[S1 guideline diagnosis and therapy of cutaneous larva migrans (creeping disease)]

 Cord Sunderkötter ¹
Esther von Stebut ²
Helmut Schöfer ³
Martin Mempel ⁴
Dieter Reinel ⁵
Gerd Wolf ⁶
Volker Meyer ¹
Alexander Nast ⁷
Gerd-Dieter Burchard <sup>8,9

1</sup> Department of Dermatology and Venereology, Münster University Hospital, Münster, Germany
² Department of Dermatology, University Hospital of Mainz, Germany
³ Department of Dermatology, Venereology and Allergology, Johann Wolfgang Goethe University Hospital, Frankfurt, Germany
⁴ Elmshorn, Germany
⁵ Hamburg, Germany
⁶ Grafschaft-Ringen, Germany
⁷ Division of Evidence based Medicine (dEBM), Department of Dermatology, Venereology and Allergology, Charité – Universitätsmedizin Berlin, Germany
⁸ Division of Tropical Medicine and Infectious Diseases, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
⁹ ifi – Institute for Interdisziplinary Medicine, Hamburg, Germany

Abstract

Cutaneous larva migrans is a skin infection with a typical clinical appearance caused by active penetration of nematode larvae and their subsequent epidermal migration. The typical clinical appearance is caused by hookworm larvae, usually Ancylostoma braziliense but sometimes other canine or feline types of hookworm.

This guideline aims to enhance patient care by optimizing the diagnosis and treatment of infections due to creeping disease (cutaneous larva migrans) and to raise awareness among doctors of current treatment options.

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Guideline objectives

These guidelines aim to enhance patient care by optimizing the diagnosis and treatment of infections due to creeping disease (cutaneous larva migrans) and to raise awareness among doctors of current treatment options.

Methods

S1 guideline, non-systematic literature search, consensus process using a circular letter

Introduction

Cutaneous larva migrans is a skin infection with a typical clinical appearance caused by active penetration of nematode larvae and their subsequent epidermal migration. The typical clinical appearance is caused by hookworm larvae, usually Ancylostoma braziliense but sometimes other canine or feline types of hookworm. These hookworm larvae that are pathogenic to animals cannot reproduce in human beings.

Cutaneous larva migrans should be distinguished from larva currens. The latter is caused by Strongyloides stercoralis larvae and usually occurs on the trunk or buttocks. Migration is less irregular and produces broad, less clearly demarcated tracks on the extremities (progressing up to 5 cm per hour, hence the name larva currens) and usually disappears rapidly. This guideline does not address larva currens. Cutaneous larva migrans should also be distinguished from the symptom “creeping eruption” which is a migrating subcutaneous swelling with redness and urticaria of the overlying skin. It occurs, for instance, in gnathostomiasis, cutaneous paragonimiasis (Paragonimus infection), and fascioliasis (liver fluke infection by Fasciola hepatica). Similar migratory symptoms may also occur in myiasis (migratory myiasis) caused by fly larva.

Pathogens

In cutaneous larva migrans due to nematode larvae which are pathogenic to animals (Ancylostoma braziliense, Ancylostoma caninum, or Uncinaria stenocephala), the infection remains limited to the skin. The larvae penetrate the intact epidermis (e.g., feet, buttocks, or other exposed areas), presumably through the hair follicles or sweat glands, before entering the epidermis where they produce characteristic winding tracks. They do not penetrate the basement membrane. The speed of migration depends on the species, but it is generally dose not exceed one centimeter per day. The pruritic lesions are an expression of an immune response to the larvae and their products. These parasites attack mainly dogs and cats. Human infection is accidental, and the larvae die after only a few weeks.

Epidemiology

Cutaneous larva migrans is widespread in warm, sandy places (especially beaches) in South America, Africa, the Caribbean, Southeast Asia, the southern USA, and in Mediterranean regions [1].

Prevalence is high in regions with a warm, humid climate where people walk around barefoot and come into contact with animal excrement. In Germany, the disease is usually seen in patients who have vacationed in areas with beaches where there are infected, roaming animals. Analyses by international observation networks on disease in travelers and migrants have shown that cutaneous larva migrans is one of the most commonly imported skin diseases. A worldwide study found that cutaneous larva migrans makes up 10% of dermatological diagnoses in returning travelers [2]. Analyses from individual centers also report that cutaneous larva migrans is one of the most common diagnoses (e.g., in France [3] and Spain [4]).

