General considerations about the treatment of loiasisIndication for specific antifilarial treatment of loiasis

The indication for treating loiasis has not yet been sufficiently investigated based on objective evidence [2]. On one hand, a considerable somatic and psychological burden of disease is usually described in newly infected travellers, which may pathophysiologically be explained by a hyperresponsive immune response [37]. This, again, usually leads to a decision to treat. On the other hand, it is currently unclear whether and under which circumstances patients residing in highly endemic regions should receive antifilarial treatment. The decision to treat or not to treat a patients residing in an endemic region for loiasis should be based on the individual morbidity, the risk for serious complications, the risk of antifilarial treatment, and the probability of reinfection [2]. The availability of specific drugs, the at times long and complex treatment regimes, and locally available means to diagnose and manage treatment-associated complications are further factors that play an important role in the treatment decision [2].

Finally, specific contraindications of respective drugs must be considered. In addition to a high microfilarial load, the presence of onchocerciasis is a major contraindication for using DEC, as this may lead to Mazzotti reaction and irreversible vision loss [73, 74]. These reactions are caused by the rapid killing of Onchocerca volvulus microfilariae and consecutive hyper-inflammation. Prior to initiation of DEC therapy, onchocerciasis has therefore to be excluded in patients residing in regions where onchocerciasis is co-endemic or where its endemicity may be unclear. The use of albendazole is relatively contraindicated in the presence of active ocular or cerebral cysticercosis and should only be used with concomitant corticosteroid therapy to avoid complications of cysticercosis [75].

Considerations about treatment objectives and assessment of treatment outcome

The main goals of treatment for loiasis can be either individual cure of infection, resolution of clinical symptoms, or prevention of transmission, mostly in population-based control programs [2]. However, the assessment of treatment outcome may be challenging.

Clearance of peripheral microfilaraemia may be observed following treatment of microfilaraemic loiasis patients. However, the absence of microfilaraemia in itself does not confirm a cure of the infection as it does not prove the clearance of the adult worms. The complete clearance of adult worms may only be deduced from the evolution of indirect parameters, as the presence of adult L. loa worms cannot be assessed directly. Indirect parameters include the continued disappearance of peripheral microfilaraemia, resolution of clinical symptoms, normalisation of pre-existing eosinophilia and IgE levels, and at times a slow, often gradual reduction of filaria-specific antibodies over several years of follow-up. While these indirect markers are relatively specific in returning travellers, this is usually not the case in endemic regions due to multiple and repeated exposures to loiasis and other parasitic infections.

In-hospital versus outpatient treatment of loiasis

Due to the occurrence of serious adverse events in the treatment of loiasis, it is of high clinical importance to consider the setting of patient management. Hospitalisation of patients ensures rapid diagnosis and treatment of adverse drug reactions and allows early discontinuation or modification of treatment if necessary. While no general recommendation for or against in-patient or out-patient management can be provided, several considerations may be taken into account to decide on an appropriate setting and at times at least temporal hospitalisation at the initiation of therapy (Table 2).

Table 2 Considerations on inpatient versus outpatient management of loiasisAntifilarial drugs for the treatment of loiasis

In general, it must be noted that the antifilarial treatment of loiasis is always associated with a certain risk. Depending on the medication used, the microfilarial load, and the individual predisposition and comorbidities of the patient, several adverse events may occur which may range from acute anaphylactoid reactions, pruritus, allergic phenomena, to acute encephalitis, coma, and death. The indication for antifilarial therapy and the choice of treatment regimen must therefore be carefully reflected.

Historically, DEC is the only drug that has been developed specifically for the treatment of human filariasis [73]. It is the only drug with a proven macrofilaricidal effect therefore capable of inducing complete cure from infection with L. loa. Besides DEC, ivermectin and albendazole are commonly used antifilarial drugs in the treatment of loiasis (Tables 3 and 4).

Table 3 Activity of anthelmintic drugs against different life-cycle stages of L. loaDEC

DEC is an anthelmintic drug of the piperazine class. DEC has been the first-line treatment for loiasis for almost a century. Due to its rapid microfilaricidal effect, it may however lead to serious adverse events when treating loiasis. DEC is authorized in several countries but it is not marketed in Germany.

Indication

Treatment of occult and microfilaraemic loiasis. In the case of microfilaraemia > 2,000 mf/mL, DEC should not be used for treatment initiation. In this case the microfilarial load should first be reduced by other means (see below), to minimize the risk for the occurrence of serious to life-threatening complications.

