Cutaneous Larva Migrans
Authors: Helmut Albrecht, M.D., Carlos Franco-Paredes, M.D., MPH
Clinically, cutaneous larva migrans (CLM) or creeping eruption, is a raised, erythematous, linear or serpiginous skin eruption, which is often accompanied by intense pruritus. Cutaneous larva migransis a widespread and well-recognized disease in the tropics and is considered the most common dermatological problem affecting westerners after travel to tropical countries (5, 11,17,19,28,32,36).
PARASITOLOGY
Larva migrans syndromes are caused by the accidental infection of humans by infective larvae of helminthic species that are normally parasitic for other carnivorous mammals. The developmentally arrested nematode larvae do not mature to adult worms within the human body, but rather migrate through superficial tissues. This aberrant migration may be prolonged, inciting a local or systemic eosinophilic response that is responsible for many of the signs and symptoms of these infections. Cutaneous larva migrans is most often caused by infective-stage larvae of animal hookworms, usually the dog and cat hookworms. Ancylostoma caninum and Ancylostoma braziliense. Other nematode parasites of domestic and wild animals have been implicated in causing similar lesions, such as Uncinaria stenocephala the Northern hookworm of dogs, Bunostomum phlebotomum, the cattle hookworm, Gnathostoma spinigerum, a nematode endemic in Asia, Dirofilaria sp, Baylisascaris procyonis, a parasite of raccoons, and Strongyloides westeri, an equine parasite. Other geographically restricted nematodes, may occasionally manifest as larva migrans syndromes, such asGnathostoma, Angiostrongylus and Anisaka. Even the larvae of some of the myaisis-inducing flies (Gasterophilus and Hypoderma sp.) have been associated with the condition. (5,14,15,17,19,24,32,34,36). Some authors also consider creeping disease due to larva ofSpiruroidea nematodes part of this syndrome. This disease, in which the patients seem to have acquired the infection by eating raw seafood or squid is the most common cause of creeping eruption in Japan.(32). Furthermore, the larvae of Ancylostoma duodenale or Strongyloides stercoralis (the latter causing the disease known as larva currens) may also penetrate the skin and cause a syndrome similar to cutaneous larva migrans. Humans are, however, also the definite host for these nematodes and may be afflicted with much more diverse clinical manifestations.(30) Finally Lagochilascaris minor may also cause cutaneous larva migrans but the larvae can develop into adult worms in humans causing severe visceral, ocular, or central nervous system disease.
EPIDEMIOLOGY
For hookworms of domestic animals man is an occasional host and is infected accidentally. This usually occurs after contact with soil, generally sandy and damp beaches of tropical and subtropical countries, contaminated by feces of infected dogs and cats. First stage larvae hatch from embrionated eggs passed in animal feces, and mature to third-stage infective larvae in the soil. After percutaneous invasion, the larvae migrate along the upper dermis, causing inflammatory erythematous lesions to form along their tortuous tracks, which can advance several centimeters in a day. Unable to complete their vital cycle they usually die after weeks or months without any specific treatment.(11,19) cutaneous larva migrans infections are endemic to the Caribbean, Central and South America, and Asia. In the United States, infection has been reported in the southeast and parts of the southwest, but the incidence is relatively low (36).
CLINICAL MANIFESTATIONS
The intensely pruritic lesions are often confined to the foot and lower extremities but may occur anywhere on the body. The tracks in cutaneous larva migrans due to Ancylostoma species, or rarely Strongyloides species, normally progress over weeks or months and are indurated and flaky. In severe infections, patients may have multiple tracks. Usually there are few, if any systemic symptoms, but some reports have documented lung infiltrates with pulmonary symptoms.(32). About one fourth of travelers have symptoms for more than a month before presenting to a physician because of the skin eruption. Misdiagnosis and ineffective treatment have been reported in up to 58% patients with the condition.(2,11,19) With the growing mobility of the world's population, cutaneous larva migrans is no longer confined to specific geographic regions. Although benign, cutaneous larva migrans may result in disturbing pruritus, which requires pharmacological treatment.
