted. Data were extracted with a detailed table collaboratively developed and reviewed by multiple researchers to ensure consistency and accuracy.

Results

The review identified 33 sources, consisting of nine guidelines, ten reviews, and 14 textbook excerpts. Publications reviewed spanned from 2001 to 2024 with no major innovations in treatment noted. Evidence quality was often low, with only two guidelines detailing their development process. Variability was particularly noted in dosage protocols for diethylcarbamazine, typically dosed incrementally. Ivermectin and albendazole were mostly noted as alternatives based on microfilarial levels. The common microfilarial threshold was 8000 microfilariae per millilitre, dictating treatment strategy adjustments. Adjunctive treatments, such as corticosteroids and antihistamines, were inconsistently proposed to mitigate side effects.

Conclusions

Inconsistencies between some recommendations were observed. There is an urgent need for internationally harmonized, evidence-based guidelines to address these inconsistencies, improve patient outcomes and minimize treatment-associated severe adverse events and fatalities.

Graphical Abstract

Background

Loa loa affects more than 20 million people in the endemic regions of sub-Saharan Africa. It is transmitted by blood-sucking Chrysops flies and leads to chronic infections characterized by Calabar swelling, migration of the adult worm through the conjunctiva of the eye, pruritus, and occasionally complications in multiple organ systems, including cardiac, respiratory, neurological, ophthalmic, renal, gastrointestinal, and dermatological manifestations. Diagnostic challenges persist, with diagnosis in endemic settings often relying only on thick smear microscopy. However, only about one third of infected individuals show detectable microfilaremia. The three drugs mainly recommended for loiasis treatment are diethylcarbamazine, ivermectin, and albendazole [1].

Classifying patients into the categories of occult, microfilaremic, and hypermicrofilaremic infection is essential for appropriate loiasis treatment decisions [2] to avoid the risk for treatment-associated severe neurological adverse events (AEs) or fatalities which is linked to microfilarial load. Occult infection is marked by indirect signs and symptoms of loiasis, such as eye worm migration and Calabar swelling due to adult worm movements, occurring without detectable microfilaremia [1]. Hypermicrofilaremia is particularly concerning due to its predisposition to severe side effects from rapidly acting drugs such as diethylcarbamazine and ivermectin, with encephalitis being the most severe AE. [3] This underscores the necessity for unambiguous therapeutic protocols that prevent incorrect allocation of therapeutic regimens.

Clear and harmonized guidelines are needed to minimize severe adverse events and deaths associated with therapy, especially given the complexity of treatment algorithms. These complexities include the influence of microfilarial levels, the contraindication of diethylcarbamazine in individuals coinfected with onchocerciasis [4], and the potential complications, such as encephalitis, in hypermicrofilaremic patients. Establishing such guidelines would help minimize therapy-associated severe AEs and deaths and to reduce the considerable burden caused by loiasis [5].

While more clinical trials are needed to establish evidence-based treatment regimens, harmonized guidelines are already an essential tool for clinicians to effectively treat their patients. This approach could reduce the use of drug regimens that lack a strong evidence base. Therefore, not only are more clinical trials needed, but their results should also be integrated into clinical practice through updated guidelines.

This review aims to compile national and international guidelines, as well as recommendations by scientific institutions and associations, to assess the available loiasis treatment guidelines for their recommendations, consistency and quality of evidence. This review therefore focusses on individual treatment protocols and not on potential recommendations for mass drug administration programs to reduce transmission on a population level.

Methods

Search strategy, inclusion and exclusion criteria

First, a systematic literature search was performed, followed by an unstructured literature search. Only guidelines, manuals, reviews and textbook excerpts were eligible for this review. The systematic literature search was performed on PubMed via the search term ‘("loa loa" OR loiasis OR loaose OR Loíase) AND (guideline OR recommendation)’ and not restricted by publication date or language. Then, a search with the search term ‘Loa OR "loa loa" OR loiasis OR loaose OR Loíase’ was performed on Trip Medical Database, Guideline Central, Guidelines International Network, JAMA Evidence, and the Harvard Medical School Library of Evidence.