Activity

Very rapid and potent activity against microfilariae. Substantial activity against adult worms. Cure rates when administered over a 4-week period are between 60 and 70%. Several cycles of DEC treatment may be necessary to achieve complete cure.

Side effects

Mazzotti reaction, which is particularly common in patients with onchocerciasis or disseminated Strongyloides infection, characterized by acute onset of itching, fever, headache, nausea, dizziness, fatigue, shortness of breath, cough, tachycardia, and proteinuria.

Contraindications

DEC may be associated with acute anaphylactic reactions in patients with high L. loa microfilariae load. Therefore, treatment with DEC requires close monitoring of patients. As the risk of allergic and encephalopathic side effects correlates in general with the microfilarial load, its use is relatively contraindicated in patients with microfilaraemia of more than 2,000 mf/ml. DEC is furthermore contraindicated in patients with active onchocerciasis. Furthermore, relative contraindications are the treatment of elderly patients, young children, patients with cardiac or renal disease, and chronic pathological, medicinal and dietary urine alkalisation. Caution should also be used when treating patients with a history of convulsions or epilepsy.

Pregnancy and lactation

relative contraindication. It is not known whether DEC passes into breast milk; breastfeeding is not recommended.

Ivermectin

Ivermectin is a macrolytic lactone that is used successfully and extensively as an antifilarial drug to control onchocerciasis and lymphatic filariasis. Due to its single-dose administration, it is used on a large scale in population-based control programs for onchocerciasis and lymphatic filariasis [68]. It interacts with glutamate-gated chloride channels of the parasite’s nerve and muscle cells. Due to its rapid and potent activity against L. loa microfilariae, ivermectin, similar to DEC, may lead to acute anaphylactic reactions and the occurrence of ivermectin-associated encephalitis.

Indication

Ivermectin is used for microfilaraemic loiasis with microfilaraemia between 2,000 mf/mL and 8,000 mf/mL. Risk for serious adverse events including encephalitis is strongly associated with microfilarial load. Therefore microfilaraemia > 8,000 mf/mL constitutes a relative contraindication. Treatment regimens combining ivermectin with albendazole (for microfilarial load < 8,000 mf/mL) may be considered.

Activity

Single dose ivermectin dramatically reduces the microfilarial load of L. loa by around 90%. So far, no convincing evidence of clinically relevant activity against adult worms has been demonstrated. Thus, the use of ivermectin is in itself not a curative regimen for loiasis. Ivermectin may be considered to reduce microfilaraemia from up to 8,000 mf/mL to enable subsequent curative therapy with DEC. Given the unclear benefit in alleviating clinical symptoms, which are mainly caused by the adult developmental stages of L. loa, the individual benefit of using ivermectin in treating loiasis is limited. A combination regimen of albendazole with ivermectin has shown promising efficacy at a single European centre [30, 81]. However, these findings were not confirmed in in a clinical trial in a highly endemic region [68]. Hence, to date the contribution of ivermectin to treatment success remains unclear.

Side effects

Risk of significant neurological complications in patients with high microfilarial load including potentially life-threatening encephalopathy that may initially present as altered mood, confusion, stupor, lethargy, headache, retinal and conjunctival haemorrhages, urinary incontinence or fever. Other side effects of ivermectin include pruritus, myalgia, urticarial exanthema, nausea, vomiting, diarrhoea, constipation, abdominal pain, dizziness, vertigo and rare cases of hepatitis.

Contraindications

Relative contraindication for use of ivermectin in patients with microfilarial load of more than 8,000 mf/mL due to the risk of treatment associated encephalitis. Ivermectin is not registered for use in children < 2 years of age or < 15 kg body weight.

Pregnancy and lactation

Use of ivermectin may only be considered after cautious risk-benefit analysis as animal experiments indicate reproductive toxicity. Breastfeeding should be suspended during the use of ivermectin, as high drug concentrations may be present in breast milk.

Albendazole

Albendazole is a broad-spectrum benzimidazole anthelmintic drug acting on parasite microtubules. Albendazole has a delayed, probably mainly indirect effect on microfilarial counts by reduction of fertility (reduction of microfilaraemia starts after about 2 weeks of treatment) and also appears to be effective against adult stages of L. loa in treatment regimens lasting several weeks [82]. To date, only a few hundred patients that underwent treatment for loiasis with prolonged albendazole regimens have been reported. Therefore no definitive conclusion can be drawn about the overall safety and efficacy of albendazole in treating loiasis [83].

