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Loa loa—does it deserve to be neglected?Wolfram Gottfried Metzger, Benjamin Mordmüller

More than 10 million people in western and central Africa are estimated to be infected with Loa loa fi larial nematodes. Like most other infectious diseases, L loa fi lariasis (loiasis) covers a wide range of symptoms. Severe complications have been reported; however, most observations are anecdotal, typically in travellers. The widespread use of fi laricidal drugs within eradication programmes of Onchocerca volvulus and Wuchereria bancrofti led to the observation that concomitant L loa infection increases the risk of severe treatment-associated, life-threatening complications. Initiatives were therefore launched to map the risk of loiasis. Insight about the epidemiology of L loa has advanced notably; however, its eff ect on the individual as well as on the community level has not been well studied. In the absence of appropriate studies, L loa is commonly judged a harmless nematode, and loiasis as a separate entity does not belong to the list of neglected tropical diseases to be controlled or eradicated in worldwide campaigns. We advocate reorientation of research eff orts towards a patient-centric view of loiasis and, as a fi rst step, to establish the disease burden in disability-adjusted life-years of this chronic infection, and to answer the question of whether loiasis should be included in future control programmes.

IntroductionThe startling feature of infection with Loa loa fi lariae is vividly depicted in an early report:1 “…a single woman, aged 29, attended Dr O’Donovan’s clinic at the London Hospital on December 17, 1930. Fifteen months ago she went to the coastal area of Nigeria as a missionary…on the boat returning to this country she noticed in a mirror a white worm about one inch long moving in the skin of the cheek toward the inner canthus of the left eye. …she was advised…to apply pressure to prevent the worm from entering the eye, and when she did so the worm retreated and disappeared.” For many years, reports described the subconjunctival passage of the eye worm through the patient’s eye (fi gure 1). Together with the so-called Calabar swelling, this is the visible and pathognomonic symptom of loiasis. Since its fi rst description by a French surgeon located in Santo Domingo in 1770,2 L loa has been a popular topic for case reports of rare diseases.

14·4 million people live in high-risk regions, which are defi ned as an area where the estimated prevalence of eye worm is greater than 40%, and 15·2 million people live in intermediate risk areas with an estimated prevalence around 30% (20–40%). From these fi gures, we estimate that at least 10 million people are infected with L loa. The endemic countries are: Angola, Cameroon, Central African Republic, Chad, Democratic Republic of the Congo, Equatorial Guinea, Gabon, Nigeria, Republic of Congo, and Sudan.3 In some endemic regions loiasis is the second or third most common cause of medical consultations.4,5

On the basis of our clinical experience in Gabon, we postulated that L loa might not be as harmless as commonly suggested. We searched the literature to identify research needs and propose topics that can be addressed by future research programmes. The earliest reference was from the year 1918.6 Many published articles had been written not because loiasis was the main focus of scientifi c interest, but the attention was drawn to L loa by other research. For example, when bacteria of the genus Wolbachia were found to have a

mutualistic relationship with some fi larial nematodes, three research groups were looking independently for the bacteria in L loa worms; none found them.7–9 In other studies, awareness of L loa increased as a result of serious adverse events to ivermectin—especially encephalo-pathies—in patients who were treated for Onchocerca volvulus while co-infected with L loa. Then, a series of articles were published on L loa treatment10–21 and epidemiology.22–26 Consequently, the number of publications on L loa increased substantially in the past 20 years.

Epidemiology and diagnosisThe fi rst comprehensive literature review on L loa epidemiology was published in 1997.27 From 2002 to 2010, a large eff ort was made to assess L loa prevalence using large-scale surveys that implemented a short question naire for the history of eye worm (rapid assessment procedures for loiasis, RAPLOA). Of the ten countries with endemic L loa, Gabon and Equatorial Guinea were classifi ed as high risk, with an estimated prevalence of eye worm history greater than 40% and representing a large proportion of the total high-risk area in Africa; in Gabon, the RAPLOA survey was complemented by microscope detection of micro-fi lariae, and an overall prevalence of 66% was reported for eyeworm history and 22% for micro fi laraemia (video).28 However, because of their low population, these two countries account for less than 5% of the total high-risk population. By contrast, the Democratic Republic of the Congo (7·4 million) and Cameroon (4 million) represent 80% of the estimated total population at high risk.3 The epidemiology of this parasite is in fl ux, since the wide distribution of the anthelmintic ivermectin in areas where O volvulus is co-endemic has led to substantial decreases in the abundance of L loa, and high prevalence is found now mainly in areas that do not harbour O volvulus.