Cutaneous larva migrans usually heals spontaneously within weeks or months. In a series of 25 patients treated with a placebo, 12% healed by the end of the first week and 36% by the end of the fourth week; the longest period required for spontaneous healing was 11 weeks in this series (22). If left untreated, however, cutaneous larva migrans has been reported to persist for up to a year.(20) Previously sensitized persons can develop a more severe allergic skin response with vesicle and bullae formation, or even erythema multiforme.(4)
LABORATORY DIAGNOSIS
Diagnosis can usually be established on the basis of pruritus and the characteristic rash in conjunction with a history of travel to endemic regions. Laboratory studies, including blood eosinophil determinations, total IgE levels, filarial antibody titers, and skin biopsy, are rarely helpful.
PATHOGENESIS
The larvae are confined to the epidermis, where they cause infiltration of eosinophils and lymphocytes. It is believed that the larvae lack the specific collagenase needed for penetration of dermis.
SUSCEPTIBILITY IN VITRO AND IN VIVO
No data exists for these parasites.
ANTIPARASITIC THERAPY
The drug of choice may now be ivermectin (1,7,33). Single doses of ivermectin resulted in 100% cure rates among patients with cutaneous larva migrans in pilot studies involving 8 to 12 patients (25,30). Since then, the efficacy of a single dose ivermectin (12mg) has been confirmed in 3 larger studies involving almost 200 patients (2,6,33). Rare treatment failures usually responded to a second or third dose of ivermectin. Ivermectin has been well tolerated in studies of patients with cutaneous larva migrans. Almost all reported adverse effects have occurred in patients with filariasis and may well have been brought on by the patient's immune response to killed microfilariae (16).
An open randomized study (8) compared the efficacy of single doses of oral ivermectin (12 mg) and oral albendazole (400 mg) in the treatment of cutaneous larva migrans. Twenty-one patients were randomly assigned to receive ivermectin (n = 10) or albendazole (n = 11). All the patients who received ivermectin responded, and none relapsed (cure rate, 100%). All but 1 of the patients receiving albendazole responded, but 5 relapsed after a mean of 11 days (cure rate, 46%); the difference in efficacy significantly favored ivermectin (P = .017). No major adverse effects were observed. The investigators concluded that a single 12-mg dose of ivermectin was more effective than a single 400-mg dose of albendazole for the treatment of cutaneous larva migrans (8).
Oral thiabendazole is rapidly absorbed and usually effective when given twice a day for 3 to 5 days. In one study, most patients treated with thiabendazole responded within the first week compared to the more than 4 weeks required in the placebo group to achieve improvement (20,30,36). Thiabendazole is poorly effective when given as a single dose with response rate below 75%. Repeated courses can improvement cure rates. Thiabendazole is often not well tolerated with anorexia, nausea, vomiting, headache, and dizziness presenting treatment-limiting adverse events in a significant number of patients. Given the efficacy and tolerability of albendazole and ivermectin thiabendazole has become a distant third choice for oral therapy of cutaneous larva migrans. Oral albendazole has been reported to be as effective as thiabendazole with significantly fewer side effects (20,30,36). For many clinicians, it has therefore become the treatment of choice for this illness. A daily dose of 400mg rarely 800mg is effective. The optimal duration of therapy is less clear. Many studies have used a three to five day course (21,23,31) but single doses of 400 mg have been reported to be effective in selected cases (27). When diffuse or multiple lesions are found, some authors recommend a seven day course of 400 mg daily. This regimen can reduce the number of relapses or non-responses occasionally observed with shorter (3-5 days) treatment courses and is not associated with new or more severe side-effects (29). Some authorities have even recommended up to 35 days of therapy for tourists diagnosed with cutaneous larva migrans as lower response rates of 46 to 100% have been reported in patients not living in endemic areas (9). Aside from mild gastrointestinal problems albendazole is virtually free from adverse effects, although there have been isolated reports of abnormal liver function tests, neutropenia, and fever. These adverse effects are more common in patients with filariasis or on long-term treatment such as patients with hydatid disease and are not usually encountered in short-term treatment of cutaneous larva migrans (30).