Indication

Albendazole may be considered for use to reduce the microfilarial load due to its slow and gradual activity on microfilaraemia. However, single case reports of benzimidazole-associated encephalitis following loiasis therapy highlight the uncertainties of its safety in the treatment of loiasis. Albendazole shall be taken with food as fat uptake increases considerably its bioavailability.

Activity

Prolonged treatment courses with albendazole lead to a consistent, gradual reduction of the microfilarial load. Longer treatment regimens may lead to an adulticidal effect. The required duration of treatment is at least 3–4 weeks.

Side effects

Fever (1/10), leukopenia (1/100), anaemia (1/1000), pancytopenia (1/10,000), agranulocytosis, pruritus, urticaria, headache, dizziness (resulting in potentially impaired ability to drive), abdominal pain, diarrhoea, nausea, vomiting, increase in liver enzymes, reversible alopecia, Steven-Johnson syndrome (1/10,000). According to the approved summary of the product characteristics leaflet, liver function tests and blood counts should be performed prior to initiation and regularly during treatment.

Contraindications

known hypersensitivity to benzimidazole, children < 6 years of age, evidence or suspicion of active ocular or cerebral cysticercosis (history of seizures).

Pregnancy and lactation

Only when strongly indicated, animal model results indicate reproductive toxicity. Albendazole should not be used in breastfeeding women.

Doxycycline and other drugs without proven evidence in the treatment of loiasis

Doxycycline kills adult worms in the treatment of other human filariasis such as onchocerciasis. Its mechanism of action is based on the elimination of obligate Wolbachia spp. endosymbionts, resulting in slow sterilisation and subsequent death of the adult worms. As L. loa does not harbour Wolbachia endosymbionts, doxycycline does not affect L. loa infections and can therefore not be used to treat loiasis [84, 85].

Imatinib, a tyrosine kinase inhibitor developed for the treatment of chronic myeloid leukaemia, was found to be active against L. loa.[86] Although a reduction in microfilarial burden has been demonstrated in a clinical trial, its overall effect is insufficient from a clinical perspective. Imatinib therefore plays no role in the treatment of loiasis [87].

Moxidectin, a macrocyclic lactone closely related to ivermectin, is currently undergoing phase II clinical trials to evaluate its safety and efficacy in the treatment of loiasis [88]. However, to date efficacy and safety are not yet sufficiently established for the treatment of loiasis.

Specific patient populationsChildren

From an epidemiological perspective, children are usually less affected by L. loa infections than adults, both in endemic regions and among travellers [6, 36]. To date there are no reports on specific clinical or therapeutic characteristics of paediatric loiasis. Treatment, therefore, follows the same principles as for adults. Age- and weight-related contraindications for respective drugs must be considered.

Pregnancy and lactation

Loiasis commonly affects pregnant women as the infection lasts for many years, often lifelong in high-transmission regions. Microfilariae may be detectable in the placenta or the umbilical cord’s blood but do not appear to cause inflammation, placental insufficiency or other clinically important pathologies [59]. To date there is no clear evidence for adverse birth outcomes due to loiasis. Vertical or peri-partal transmission of L. loa from the mother to the child has not been reported. Given the often-uncertain risks of anthelmintic therapy during pregnancy, treatment should in general be postponed until after delivery and possibly after breastfeeding. In case of substantial clinical or psychological burden due to loiasis in an individual pregnant patient, benefits and risks of treatment have to be discussed with the patient in light of the lack of systematic evidence.

Elderly patients and patients with co-morbidities

The risk of clinically important adverse drug reactions of DEC may be increased in patients with pre-existing cardiac and renal morbidity. Prolongation of DEC’s half-life has been reported in patients with renal insufficiency or in conditions with chronic urine alkalisation. A dose reduction is therefore recommended in patients with renal insufficiency. Caution is also advised in patients with a history of seizures, as seizure threshold may be lowered.

Albendazole should be used with caution and monitored closely in patients with pre-existing hepatic impairment and in elderly patients.

Non-medical treatment options for loiasisSurgical removal of adult worms

Surgical removal can be performed during the migration of the adult worm through the eye or the superficial cutis [89]. These migrating worms can be removed by incision and extraction under sterile conditions to avoid secondary bacterial infection. Extraction has to be performed within a short period of time to avoid the disappearance of the worm in the adjacent soft tissue. Extraction may at times be curative in travellers with single worm infections. However, patients in high transmission regions are usually infected with multiple adult worms, so that extraction of a single adult worm is not curative and therefore constitutes not a therapeutic priority.