Alongside patient history of an adult worm passing through the eye or itchy swellings on the body (Calabar

Lancet Infect Dis 2014; 14: 353–57

Published OnlineDecember 12, 2013http://dx.doi.org/10.1016/S1473-3099(13)70263-9

Centre de Recherches Médicales de Lambaréné (CERMEL), Lambaréné, Gabon, and Institute of Tropical Medicine, Eberhard Karls University, Tübingen, Germany (W G Metzger MD, B Mordmüller MD)

Correspondence to:Dr Wolfram Metzger, Institute of Tropical Medicine, Wilhelmstrasse 27, 72074 Tübingen, Germanywolfram.metzger@uni-tuebingen.de

See Online for video

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swellings), an infection with L loa can be diagnosed by the detection of larvae (microfi lariae), which are released by the adult worms into the peripheral blood. In peripheral blood samples, microfi lariae can be detected with microscopy and L loa specifi c DNA with PCR tests. An additional diagnostic instrument is the detection of L loa specifi c antibodies in serum samples. Generally, the diagnosis of loiasis is challenging for two reasons. First, densities of microfi lariae in the blood are high between 1000 h and 1600 h. Thus, a reliable detection of parasites, or pathogen-associated molecules, in the peripheral blood is possible only in the window of a few hours. Second, more than half of patients harbour adult worms without detectable microfi lariae in the bloodstream at any time.5 These occult carriers are diffi cult to identify with either microscopy or highly sensitive and specifi c PCR.29,30

Disease treatmentThe WHO-recommended fi rst-line treatment of loiasis is diethylcarbamazine,31 which has been clinically studied in patients with onchocerciasis and lymphatic fi lariasis.32,33 However, only one randomised controlled trial has investigated a prophylactic regimen in immunologically naive volunteers from the US Peace Corps,34 and we could fi nd no trial on effi cacy and adverse events of diethylcarbamazine treatment in patients from an endemic region with ongoing loiasis in our literature search. Eff ectiveness of diethylcarbamazine has been seen in expatriate visitors to endemic regions, and several case reports have been published because patients suff ered adverse events.35–37

Especially in individuals with high burdens of L loa microfi lariae, the use of diethylcarbamazine has frequently been associated with severe encephalopathy, not unlike the syndrome evoked by ivermectin in patients with high microfi laraemia. Unfortunately, strategies to ameliorate these encephalopathies have not been identifi ed. In general, patients with high microfi laraemia bear a high risk for severe side-eff ects to treatment brought on by decomposing larvae, and any new therapy targeting this infection needs to anticipate the possible consequences. That these reactions typically occur in remote regions is a serious complication to their treatment and favourable resolution. Why some of the patients develop life-threatening treatment complications and others do not has not been investigated. Diagnostic methods that can identify people at risk are urgently needed.

Alternative drugs are ivermectin and albendazole. The profi les of both drugs are completely diff erent with respect to L loa. Ivermectin has no activity against adult worms. It kills microfi lariae through an unknown mechanism that relies on the host’s immune system (similar to diethylcarbamazine), and can lead to an overwhelming immune response. As a result, ivermectin is highly active but not curative (since the adults remain unaff ected) and the safety profi le is problematic, especially in cases of high fi larial load where life-threatening, post-treatment reactions have occurred repeatedly.17

To extend treatment options, albendazole was studied in L loa endemic regions.38 Albendazole is eff ective in reducing microfi lariae through its action on adult worms and has been useful in treating loiasis refractory to diethylcarbamazine.39 It does not require a host immune response. Microfi lariae are reduced slowly and the risk to patients is low compared with diethyl carbamazine and ivermectin,40 but treatment lasts longer and it does not suffi ciently reduce high microfi larial levels to allow safe therapy with diethylcarbamazine in most cases.

Both agents, ivermectin and albendazole, have been investigated by means of randomised controlled trials in patients infected with L loa.41–45 To improve effi cacy and reduce side-eff ects, currently proposed therapeutic

Figure 1: Adult Loa loa fi laria decomposing in human eyeThis patient was seen by the doctor after an unsuccessful manual extraction attempt of the worm at home.

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Figure 2: Loa loa microfi laria in human placentaMicrofi laria in placenta of a young woman.

Carm

en L

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ina

Sala

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Lam

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abon

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regimens combine these chemotherapeutic agents in diff erent combinations depending on the microfi larial load of the patient.46

Another strategy is the physical separation of microfi lariae from the blood by apheresis techniques. These high-tech methods have been used in a few patients from resource-rich countries only.47–49 The treatment of loiasis is therefore diffi cult because easily applicable therapies, which can clear parasites and bear a low risk for side-eff ects, are not available.

Disease symptoms and burdenThe range of loiasis symptoms and complications goes from no symptoms at all to various severe complications, such as cerebral (eg, encephalopathy in the absence of treatment), cardiac (eg, endomyocardial fi brosis), pulmonary (eg, pulmonary infi ltrates), and renal complications (eg, renal failure), as well as neurological and psychiatric disorders. Many complications are presumably due to immune complex deposition and are frequently accompanied by marked eosinophilia.50,51 Most publications present isolated histories seen in American or European expatriates and do not focus on the majority of cases that occur in endemic countries (fi gure 2).

