Loiasis: New Epidemiologic Insights and Proposed Treatment Strategy

Among the two cases of loiasis published in this issue,1,2 one particularly deserves to be commented on because it is atypical in some respects.1 The patient was an expatriate who had an upper eyelid swelling from which a nematode was extracted. During the preceding 2 years, he had had transient swellings at various sites of the head, and at referral his eosinophilia was normal and no microfilaria (mf) was found in his blood. No serologic or polymerase chain reaction (PCR) assays were performed on blood samples. The parasite removed has not been examined morphologically to seek classical characteristics of adult Loa loa (cuticle with numerous, randomly arranged, smooth, round bosses); but the real‐time PCR assay performed on a piece of the worm demonstrated unambiguously that it was a L loa specimen. The first interesting point in this case is that the patient reported to have visited sub‐Saharan Africa only once for a business trip, 20 years before the extraction of the worm. Unlike Onchocerca volvulus or Wuchereria bancrofti (the most pathogenic human filariae), the average lifespan of adult L loa has never been evaluated. However, it is known that the parasite can live more than 10 years,3 the record reported so far being 17 years.4 The possibility that the patient presented in this report had been infected elsewhere than in Africa could be considered: experimental infections using monkey models have shown that at least one American Chrysops species supports the development of L loa up to the infective stage, and could thus theoretically retransmit the parasite locally after having taken a bloodmeal on an infected individual.5 However, this is rather unlikely (as stated by Orihel and Lowrie,5 no report exists of Loa establishment in America, even at the height of the slave trade) and consequently the present case represents probably the record of longevity for L loa. A second point to mention is that the patient does not seem to have presented any symptom of loiasis up to 2 years before the removal of the adult worm. Such a long clinical prepatency has been mentioned in many cases, the maximum reported being 15 years.3,6 However, one should keep in mind that the interval between infection and appearance of the first clinical manifestations can be much shorter, and even as short as 2 months.7 The third point that makes the case extraordinary is the fact that the patient stayed only 3 days in Africa, and in an urban area, Lagos, Nigeria. Most of the travelers or expatriates who have been found infected by L loa had stayed several months or years in forested endemic areas, with periods of less than 3 weeks reported only rarely.8–10 While Lagos is surrounded by forested areas favorable to the biology of Chrysops, the dispersal of these vectors over cleared areas is fairly low 11 and the prevalence of Loa infection found during a hospital‐based study conducted in 1988 in metropolitan Lagos was only 5%.12 Thus, if the only possibility of exposure to vector bites is really as reported by the patient, one must recognize the latter was particularly unlucky… The case reported in this issue is thus interesting because it reminds us that a diagnosis of loiasis should be considered even if the patient has left an endemic area and remained asymptomatic for many years, and even if he was potentially exposed to infective vector bites for only a few days. As Chrysops can harbor more than 100 infective larvae in their head,13 a single bite may be sufficient to infect an individual. Another aspect of this case report that should be discussed is that of the treatment of loiasis. The authors say that the patient received a single dose of diethylcarbamazine (DEC, 6 mg/kg) and remained asymptomatic during the year of follow‐up. A single dose of DEC is not sufficient to cure a L loa infection as evidenced by the fact that a proportion of patients continue to be symptomatic even after a full course of 21 days of DEC.14 It is possible that the patient described in this issue harbored only one adult worm and that the cure was due to its extraction and not to the drug. The present case offers an opportunity to discuss the optimal treatment strategy for loiasis, in the light of what is known about the efficacy and safety of the three drugs currently used to treat it: DEC, albendazole (ALB), and ivermectin (IVM). Regarding efficacy, the only one of the three drugs for which a macrofilaricidal effect, ie, a lethal effect on adult worms, has been demonstrated is DEC. In 10–25% of the cases, more than one course of DEC has to be given to achieve a complete cure; patients who are refractory to more than four courses are very rare.15,16 DEC treatment also brings about a rapid decrease in the Loa microfilaremia. Short courses of ALB have little effect on L loa17,18 but when given at a dose of 200 mg twice a day for 21 days, the drug has probably an embryotoxic effect (ie, it interrupts embryogenesis in the uteri of the adult female worms), and perhaps also a macrofilaricidal effect.19 After a single dose of IVM (150 µg/kg), Loa microfilaremia decreases by 70–80% within the first 3 