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Loa loadoes it deserve to be neglected?Wolfram Gottfried Metzger, Benjamin Mordmller
More than 10 million people in western and central Africa are estimated to be infected with Loa loa larial nematodes. Like most other infectious diseases, L loa 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 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 e 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 e orts towards a patient-centric view of loiasis and, as a 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 lariae is vividly depicted in an early report:1 a single woman, aged 29, attended Dr ODonovans clinic at the London Hospital on December 17, 1930. Fifteen months ago she went to the coastal area of Nigeria as a missionaryon 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 advisedto 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 patients eye ( gure 1). Together with the so-called Calabar swelling, this is the visible and pathognomonic symptom of loiasis. Since its 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.
144 million people live in high-risk regions, which are de ned as an area where the estimated prevalence of eye worm is greater than 40%, and 152 million people live in intermediate risk areas with an estimated prevalence around 30% (2040%). From these 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 scienti 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 larial nematodes, three research groups were looking independently for the bacteria in L loa worms; none found them.79 In other studies, awareness of L loa increased as a result of serious adverse events to ivermectinespecially encephalo-pathiesin patients who were treated for Onchocerca volvulus while co-infected with L loa. Then, a series of articles were published on L loa treatment1021 and epidemiology.2226 Consequently, the number of publications on L loa increased substantially in the past 20 years.
Epidemiology and diagnosisThe rst comprehensive literature review on L loa epidemiology was published in 1997.27 From 2002 to 2010, a large e 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 classi 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- lariae, and an overall prevalence of 66% was reported for eyeworm history and 22% for micro 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 (74 million) and Cameroon (4 million) represent 80% of the estimated total population at high risk.3 The epidemiology of this parasite is in 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: 35357
Published OnlineDecember 12, 2013http://dx.doi.org/10.1016/S1473-3099(13)70263-9
Centre de Recherches Mdicales de Lambarn (CERMEL), Lambarn, Gabon, and Institute of Tropical Medicine, Eberhard Karls University, Tbingen, Germany (W G Metzger MD, B Mordmller MD)
Correspondence to:Dr Wolfram Metzger, Institute of Tropical Medicine, Wilhelmstrasse 27, 72074 Tbingen, Germanywolfram.email@example.com
See Online for video
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swellings), an infection with L loa can be diagnosed by the detection of larvae (micro lariae), which are released by the adult worms into the peripheral blood. In peripheral blood samples, micro lariae can be detected with microscopy and L loa speci c DNA with PCR tests. An additional diagnostic instrument is the detection of L loa speci c antibodies in serum samples. Generally, the diagnosis of loiasis is challenging for two reasons. First, densities of micro 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 micro lariae in the bloodstream at any time.5 These occult carriers are di cult to identify with either microscopy or highly sensitive and speci c PCR.29,30
Disease treatmentThe WHO-recommended rst-line treatment of loiasis is diethylcarbamazine,31 which has been clinically studied in patients with onchocerciasis and lymphatic 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 nd no trial on e cacy and adverse events of diethylcarbamazine treatment in patients from an endemic region with ongoing loiasis in our literature search. E ectiveness of diethylcarbamazine has been seen in expatriate visitors to endemic regions, and several case reports have been published because patients su ered adverse events.3537
Especially in individuals with high burdens of L loa micro lariae, the use of diethylcarbamazine has frequently been associated with severe encephalopathy, not unlike the syndrome evoked by ivermectin in patients with high micro laraemia. Unfortunately, strategies to ameliorate these encephalopathies have not been identi ed. In general, patients with high micro laraemia bear a high risk for severe side-e 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 pro les of both drugs are completely di erent with respect to L loa. Ivermectin has no activity against adult worms. It kills micro lariae through an unknown mechanism that relies on the hosts 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 una ected) and the safety pro le is problematic, especially in cases of high 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 e ective in reducing micro 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. Micro 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 su ciently reduce high micro 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.4145 To improve e cacy and reduce side-e ects, currently proposed therapeutic
Figure 1: Adult Loa loa laria decomposing in human eyeThis patient was seen by the doctor after an unsuccessful manual extraction attempt of the worm at home.
Figure 2: Loa loa micro laria in human placentaMicro laria in placenta of a young woman.
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regimens combine these chemotherapeutic agents in di erent combinations depending on the micro larial load of the patient.46
Another strategy is the physical separation of micro lariae from the blood by apheresis techniques. These high-tech methods have been used in a few patients from resource-rich countries only.4749 The treatment of loiasis is therefore di cult because easily applicable therapies, which can clear parasites and bear a low risk for side-e 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 brosis), pulmonary (eg, pulmonary in 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 ( 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 con 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 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 signi cance.55,56
Some studies compare clinical and immunological parameters in African and expatriate patients. The ndings support the hypothesis that di 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 di erent symptoms than did endemic populations.57,58 However, the e 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.56,5961 As a big part of the endemic countries are francophone, the language barrier might result in an under-representation of French publications in the scienti 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 a ecting more than 10 million people. The main nding of this literature search is that systematic studies assessing the overall disease burden of loiasis do not exist. This 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 e 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 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 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.