In the following, unstructured literature search, we used different approaches. For endemic countries, a search for loiasis treatment guidelines was conducted on the websites of health ministries. Additional sources that discuss treatment recommendations were identified via Google search, personal literature collections and professional connections. This was supposed to yield scientific publications not found via the systematic search, as well as grey literature. Lastly, renowned textbooks in the field of Tropical Medicine from the libraries of the Bernhard Nocht Institute for Tropical Medicine and the Central Medical Library of Hamburg were screened for specific treatment recommendations. During this search stage, eligible languages were English, German and French due to the authors’ language skills.

Quality assessment of included literature

The quality of the included literature was assessed by reviewing the presence of evidence grading systems and detailed methodologies within the sources.

Evidence extraction and analysis

A table was collaboratively developed by two reviewers to capture information during the literature search. Initially, one reviewer conducted the literature search, and it was later updated and refined by another to enhance accuracy. The process was supervised by a third author, with guidance provided on where and how to search for additional sources. This iterative approach ensured the data collection template effectively captured all relevant variables.

Gap analysis

The gap analysis involved identifying inconsistencies and omissions across different guidelines, focusing on the lack of standard methodologies and consistent microfilarial thresholds, to pinpoint areas requiring further research and development.

Results

The search performed yielded 33 sources: nine guidelines, ten reviews, and 14 textbook excerpts (Fig. 1, Table 1). Among the searched guideline repositories, only the Association of the Scientific Medical Societies in Germany offers specific guidelines on loiasis therapy. Country-level guidelines were identified from Gabon, Germany and the United Kingdom [6,7,8]. Several guidelines from the United States of America are aimed at practitioners worldwide [9,10,11,12].

Fig. 1

Flow of literature search

Table 1 Recommendations for the treatment of loiasis

The recommendations date from 2001 to 2024, with no major changes or new treatment options observed. All publications that did not specify whether they applied to endemic populations or to travellers and migrants were considered applying to both. Of the 33 sources examined, five offered recommendations specifically for treatment in endemic areas, while seven focused solely on returning travellers and migrants. 21 sources provided guidance applicable to both populations. Among the medical guidelines, two addressed only endemic populations, and three focused exclusively on returning travellers and migrants, whereas four covered both groups. In terms of reviews, one was implicitly dedicated to treatment in endemic regions [13], three concentrated on the treatment of returning travellers and migrants, and six addressed both demographics. When considering textbook excerpts, two were specific to endemic regions, one was dedicated to travellers and migrants, and eleven covered both populations. While all selected sources provided recommendations for treating L. loa infection, eleven also offered guidelines on prophylactic therapy, and six made recommendations for managing cases of eye migration. Additionally, one source suggested a treatment regimen suitable for mass drug administration [6]. Four sources considered treatment restrictions for pregnant women or children [9, 12, 14, 15].

Methodology and quality of publications

The evidence-base, quality, and certainty of the recommendations were low and none except two specified the underlying methodology for the guideline development [7, 8]. Most guidelines lacked evidence grading systems for their recommendations. The recommendations were often very concise, omitting microfilaremia thresholds or drug dosage [16]. Only one of the reviews was a systematic review, which focused rather on symptoms than treatment of loiasis [17]. There is no meta-analysis available which systematically analyses treatment for loiasis.

Curative treatment recommendations

The identified treatment recommendations showed both similarities and contrasts, particularly in dosage recommendations for diethylcarbamazine, commonly used as a primary treatment across different regions. Most sources recommend initiation of treatment with diethylcarbamazine at a low dose and gradually increasing it, to manage patients effectively and avoid adverse reactions [18, 19]. Typically, diethylcarbamazine full-dose regimens for adults with detected microfilaremia range from 300–400 mg daily [18, 20] to 8–10mg/kg daily [8, 21, 22] over 12 [23] up to 28 days [14, 20], often with repetition of treatment cycles advised if necessary. The starting dose ranges from 3–6 mg daily [10, 24] to 1 mg/kg daily [9, 25,26,27,28]. For hypermicrofilaremic patients, the recommended initial dose can be as low as 0.5 mg/kg [22].

