Loa Loa

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Parasitology

The filarial nematode, Loa loa, is transmitted by the bite of an infected deerfly (Chrysops spp.). Infective larvae deposited during the bite develop over the course of several months into adult worms, which reside in the subcutaneous tissues of the human host. Gravid adult female worms produce blood-borne microfilariae that may be taken up by the vector during a bloodmeal, completing the cycle of transmission. Although Loa loa microfilariae are usually detectable in the blood only at midday (diurnal periodicity), recent data suggests that night periodic strains exist in some settings (2). Unlike the other filarial parasites that infect humans, Loa loa worms do not contain the intracellular endosymbiont, Wolbachia (4, 27)

Epidemiology

Loa loa infection, or loiasis, is endemic in Central and West Africa, where it is estimated that up to 13 million people are infected (31, 38). Whereas long-term travelers (>3months) to endemic areas are clearly at risk for developing loiasis, infection of short-term travelers is uncommon (25).

Clinical Manifestations

Clear differences have been demonstrated between the clinical manifestations of loiasis in endemic populations and those in travelers to endemic areas and are thought to reflect the host immune response to the parasite (16, 23). Infected individuals from areas endemic for loiasis are commonly asymptomatic despite extremely high levels of circulating microfilariae (microfilaremia). In contrast, visitors to endemic areas who acquire loiasis tend to present with a predominance of "allergic" symptoms, including urticaria, pruritus and the characteristic intermittent subcutaneous swellings (Calabar swellings), but no or few detectable microfilariae in the blood (16, 29). Complications of loiasis, while rare, are also more common in non-endemic patients. In contrast, subcutaneous migration of the adult parasite (eyeworm) occurs in up to 70% of infected individuals depending on the series and is more common in residents of endemic areas than travelers (15, 16).

Laboratory Diagnosis

Definitive diagnosis of loiasisrequires the demonstration of characteristic sheathed microfilariae or Loa loa DNA (11) in a peripheral blood sample or identification of an adult parasite in the subconjunctiva or subcutaneous tissue. Blood is typically drawn between 10 a.m. and 2 p.m. to account for the diurnal periodicity of the parasite in most regions.Quantification of blood-borne microfilariae is essential prior to treatment with microfilaricidal drugssince patients with high microfilarial loads are at risk of serious (potentially fatal) post-treatment reactions. In the absence of parasitologic confirmation, diagnosis generally depends on a compatible clinical history in the setting of eosinophilia and elevated antifilarial antibody levels. Marked eosinophilia and elevated polyclonal IgE levels are typical in loiasis, although recurrences can occur in the absence of these findings (24). Antifilarial IgG and IgG4 antibodies are also elevated, but do not distinguish between active and past infection. Consequently, antifilarial antibody levels are most useful in diagnosing infection in untreated persons from nonendemic areas and in excluding Loa loa infection in amicrofilaremic persons. Other laboratory abnormalities, including hematuria and proteinuria, can occur in Loa loa infection, but generally resolve with therapy.

SUSCEPTIBILITY IN VITRO AND IN VIVO

Since Loa loa parasites cannot be maintained in vitro and Loa loa infection occurs only in primates, drug susceptibility data are restricted to in vivo studies of the effect of diethylcarbamazine (DEC) on loiasis in monkeys and humans. Rapid clearance of microfilariae from the blood following the administration of DEC has been demonstrated in both human and non-human primates (9) suggesting a direct effect of DEC on circulating microfilariae. This is supported by the finding of microfilariae surrounded by phagocytes in a liver biopsy done 12 hours after, but not before, DEC treatment of a patient with loiasis (37). Macrofilaricidal activity of DEC has been inferred by the fact that that most patients appear to be cured of loiasis following DEC therapy. Direct killing of adult worms by DEC is further supported by the finding of dead worms in the subcutaneous vermiform swellings that frequently occur following DEC administration to patients with loiasis (32) and in the subcutaneous tissues of DEC-treated, experimentally infected mandrills (9).

Although there is no definitive evidence of parasite resistance to DEC, a minority of patients remain symptomatic despite multiple courses of therapy (23). In addition, in a study of DEC treatment of 3 experimentally infected mandrills, none of the animals were found to be completely free of adult worms at necropsy (9). Whether these findings reflect parasite resistance to the drug or an inadequate immune response by the host remains unclear at this time.