Clinical appearance of larva migrans

A few days after contact with infected soil, a papule appears, then a winding tract develops and there is a local inflammatory reaction (Figure 1 [Fig. 1]). The incubation period can last days, weeks, or months [5]. Simultaneous infestation with multiple nematodes is also possible (Figure 2 [Fig. 2]). The tracts may be filled with serous fluid. Blisters may develop due to the inflammatory reaction. Pruritus is a typical symptom. Itching may begin before lesions appear, and it worsens significantly over the course of disease [6]. The cutaneous form of disease is self-limiting, because the larvae cannot survive in humans. Occasionally, lesions may persist for several months without histological detection of larvae; the cause is uncertain and may be due to persistence of larvae or a prolonged immune response to the larval debris [7]. A secondary bacterial infection (such as erysipelas) can develop from the initial entry site or because of excoriations. This complication is especially common in endemic regions.

Prophylaxis

Patients should wear shoes (or sandals) when walking on potentially contaminated beaches and soil. Bathers should not lie on the sand or even on towels, but rather should use a mattress or chair. Beachgoers should try to visit areas of the beach where the sand is regularly washed away by the tides. If possible, vacationers should avoid beaches where there are cats or dogs.

Diagnosis/differential diagnosis

The serpiginous exanthems are pathognomonic. Suspicion is confirmed by a history of travel and exposure.

In infestation with Strongyloides stercoralis, the lesions usually begin in the perineal region and spread in wide, and less sharply demarcated, tracks along the extremities, moving much more rapidly (up to 5 cm per hour, hence the name larva currens).

Indication for treatment

Infection with cutaneous larva migrans is self-limited and generally ends after 1–3 months with the death and resorption of the larvae. Treatment is mainly required because of the severe, lasting pruritus, the psychological burden of parasite infection, and the risk of a possible superinfection (such as after excoriation due to scratching).

Therapy

In Germany and other countries, for years the recommended treatment was topical thiabendazole in a lipophilic base [8]. Although there were virtually no studies, it was believed to have a broad therapeutic spectrum. Thiabendazole has not been approved for use in Germany since 1988, nor is it available in its pure form as a pharmaceutical grade drug.

After consulting the literature, and based on our own experience, we suggest the following treatment:

Adults and adolescents:

1. Ivermectin 1×200 µg/kg of body weight (Stromectol^® 3 mg, Mectizan^® 3 mg, Ivermec^® 6 mg, Revectina^® 6 mg tablet), oral administration. Patients should avoid eating anything for two hours before or after taking the medication. In general, a single dose is sufficient; if there is no improvement after 10 days, a second dose may be given [9]. In patients with severe disease, if ivermectin is unavailable, ineffective, or not well-tolerated, systemic albendazole may be an alternative.
2. Oral albendazole 800 mg/daily for 3 days (e.g., Eskazole^® 400 mg tablets). In young people weighing less than 60 kg who are more than 6 years old: 15 mg/kg of body weight up to a maximum of 800 mg/daily). If the drug is not tolerated (gastrointestinal complaints), reduce dosage to 400 mg/daily for 5 days.
   Take with meals in 2 single doses in the morning and evening.
3. Topical albendazole 10% in a lipophilic base (e.g., albendazole 1,200 mg which corresponds to 3 tablets of 400 mg in white Vaseline ad 12.0) three times daily for 7–10 days. Apply generously. Used mainly in children weighing less than 15 kg (no ivermectin) and children under age 6 (inadequate experience with albendazole). Also used in patients with discrete lesions (e.g., a single lesion or mild itching) or those who refuse systemic therapy. (See also comments below on treatment with topical albendazole).
   To reduce inflammation and itching, we also recommend brief topical treatment (1–5 days) with a corticosteroid cream (expert opinion) and, if necessary, systemic antihistamines to stop the itching.

Pregnancy and nursing:

Ivermectin and albendazole must not be used by pregnant women. We can only recommend the symptomatic treatment described above; to alleviate inflammation and itching, topical treatment consisting of a corticosteroid cream may be given. If necessary, systemic antihistamines, which are approved for use in pregnant women, may be administered as well to stop the itching.

Effective treatment significantly reduces itching in 3 days and dermatitis after 7 days.