In occult loiasis, maintenance doses of diethylcarbamazine range from 400 mg daily [10, 19, 24, 29] to 8–10 mg/kg daily [8, 22] for the same duration as microfilaremic infection. Not all recommendations mention incremental increase of dosing for occult cases, but those who do, recommend initial doses of 50 mg [8, 10, 19, 24, 29] to 6 mg/kg daily [26]. While most sources recommend repetition of the whole treatment cycle in case of persistent infection, another suggestion is treatment for 10 days per month for three to six months, if needed [19]. However, the difficulties in procurement of diethylcarbamazine are also acknowledged [13].

Alternative treatment recommendations: Ivermectin and albendazole

Ivermectin is another frequently recommended treatment, particularly for patients with a microfilarial load below specific thresholds, highlighting its effectiveness in quickly reducing microfilarial counts [10, 12]. Ivermectin dosing is recommended as alternative treatment when diethylcarbamazine cannot be used, with guidelines recommending a dose of 150 µg/kg [10, 14, 21, 24, 29] to 200 µg/kg [6, 13, 30], most-often as a single-dose [1, 7, 10, 13, 14, 20, 21, 24, 26] but up to a period of ten days in daily doses [6]. Repetitive administrations of ivermectin are considered in some guidelines in monthly [10, 14, 24, 29], quarterly [10, 14, 24, 29] or biannual [13] intervals. Differences arise in frequency and context, such as the Gabonese Health Ministry's recommendation of 200 μg/kg daily for ten days in an endemic setting [6].

Albendazole dosing is commonly prescribed from 400 mg daily [8,9,10,11,12, 14, 15, 18, 20, 21, 24,25,26, 28, 29] to 800 mg daily [1, 2, 6, 7, 31] for 10 days [6] up to 28 days [1, 7, 15, 31], especially for higher microfilarial loads or when diethylcarbamazine treatment is not feasible [10, 12, 29]. Dosing can be as low as 200 mg three times weekly [25] for low microfilaremia. 800 mg dosing is recommended in case of failure to clear infection by diethylcarbamazine regimens [15]. Rarely, mebendazole is given as an albendazole alternative [17, 26, 31].

Microfilarial thresholds

Microfilarial thresholds show notable similarities across guidelines, with 8000 microfilariae per millilitre (mf/ml) commonly acknowledged as a critical point for altering treatment strategies. This threshold often prompts more cautious interventions, such as the use of albendazole or apheresis instead of diethylcarbamazine. The threshold recommended for diethylcarbamazine treatment is typically below 1000 mf/ml [8, 15, 18, 20, 25, 26, 28], with some guidelines allowing up to 2000 mf/ml [1, 7, 10, 14, 24, 29]. However, a considerable number of publications set the safe threshold for diethylcarbamazine at 8000 mf/ml [2, 11, 12, 21, 30, 32], with a few sources recommending diethylcarbamazine usage at microfilaremia up to 30,000 mf/ml [22, 33, 34].

For ivermectin therapy, there is more consensus on maintaining the microfilarial threshold below 8000 mf/ml [1, 7, 12, 14, 17, 18, 20, 24,25,26, 28, 29], although some guidelines still suggest it is safe at levels up to 30,000 mf/ml [10, 19, 29, 33] or only mention elevated risk for Mazzotti reaction above 50,000 mf/ml [13]. The least consensus is seen regarding the microfilarial threshold for albendazole treatment. While there is mostly no upper limit of microfilaremia mentioned, the indication for use of albendazole is varies from > 1000 mf/ml [8, 15] to > 30,000 mf/ml [10, 14, 29], with most recommendations suggesting a threshold of > 8000 mf/ml [6, 11, 12, 17, 18, 20, 21, 25, 26].

Similarly, apheresis is proposed as adjunct treatment strategy for high microfilarial loads of > 8000 mf/ml [11, 12, 25, 26, 30, 32], and at times already at > 2500 mf/ml [9, 35] or for hypermicrofilaremia at > 30,000 mf/ml [1, 7, 22]. Higher thresholds typically signal the necessity for multiple strategies, including inpatient management, to mitigate the risk of severe complications like encephalopathy by close observation of the patient [14, 24, 26, 36].