Only two studies of residents in endemic areas exceeded the size of case reports, excluding other infections and using a control group of non-infected individuals. One is a cross-sectional study showing that loiasis (n=142) is associated with pruritus, skin eruptions, oedemas, joint and muscle pain, and severe headache, when compared with the non-infected control group (n=98). As expected, the low number of participants meant that the risk for severe complications could not be assessed in this study.52 Uncontrolled observations in cohorts of African patients confi rm these results.53,54

The other study investigated cardiac complications in L loa carriers (n=219) versus L loa-negative controls (n=63). In this study, all three patients with endo-myocardial fi brosis had detectable L loa infection, negative stool examination for intestinal helminths, and marked eosinophilia. However, also in this study, the number of participants was too low to draw a conclusion on the cause of this rare complication backed by statistical signifi cance.55,56

Some studies compare clinical and immunological parameters in African and expatriate patients. The fi ndings support the hypothesis that diff erences in the modulation of the immune response to parasite antigens are responsible for much of the variation in clinical presentation: L loa-naive expatriates developed more and diff erent symptoms than did endemic populations.57,58 However, the eff ect of age on symptoms and complications of loiasis has not been investigated, and studies focusing on clinical manifestations in African infants and children were not found.

The clinical features of loiasis were the subject of some doctoral theses in Cameroon.56,59–61 As a big part of the endemic countries are francophone, the language barrier might result in an under-representation of French publications in the scientifi c arena dominated by English as lingua franca. This, in consequence, might also contribute to the low visibility of disease manifestations.62

In general, the roughly 500 PubMed-indexed articles published within about 100 years is a fairly low number for an infection aff ecting more than 10 million people. The main fi nding of this literature search is that systematic studies assessing the overall disease burden of loiasis do not exist. This fi nding is noteworthy, because case reports and medical experience in endemic areas show that L loa causes a broad range of symptoms and is a chronic, sometimes lifelong, infection.

One way to measure disease burden is the deter-mination of disability-adjusted life-years (DALY). The use of DALYs has become central to quantifying the health eff ect of a pathological condition. Certainly, this abstract indicator is far from perfect, but it shall be useful to facilitate decisions on the implementation of control programmes or other health interventions. Oncho-cerciasis, for example, had directly not caused a single death, but its global burden was nearly 1 million DALYs according to the Global Burden of Disease report of 2002; pruritus caused by onchocercarial fi lariae accounted for 60% of the DALYs.63

Similar assessments exist for headache caused by migraine or joint pain caused by rheumatic diseases. Extensive data analysis has also been accomplished on other nematodal infections, such as schistosomiasis, lymphatic fi lariasis, ascariasis, trichuriasis, and hookworm disease, on the global and the national level.

Figure 3: There is a worm, there are medical records, but is there a disease?Single sheathed Loa loa larva.

Jean

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ConclusionsThe chronic nature of infection, range of symptoms and complications, treatment complications, comorbidity, and economic restrictions mean that large, standardised, and longitudinal studies would be needed to assess fully the eff ect of L loa on aff ected populations. Such studies would be complex and might not be cost-effi cient. We suspect that the paucity of data is evidence that the disease is viewed as less serious than it really is, and, vice versa—because the disease is thought to be less serious, no research eff orts are done to determine the disease burden.

As a consequence, research that aims to improve diagnosis, therapy, and case-management is not funded, and patients are therefore neglected; loiasis is not listed as a separate entity in the report on the global burden of disease.64 Its eff ect on social life and economy, on the individual and on the community level, has never been assessed adequately, and the possible benefi ts from disease control, or at the very best, eradication, have never been estimated (fi gure 3).

As with many other neglected tropical diseases, loiasis is a chronic disease of poor populations in resource-limited countries, which, in turn, can trap these people in poverty.65 We are well aware that many publications close with the statement that “more research is needed”. In the case of L loa infection, this conclusion is defi nitively justifi ed. Appropriate primary data for the disease burden of loiasis (in DALYs) must be gained, and L loa should be included in research and control programmes for neglected tropical diseases.

ContributorsBoth authors contributed equally to the literature search and writing of

the manuscript.

Confl icts of interestWe declare that we have no confl icts of interest.

AcknowledgmentsWe thank Marco Jacobi for helping in the literature search and

Sorina Köhler for brushing up our English.

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Search strategy and selection criteria

We searched PubMed, and included all publications with “Loa loa” or “loiasis” in the title. Non-English publications were included as far as they were indexed in PubMed. Because some non-English, and some earlier literature, used diff erent spelling, the terms “loaiasis” and “Filaria loa” were added to the search. References were subjectively labelled by the two authors in categories: epidemiology, diagnosis, treatment, vector studies, animal models, host parasite interactions, case reports, “other”, and reviews/comments/editorials. The rationale behind the chosen labels was to obtain a rough overview of the research done on L loa. 480 references remained after eliminating double entries in the four lists (last retrieved Feb 1, 2013). 122 references (25%) were written in 16 languages other than English, with articles in French representing the biggest part (n=68 [14%]). A third of the references were case reports (165 of 480 [34%]), and one in ten publications (46 [10%]) were review articles, comments, or editorials. The remaining articles were divided into the categories of epidemiology (41 [9%]), diagnosis (28 [6%]), treatment (71 [15%]), vector studies (37 [8%]), animal models (26 [5%]), host parasite interactions (41 [9%]), and other (25 [5%]).

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