Apheresis

For several decades apheresis has been described as a safe method to gradually and safely reduce high levels of circulating microfilariae from peripheral blood [90]. Mechanical reduction of the microfilarial load, which usually requires several cycles, is not curative as it does not clear the adult worms. However, it may constitute a safe option for substantial reduction of microfilarial load prior to initiation of a drug-based curative treatment approach.

Drug regimens to treat loiasis

The appropriate choice of a specific treatment regimen depends on several factors and should be made by a specialist experienced in tropical medicine. In addition to the drugs’ local availability and the patient’s specific contraindications, the microfilarial load is of decisive importance when choosing a treatment regimen. It needs to be emphasised here again that the microfilarial load should be measured on several days during the midday hours (10 a.m. − 4 p.m.) to obtain reliable microfilaraemia estimates, as there is a strong periodicity of microfilaraemia over the 24 h of the day (see Table 4).

Table 4 Antifilarial treatment of loiasis

The following treatment regimens are recommended, depending on the microfilarial load and taking into account individual contraindications:

Adjunct treatments for loiasis

Antihistamines and corticosteroids may be used during treatment initiation to reduce the severity of adverse events. However, these adjunctive treatments are considered not to alter the overall risk or seriousness of potentially life-threatening serious adverse events, including encephalopathy [10].

The monoclonal anti-IL-5 antibody reslizumab was evaluated in a clinical trial for its potential to reduce eosinophilia [91]. While a significant reduction in absolute eosinophil count without a delay of reduction of microfilarial load was observed, a clinically relevant benefit from this treatment has not been concluded. Thus, reslizumab therapy is not currently recommended for the treatment of loiasis.

Treatment of clinical signs, symptoms, and complications of loiasis

The clinical manifestations of loiasis cause a significant subjective disease burden for affected patients [6]. Symptoms often persist for decades or even life-long in patients residing in high transmission regions due to the longevity of the adult worm and frequent re-infections. Clinical symptoms are often even more pronounced in returning travellers [37]. The only causal treatment of these symptoms constitutes antifilarial treatment to kill the adult worm. To date, there are no evidence-based treatment recommendations for many of the clinical symptoms of loiasis. However, considerations on the appropriate reduction or relief of clinical symptoms and the management of potentially life-threatening complications are of medical importance and shall be addressed here (see Table 5).

Table 5 Treatment of clinical signs, symptoms, and complications of loiasisFollow-up of loiasis

Since loiasis is a chronic infection, prolonged follow-up of patients is necessary to assess potential complications and to monitor treatment outcomes after curative therapy.

Treatment evaluation

The overall reduction in microfilarial load is a simple parameter for assessing the microfilaricidal effect of anthelmintic treatment regimens. Depending on the respective drug, the maximum effect on microfilarial load may be expected within the first 4 weeks. If microfilaraemia persists over several months after treatment, it is therefore likely that the treatment has failed to clear active infection.

It is not possible to ascertain treatment success against adult worms in human infections, as there is currently no means to detect the adult stages of L. loa directly. The death of adult worms is likely to take several days to weeks after treatment initiation. Similarly, it may take several months until the dead adult worm has been cleared from the tissue. Successful treatment is usually accompanied by a transient increase in eosinophilia and IgE levels over the first few weeks, followed by subsequent normalisation of these two laboratory parameters. Without further clinical symptoms and normalisation of eosinophil count and IgE levels, complete cure from active L. loa infection can be assumed. Follow-up examinations at intervals of several months up to at least one year after the start of therapy are recommended to reliably evaluate the therapeutic success over time [30, 33, 83].

Specific filarial serology, which is of diagnostic importance in the initial diagnosis of travellers, plays only a minor role in follow-up. After successful treatment, filaria-specific antibody titres usually reduce only gradually over long periods of time, often over several years. At the same time, anti-filarial titres may persist without suggesting treatment failure. Therefore, the follow-up of filarial serology is not routinely recommended and, if at all, may only provide indirect evidence for cure or treatment failure.

It is not uncommon that the first treatment cycle may not lead to complete cure [79, 80]. It is estimated, that cure rates of the standard 3-week DEC regimen ranges between 60 and 70%. Repetitive treatment cycles of DEC are at times necessary to fully cure patients of L. loa infection [79]. Even in the absence of specific drug resistance of L. loa to DEC, an alternative regimen (e.g. prolonged albendazole or albendazole-ivermectin combination therapy; see Table 4) may be considered in case of persistence of infection several months after treatment [80]. Patients should be informed of the not uncommon necessity for multiple cycles prior to treatment initiation. In case of presence of complications of loiasis, further follow-up is required even after successful curative treatment.