Adjunct therapies

Adjunct therapies exhibit notable similarities, with antihistamines and corticosteroids being the most frequently recommended to manage adverse drug effects and improve patient tolerance to treatment regimens with diethylcarbamazine and ivermectin [7, 9, 12]. However, specific recommendations can vary in dosage [6, 19, 21]. While 16 sources made no statement on adjunct therapy and 16 sources suggest possible use of antihistamines and/or corticosteroids, Médecins Sans Frontières Practical Guidelines suggest using paracetamol in case of pain during the initial phase of hypermicrofilaremic treatment and one review mentions reslizumab (anti-interleukin 5) to questionably reduce diethylcarbamazine-induced AEs [14, 21]. While six guidelines propose possible surgical removal for eye migration and 23 make no statement on this matter, Médecins Sans Frontières Practical Guidelines considers this gratuitous, emphasizing non-surgical management approaches. [14, 23],

Prophylaxis and mass drug administration

Thirteen of the recommendations suggest the possibility of chemoprophylaxis with diethylcarbamazine in selected high risk travellers, mostly at 300 mg weekly [7, 9, 10, 18, 22,23,24, 27, 30, 35] to 400 mg on three consecutive days monthly [10, 24], to prevent loiasis, demonstrating a consistent strategy across regions [12, 22]. While four sources suggest alternative dosing, 20 sources do not discuss prophylaxis [19]. Mass drug administration for controlling loiasis in endemic areas is mentioned in the Gabonese guideline, using albendazole and ivermectin to reduce community transmission [6].

Limitations of the review

The scarcity of guidelines from endemic countries may be attributable to publication bias, whereby health authorities disseminate treatment guidelines through alternative means, such as professional bodies or direct communication, rather than through online publication. This issue could be resolved through direct communication with the relevant authorities. Moreover, the reviewers’ language restriction may have resulted in the omission of sources in Spanish, Portuguese, Arabic, or other languages from endemic countries. This review employed a structured methodology to identify sources that summarise loiasis therapy. A more focused, ideally systematic, review with minimal language restrictions would be beneficial in reliably determining treatment strategies for individual parts of the therapy algorithm, such as through separate reviews of drugs, microfilaremia thresholds, or specific populations.

Conclusions

The review of clinical management recommendations for loiasis revealed significant variability and inconsistencies across available guidelines, underscoring the challenges faced in achieving effective treatment amidst risks of severe adverse events. Harmonization of guidelines is crucial for improving patient outcomes and establishing safe, evidence-based treatment protocols tailored to diverse healthcare settings.

This review is drawing from a diverse array of sources, including clinical guidelines, reviews, and textbooks. The majority of antiparasitic regimens, including diethylcarbamazine, ivermectin, and albendazole, are recommended as the primary treatment option. Mebendazole is occasionally suggested as an alternative. The higher the microfilarial load, the more likely diethylcarbamazine is to be deferred in favour of ivermectin, then albendazole, and then apheresis. Prophylactic strategies and adjunct therapies, such as corticosteroids and antihistamines, are also frequently proposed, underscoring the necessity of addressing treatment-associated adverse events, particularly in patients with elevated microfilarial loads. It is notable that recommendations vary significantly in detail, dosage, and the microfilarial density categories used to guide treatment selection. This variation encompasses national guidelines from Gabon, the UK and Germany, as well as institutions like the U.S. Centers for Disease Control and Prevention and Médecins Sans Frontières. While there is some consensus globally concerning drugs of choice and need of consideration of microfilarial load, considerable variation in treatment approaches persists. It is notable that the methodological approaches used to formulate these recommendations are often unspecified, which limits the current guidelines' applicability and adaptability. This highlights the need for developing evidence-based guidelines using rigorous methodologies to ensure unbiased recommendations.