Special Situations
Immunosuppressed Hosts
While there have been reports of cutaneous larva migrans in patients with advanced HIV infection there are no data to confirm a higher incidence of cutaneous larva migrans in immunedeficient patients.
Therapy with thiabendazole for 5 days was effective in one patient with AIDS and advanced level of immunosuppression (3,13). In a study of 67 Belgian patients, however, the only ivermectin treatment failure was observed in an immunedeficient patient (33).
Alternative Therapy
Topical Drugs
For decades multiple studies have demonstrated the effectiveness of topical thiabendazole. Moreover, this form of therapy is devoid of the frequent side effects associated with systemic administration of thiabendazole. While topical thiabendazole is not available as a commercial preparation in many countries, it can easily be formulated by crushing 500 mg tablets into a water soluble cream base at a concentration of 15% and applying it to the affected area three times daily for 5 days. An even simpler approach is to use the commercially available 10% oral suspension of thiabendazole as topical therapy (12,19,36). In two large studies in Canada and Germany cure rates exceeded 98% (12,19). Recently lipophilic vehicles have been evaluated (10).
The main disadvantages of topical therapy are that they have limited value for multiple lesions including hookworm folliculitis and that they require multiple daily applications for several days.
ADJUNCTIVE THERAPY
Freezing the leading edge of the skin track is both ineffective and painful and should be avoided. The visible end of the trail hardly ever indicates the true location of the moving larvae as the inflammatory response usually lags.
Many physicians still torture patients with ethylene chloride spray, carbon dioxide snow, or liquid nitrogen despite evidence to the contrary. In one study, none of seven patients treated with liquid nitrogen was cured (11). In a German study cryotherapy with liquid nitrogen was unsuccessful for 6 patients and resulted in severe blistering or ulceration in 2 patients (19). Other studies have reported foci of altered pigmentation, particularly in persons with darker skin and local irritation (20,36).
With the availability of effective oral agents surgery, which was once the mainstay of therapy of cutaneous larva migrans, has also become obsolete.
ENDPOINTS FOR MONITORING THERAPY
Cessation of pruritus and lack of further advancement of active lesions are probably the best markers for successful therapy.
VACCINES
Our knowledge of the immune responses generated during parasite infections has increased enormously over the past 10 years (18). These advances however have not yet translated into commercially available vaccines. This can be attributed in part to the fact that different immune rejection and immune evasion mechanisms may exist for each host-parasite system.(26) Various attempts have been made to develop attenuated and killed larval vaccines against nematode infections. The first successful attempt in inducing resistance to re-infection in dogs with Ancylostoma caninum was reported by Herrick as early as 1928.(35) Studies have been done comparing 3 types of vaccines: a sonicated extract of killed larvae, 5-fluorouracil-treated larvae and 40krad x-irradiated larvae in canine hookworm disease by Ancylostoma caninum. The irradiated vaccine provided maximum protection in dogs against infection.(35) Recent studies have been done to elucidate possible mechanisms of protective immunity by administering Ancylostoma caninum third-stage (L3) infective larvae into mice. The protective process might be associated with circulating Anti-L3 antibodies, including some directed against a 132-200 KDa L3 antigens.(34)
PREVENTION
While antimicrobial prophylaxis is not usually recommended, prevention of cutaneous larva migrans is feasible when simple precautionary measures are followed. Because most affected patients are infected by lying or walking on tropical sandy beaches contaminated with cat or dog feces, prevention of cutaneous larva migrans may be best achieved by banning these animals from the beach. Because this is often not feasible in developing countries, tourist should be advised to wear shoes while walking on tropical sandy beaches frequented by dogs. It is also advisable to either lie on sand washed by the tide or to use a mattress (towels are insufficient).
CONTROVERSIES, CAVEATS, OR COMMENTS
A major obstacle to successful therapy in many patients is the failure to correctly diagnose cutaneous larva migrans. In large studies more than 50% of patient were initially given the wrong diagnosis before the diagnosis of cutaneous larva migrans was eventually established (2,11). This may result in bizarre therapeutic interventions. In a German study (19) 22 patients received 12 different treatments, including French brandy or surgical interventions, before they were referred to a specialized center.
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