ANTIPARASITIC THERAPY

Drug of Choice

The drug of choice for the treatment of loiasis is diethylcarbamazine (DEC) at a dose of 8-10 mg/kg per day given orally in three divided doses, although dose finding studies in Loa loa infection have not been performed (1). The mechanism of action of DEC on filarial parasites is unclear, but appears to involve the host immune response (26). Although the drug is well-tolerated in persons with low or undetectable levels of circulating microfilariae (microfilaremia), severe adverse reactions, including renal failure and fatal encephalopathy, have been observed in the setting of high levels of microfilaremia despite slow dose escalation and concomitant administration of steroids (5). DEC is effective against both the microfilariae and adult worms of Loa loa, and is curative in the majority of patients with loiasis, although multiple courses of therapy may be required, and clinical relapses may occur up to 8 years following apparently successful treatment (24).

Special Situations

Coinfection with Other Filarial Parasites: Since the geographic distribution of loiasis overlaps with that of several other filarial infections of humans, including onchocerciasis, lymphatic filariasis, and Mansonella perstans infection, diagnostic evaluation of a patient with presumptive loiasis should include exclusion of coinfection with a second filarial parasite. This is particularly true in the case of onchocerciasis, where DEC treatment can result in a severe systemic reaction (Mazzotti reaction) and exacerbation of underlying skin and eye disease (33). In most patients, treatment of concomitant loiasis and onchocerciasis can be accomplished safely by clearance of eye and skin-dwelling microfilariae with ivermectin prior to DEC treatment (see section VIII for controversies regarding ivermectin use in loiasis). Alternatively, doxycycline, which has both microfilaricidal and macrofilaricidalactivity in onchocerciasis and lymphatic filariasisdue to its effect on the intracellular bacteria Wolbachia, can be used safely in patients coinfected with Loa loa (35).

Immunosuppressed Hosts: The effect of immunosuppression on the clinical manifestations of loiasis has not been examined directly. However, since many of the symptoms and signs of infection are thought to be the result of the host immune response against the parasite, immunosuppression would be expected to ameliorate rather than exacerbate the clinical manifestations of infection. The potential effects of immunosuppression on susceptibility to infection and the response to treatment have not been studied to date.

Alternative Therapy

Disadvantages of DEC therapy for loiasis include adverse reactions, which may be severe in patients with high levels of microfilaremia, the need for multiple 3-week courses in a majority of patients, and the apparent lack of efficacy in a small percentage of patients. Consequently, alternative therapies have been actively sought.

Ivermectin, the drug of choice for the treatment of onchocerciasis, is a semisynthetic macrolide that is effective against the microfilariae (but not the adult worms) of Loa loa. A single dose of 200 mg/kg has been shown to reduce microfilarial levels by 70-90% for up to 1 year (14). Resolution of the signs and symptoms of amicrofilaremic loiasis for up to 1 year following ivermectin treatment has also been reported in two small studies (12, 17). Despite these promising preliminary results, reports of neurologic complications, including fatal encephalopathy, following ivermectin treatment of onchocerciasis in patients with high levels of Loa loa microfilaremia (3, 6) have led to questions about the safety of ivermectin in this setting. Although low dose ivermectin therapydid appear toclear microfilaremialess efficiently than standard dose therapy in a randomized controlled trial, the difference was not sufficient to reliably decrease the risk of ivermectin treatmentin patients with high levels of microfilaremia (18).

In view of these safety concerns and the lack of efficacy of ivermectin against adult worms, ivermectin cannot be recommended as first line therapy in patients with high levels of microfilaremia (>30,000 mf/mL)or those with very low levels of microfilaremia (0-2000 mf/mL of blood). Whether ivermectin therapy should beadministeredto lower the microfilarial counts in patients with 2000-30,000 mf/mL prior to definitive curewith DEC remains controversial, as there have been no studies comparing the incidence and intensity of adverse events following DEC and ivermectin inpatients with loiasis.

The benzimidazoles, including mebendazole and albendazole, are broad spectrum anthelmintics that bind preferentially to parasite b-tubulin leading to the disruption of microtubules and, ultimately, to the death of the parasite. Although several studies have demonstrated the efficacy of high dose mebendazole against adult worms of Loa loa, its poor and variable absorbance and the incidence of side effects when used in high doses have limited its usefulness in the treatment of loiasis (36).

The related benzimidazole, albendazole, has a broader spectrum of activity and increased oral bioavailability as compared to mebendazole. In a double-blind, placebo-controlled trial, albendazole at a dose of 200 mg po bid for 21 days led to a gradual reduction of microfilarial levels in patients with loiasis to 20% of pre-treatment levels at 6 months. The slow decline in microfilaremia is consistent with a primary effect on the adult parasites, as has been proposed in other filarial infections. Despite extremely high microfilarial levels in some patients (>50,000/ml of blood), there were no clinical adverse effects and no observed hepatotoxicity, renal toxicity or hematologic abnormalities attributable to the drug. The utility of albendazole in reducing the numbers of circulating microfilariae (and presumably the side effects of therapy) prior to definitive treatment with DEC has not been examined. Shorter courses of albendazole (1-3 days)have been shown to significantly lower microfilarial counts in some studies, although the effect is variable and transient (19, 34). Albendazole has also been used successfully in the treatment of 3 patients with symptomatic loiasis refractory to multiple courses of DEC (21), and should be considered in the treatment of patients refractory to or intolerant of DEC.