days.20–22 The densities then plateau or decrease more slowly, and remain at very low values up to 1 year after treatment.23 Whether this is due to a partial macrofilaricidal or to an embryostatic effect (preventing the release of developed mf from the uteri of the adult female worms) is not known. Monthly treatment with IVM has a cumulative effect, leading after six doses to extremely low microfilarial densities, which remain so for at least several months.24 Besides its effects on the parasite, IVM also has a beneficial effect on the clinical manifestations of loiasis, and seems to prevent the reappearance of Calabar swellings for several months.25 Lastly, it should be reminded that as L loa does not harbor Wolbachia endosymbionts,26 antibiotics (doxycyclin) are useless in the treatment of loiasis. This being said, the treatment strategy depends firstly on the risk of adverse events, which is related to the patient's Loa microfilarial density. The latter must mandatorily be quantified before any therapy decision by examining a Giemsa‐stained thick blood smear (50 µL) prepared between 10:00 am and 4:00 pm, ie, when Loa microfilaremia in the peripheral blood is the highest. In countries located outside the loiasis distribution area, this assessment and the resulting treatment should be conducted in specialized units or by specialized physicians. DEC and IVM can induce potentially fatal encephalopathies in persons harboring >30,000–50,000 mf/mL of blood.27,28 Functional impairment without alteration of consciousness but requiring assistance for several days can occur after DEC in individuals with >2000 mf/mL,29 and after IVM in patients with densities exceeding 8000 mf/mL.28 Use of ALB in loiasis patients is usually very safe. Given the risk of serious adverse events after DEC or IVM treatment, one can propose the following strategy: If the patient's microfilarial density is below 2000 mf/mL, DEC—the only proven macrofilaricidal drug—can be administered straightaway. The first course should last 3–4 weeks and start with low doses (3 or 6 mg/d if mf are present in the blood, or 50 mg/d if the patient is amicrofilaremic) divided into two or three doses. The dose is doubled every day until 400 mg/d (or 8–10 mg/kg/d) still divided in two to three doses. Treatment should be started in hospital and oral antihistamines or corticosteroids may be useful in the first days to reduce the severity of side effects (pruritus, angioedema, arthralgias, headache, fever, etc.) which occur in 50% of the cases. As stated above, several courses of DEC may be needed. If the patient is refractory to DEC, a course of ALB (200 mg twice a day for 21 d) can be useful.16 In subjects with Loa microfilarial densities between 2000 and 8000 mf/mL, it is advisable to begin treatment by using IVM (a single dose of 150 µg/kg). Mild side effects similar to those mentioned above after DEC can occur. Treatment with IVM can be repeated at intervals of 1–3 months to reduce the microfilarial loads further. When the microfilaremia is less than 2000 mf/mL, a course of DEC can be started, using to the protocol proposed above. When the microfilarial loads are between 8000 and 30,000 mf/mL, IVM can also be given, but a close surveillance is needed, with hospitalization during the first 3–4 days. An alternative is to start with a course of ALB (200 mg twice daily for 21 d) which reduces the Loa microfilaremia by 60% at 6 months and to continue with IVM treatment with or without hospitalization depending on the microfilarial loads at that time. If the microfilaremia exceeds 30,000 mf/mL, ALB is probably the best option, even if the effect of long courses of ALB has never been evaluated in patients with such high loads. Apheresis, which allows to rapidly reduce the loads by 75% after three sessions has also been proposed.30 However, this technique is expensive and probably indicated only exceptionally given the usually mild manifestations of loiasis. In conclusion, definitive cure of Loa infection can sometimes be difficult and this is all the more true because DEC is not widely available. It should also be kept in mind that in travel medicine practice, two types of loiasis patients can be seen: natives from endemic areas who are frequently microfilaremic, but often asymptomatic, and travelers or expatriates who visited endemic areas, who are in the majority amicrofilaremic but suffer more from annoying manifestations, such as angioedemas (Calabar swellings).31–33 Due to these immunologically mediated differences, the diagnostic methods and the treatment and follow‐up strategy can differ significantly. Regarding diagnosis, highly specific and sensitive assays enabling to detect patients with very low microfilaremias have been developed recently.34,35 Regarding treatment, there is no indication that expatriates and natives from endemic areas with similar microfilaremias respond differently to treatment in terms of efficacy 32 but as the latter harbor sometimes very high microfilarial densities, particular attention should be given when managing these cases in order to prevent possible serious adverse events. The author states he has no conflicts of interest to declare.