Follow-up of patients without curative treatment for loiasis

In case that loiasis is not treated curatively (either on purpose withholding therapy or in case of unsuccessful therapy), particular attention should be paid to the possible long-term consequences of hypereosinophilia. 6-12-monthly follow-up examinations including echocardiography and, if necessary, other imaging techniques are indicated to appropriately detect and treat chronic long-term consequences of hypereosinophilia at an early stage.

Prevention and prophylaxis of loiasis

L. loa is an only occasionally imported travel-related infectious disease. This fact is due to multiple reasons: The rural transmission cycle of loiasis does not coincide with typical tourist destinations; transmission occurs only during the day in forest and savannah regions of endemic countries and transmission does not appear to be very efficient, so that in most cases only prolonged exposure is associated with infection. At the same time, patients who have already had a L. loa infection are often at a disproportionate risk of acquiring another new infection, as these individuals frequently travel to the high transmission regions due to family (visiting friends and relatives) or professional reasons (missionaries, researchers, forest workers, military, etc.) [30]. Repeated and/or prolonged exposure in transmission regions therefore poses a relevant risk of re-infection with L. loa.

Several preventive tools are available to protect oneself against infection. Firstly, bites by the diurnal deerflies of the genus Chrysops should be avoided. This may be achieved by avoiding exposure in the relevant regions, by wearing long and light-coloured clothing and by applying repellents to the skin and cloths. Although no systematic studies on the effectiveness of repellents against Chrysops silacea and Chrysops dimidiata are available to date, a certain degree of protection may be assumed by standard repellents. Other protective measures against Chrysops bites, such as mosquito-net hats, caps or helmets, as well as protection by bednets when outdoors and screening of houses and apartments with nets on windows and doors, should be considered to prevent bites by deerflies.

In case of particularly high risk, such as multiple new infections after successful treatment due to repeated high-risk exposure in endemic areas, chemoprophylaxis for L. loa may be considered for individual cases. The effectiveness of DEC for the prophylaxis of loiasis was first described in animal models [94]. In a later randomized, controlled clinical trial, weekly oral administration of 300 mg DEC showed high protective efficacy (100% protection against clinical disease) in US adults traveling to high-transmission regions for long-term stays [95]. This chemoprophylaxis regimen, which was taken over a period of 2 years in the clinical trial, may therefore be considered for individual cases. However, detailed information on the off-label use of this drug, which is not approved for this indication in Germany, has to been provided to the traveller.

Regular laboratory follow-up appears to be useful in the long-term use of DEC to ensure tolerability and safety of the chemoprophylaxis regimen. Compared to placebo, nausea was described more frequently in the DEC group in this study. Relevant contraindications of DEC (onchocerciasis, active L. loa infection with microfilariae load > 2,000/mL, caution of accumulation in case of prolonged alkalinised urine) must be taken into account, particularly when considering chemoprophylaxis in individuals from endemic regions.

Loiasis and blood transfusions

Blood transfusions are in general not necessary to treat L. loa infection as loiasis does not lead in itself to clinically important anaemia. However, in endemic regions with high prevalence of infection, the decision whether microfilaraemic individuals may serve safely as blood donors is commonly encountered as medical conundrum.

In the case of L. loa microfilaraemic blood donors, a risk-benefit analysis needs to be considered [96]. On the one hand, transfusion of microfilariae may cause secondary activation of the immune system of the blood transfusion recipient, leading to eosinophilia, increase of IgE and potential transient clinical symptoms including pruritus and urticaria. On the other hand, no patent infection is caused by administration of microfilaraemic blood, as microfilariae cannot multiply themselves within the human host. Consecutively microfilaraemia clears within several days or weeks without further medical intervention. Importantly, blood transfusions cannot transmit adult worms of L. loa due to their extravascular location in the soft tissues of the human host, thus precluding the possibility of blood-borne transmission of infection [2].

In summary, it may therefore be concluded that blood transfusions from blood donors without L. loa microfilaraemia are preferred. The presence of microfilariae in donor blood may, however, be considered of only minor medical risk for the recipient and must at all means not preclude the administration of a lifesaving blood transfusion.