ADJUNCTIVE THERAPY

Diethylcarbamazine (DEC) therapy of loiasis is often associated with a transient exacerbation of symptoms, including urticaria and Calabar swellings. These relatively mild side effects of treatment may respond to antihistamines or a short course of corticosteroids. In patients with high levels of circulating microfilariae (microfilaremia), however, the rapid release of parasite antigens from dying microfilariae following the administration of DEC may precipitate severe complications, including renal failure, shock, coma and fatal encephalitis (5). Corticosteroids and antihistamines have not proven effective in preventing these complications. Although apheresis has been shown to be effective in lowering the level of microfilaremia and preventing serious side effects of DEC treatment, this procedure is expensive and not widely available (28). Lowering blood microfilarial levels with albendazole is a potential alternative approach (see above).

Surgical removal of adult worms from the subconjunctiva is generally not indicated, since migration of the adult parasite across the eye is transient and, while uncomfortable, does not lead to permanent ocular damage. Furthermore, the procedure is unlikely to be curative, as infection with a single adult parasite is unlikely. Most adult parasites in the subcutaneous tissues do not cause symptoms until the patient is treated with DEC, at which time pruritic subcutaneous vermiform papules containing dying adult worms may appear. Since the swellings resolve within hours to days without sequelae, surgical removal is rarely necessary.

ENDPOINTS FOR MONITORING THERAPY

Microfilarial clearance occurs within days of the onset of DEC treatment (37). This may be accompanied by a transient exacerbation of symptoms, including Calabar swellings, urticaria, vermiform subcutaneous papules, arthralgias and myalgias, and of laboratory abnormalities, including eosinophilia, hematuria, and proteinuria. These generally resolve by the end of the three weeks of therapy. Because of the potential for end organ damage in the setting of marked eosinophilia, resolution of eosinophilia should be documented, and retreatment of asymptomatic patients with persistent eosinophilia should be considered. Although relapse of microfilaremia following successful clearance has been reported following DEC therapy in the absence of re-exposure, levels are typically low and monitoring of blood microfilarial levels following documentation of amicrofilaremia post-DEC therapy (in the absence of re-exposure) would appear unnecessary.

Neither pre- nor post-treatment laboratory parameters, including eosinophil count, polyclonal IgE or antifilarial antibody levels are predictive of clinical relapse. Furthermore, relapse, as documented by recurrence of Calabar swellings or subcutaneous parasites, may occur in the absence of laboratory abnormalities for at least 8 years following apparently successful therapy (24). Thus, patients should be followed clinically for evidence of relapse for an extended period of time (adult parasites can live for up to 17 years (10).

Prevention

General

Personal protective measures, including the avoidance of places where biting flies are numerous, the use of protective clothing and insect repellents, can help reduce exposure to infective flies.

Antiparasitic agent prophylaxis

In a double-blind, placebo-controlled study, DEC at a dose of 300 mg weekly provided effective chemoprophylaxis for long-term travelers to Loa-endemic areas (30). Although monthly administration of 100 mg DEC on three consecutive days has been suggested, controlled studies of this regimen have not been performed (8).

VACCINES

No vaccines are currently available for the prevention or treatment of loiasis.

CONTROVERSIES AND CAVEATS

The major controversy in the treatment of loiasis is whether and how to treat patients with high levels of circulating microfilariae, who may experience severe and life-threatening complications of therapy. In areas of Africa where loiasis is endemic, treatment of loiasis is generally reserved for those individuals who are symptomatic and have low levels of microfilaremia. Because of its safety and efficacy in microfilarial clearance in onchocerciasis, single dose ivermectin has been used to lower microfilarial loads in loiasis prior to DEC treatment. However, data from Cameroon and other endemic areas in Africa indicate that severe neurologic complications secondary to ivermectin treatment can occur in patients with high levels of Loa loa microfilaremia (13). Although albendazole was effective in one study in reducing Loa loa microfilaremia without appreciable side effects, the utility of this regimen is limited by the length of the course used (3 weeks) and the delay between drug administration and microfilarial clearance (3-6 months) (22).

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