Interpretation of differences

The discrepancies in treatment recommendations for L. loa infection might be attributed to a number of factors, including diverse clinical experiences across regions, access to local resources, and differing perspectives from endemic versus non-endemic areas. It is notable that there is considerable variation in the recommended dosage of diethylcarbamazine across different guidelines. This highlights the need for the establishment of universal standards based on robust clinical trials. The methodologies employed for the management of patients with disparate microfilarial loads are inconsistent. Some guidelines recommend adjustments in treatment regimens based on specific microfilarial thresholds, while others lack such criteria. There is considerable variation in the exact thresholds, suggesting uncertainty of when risks are to be expected. Furthermore, the use of adjunct therapies such as antihistamines and corticosteroids is inconsistently addressed. There is also a lack of consensus regarding the prophylactic therapy and management of associated symptoms, such as eye worm migration. Some guidelines advocate for cautious, incremental increases in drug dosage, whereas others provide no such strategies, resulting in inconsistent practices. When discussing diethylcarbamazine, it is crucial to note that diethylcarbamazine is often recommended for use under inpatient conditions in non-endemic settings [7]. However, this may not be feasible in areas with limited healthcare infrastructure, necessitating alternative strategies to ensure safe and effective treatment. The same applies to the availability of apheresis [37]. Finally, as underlying studies for the respective treatment recommendations were mostly not provided in the guidelines, no formal comparison was feasible whether the interpretation of study results was the cause for the differing recommendations.

Developing robust and adaptive guidelines

In light of the considerable variation in treatment recommendations for L. loa infection, there is a pressing need for the development of uniform, evidence-based guidelines that can adapt to diverse health contexts. It is imperative that these guidelines are developed with clear methodologies, including a robust assessment of the risk of bias in the underlying studies and explicit evidence grading. It is essential to define appropriate endpoints and criteria in order to determine the most appropriate course of treatment. This should take into account factors such as microfilaremia, as well as the distinction between endemic and non-endemic areas or high and low resource settings.

There is currently a lack of an agreed-upon definition of cure of loiasis, which complicates the assessment of treatment outcome. As a prerequisite for harmonized treatment guidelines, cure of loiasis as an endpoint of clinical trials should be better defined. Some potential definitions include clinical cure, characterized by the disappearance of symptoms and signs, and parasitological cure, defined as the absence of microfilaremia in the blood. Other indirect indicators, such as the resolution of eosinophilia, decreasing antifilarial antibody titres and the sustained absence of symptoms, may also be used. However, these definitions have significant limitations. Clinical symptoms can be non-specific or absent, and eosinophilia is not observed in all patients. Parasitological cure can be misleading, as macrofilariae might persist despite cleared microfilariae and as accurate detection of microfilariae is not readily available in all endemic settings. Additionally, achieving these endpoints may require multiple treatment courses, complicating the assessment timeline [12, 38,39,40]. Establishing a clear and clinically relevant definition for cure would aid in standardizing outcomes in research as well as in clinical practice, thereby accelerating the development of more effective treatments and facilitating concise treatment recommendation.

It is imperative that representatives from both endemic and non-endemic areas participate in a global collaboration to harmonise the guidelines. The consideration of resources available in different regions should inform the development of appropriate and locally feasible approaches. The capacity to update guidelines in a dynamic manner through technical solutions such as MAGICapp can facilitate the creation of globally applicable recommendations [41]. It is also imperative that emerging treatments are integrated into these guidelines to ensure their continued relevance.

Although this review is not primarily focused on mass drug administration (MDA) strategies, some of our sources did address this topic. Established MDA campaigns exist for lymphatic filariasis and onchocerciasis, but similar programs for loiasis are not yet in place. Integrating loiasis MDA into broader health initiatives could significantly enhance the overall effectiveness of these programs.

It is also essential to proactively manage policies addressing potential drug unavailability, in the context of loiasis especially regarding diethylcarbamazine. Furthermore, ensuring that healthcare providers are adequately educated and trained in these treatment pathways will further improve patient outcomes. Guidelines should support practitioners in ensuring patient safety and assist in managing severe AEs.

The findings underscore the need to draw up harmonised international guidelines for the effective management of loiasis. By standardising treatment pathways and addressing the complex therapeutic needs of patients, particularly in endemic regions, the risk of severe AEs and fatalities associated with current treatments can be mitigated. Future endeavours should prioritise the development and implementation of evidence-based recommendations that are universally adaptable, thereby ensuring safer and more effective management of this challenging condition.