The following treatments are not recommended:

1. Topical mebendazole. Reasons: a) Compared to albendazole, it appears to be less effective in larva migrans (and in general against hookworms) [10], [11]; b) intestinal resorption is inadequate, and thus at normal dosages, it is effective against intestinal nematodes, but not against nematodes in tissue; c) we found no publications on systemic administration of mebendazole to treat larva migrans.
2. Cryotherapy (although sometimes advised), given that the location of the larvae (usually 1–2 cm around the visible end of the track) is not precisely known [12] and their low sensitivity to cold skin temperatures (>5 minute survival at –21°C).

Comments on ivermectin

Ivermectin is approved for use in Germany only in veterinary medicine and is sold under the name Eraquell Tabs^® 20 mg. In France, Belgium, and the United States, the drug is approved for use in humans for the treatment of the related visceral form of strongyloidiasis due to Strongyloides stercoralis.

The tablets may be obtained from foreign pharmacies as Stromectol^® 3 mg, Ivermec^® 6 mg, or Revectina^® 6 mg (N1). The patient should be informed that ivermectin is not available in Germany nor officially recommended in other countries as larva migrans treatment. The discussion and the risk/benefit assessment of off-label use should be documented in the patient’s file.

Its use is contraindicated in children weighing less than 15 kg and in pregnant women. Adverse effects limiting its use are transitory and have rarely been reported, despite having been used millions of times to treat onchocercosis [13].

Comments on systemic albendazole

Systemic albendazole is currently only available in packages containing 60 tablets (N3) which cost 590.38 € (imports: 549.09–556.09 €/Prices from: 05/2013, as Eskazole^® [14]). Smaller sizes would be desirable, given that the incidence of larva migrans is more than negligible, and thus small amounts are needed rather frequently.

Pharmacies that provide Eskazole^® have the right to charge for the entire package, even if only 6 tablets are used in accordance with the legally binding. Hospital pharmacies may only charge for the amount actually used. Theoretically, one could apply this to pharmacies as well, but such a change conflicts with the “pharmacy tax”. Albendazole is approved as an anthelminthic in Germany, including for attempted treatment of Strongyloides stercoralis (see above) infections, but not for treatment of larva migrans, so that treatment of the latter is off-label. Patients should be informed of this, and the discussion as well as the risk/benefit assessment should be documented in the patient’s file.

Comments on topical albendazole

The suggested formulation is based on a case report [15] albendazole 1.2 g, white Vaseline ad 12 g.

One co-author uses albendazole 10.0, paraffin oil 10.0, white petrolatum ad 100.0.

If Eskazole^® is prescribed, the pharmacy has the right to charge full price, even if only 3 tablets are needed (see above).

Albendazole has also been offered since 2013 to pharmacies in its pure form (Fagron, Barsbüttel, Germany). This would reduce the cost of producing a topical treatment. In our own experience, there have been problems obtaining the product, apparently due to impure substances from different providers. In addition, after delivery of a pure substance with a certificate of analysis, before creating the albendazole formulation, the pharmacy must also conduct an analysis for identification of the substance using infrared spectroscopy and thin-layer chromatography. Yet, only a few pharmacies can perform infrared spectroscopy.

Thus physicians should first find out (a) which pharmacy can perform the identification procedure, and (b) whether it can order albendazole. The pharmacy may need to order, and pay for more (if there is a minimum amount) than an individual prescription requires.

If these requirements are met, however, the cost is much lower for the patient than topical Eskazole^®. We therefore recommend for centers which often treat patients with larva migrans that they contact a pharmacy, discuss the situation, and establish cooperation with that pharmacy to avoid having to start from scratch each time.

Assessment of effectiveness

There are only a few comparative prospective randomized studies on effectiveness of the drug. A single administration of ivermectin (n=10 patients) was shown in one comparative randomized study to be more effective than 400 mg albendazole (n=11 patients) [16]. Compared to albendazole, ivermectin was shown in a prospective study on strongyloidiasis (i.e., a disease caused by a related type of worm) that a single dose was more effective than a 7-day regimen of 800 mg albendazole [17].

In addition to comparative studies, there are a number of partly retrospective analyses on individual medications.

Ivermectin: Two smaller studies from the 1990s showed a single dose to be effective in patients in Cameroon and in French tourists [18], [19]. These findings were later confirmed by larger studies [9]. In a study done in Paris, 62 Europeans were treated with ivermectin; after receiving a single dose, the healing rate was 77%; it was 97% in patients who received one or two additional doses [20]. Another study from France reported healing in 59 out of 62 patients who were treated with ivermectin [21]. A study from an endemic region in Brazil reported that all 92 patients, some of whom had severe disease, had a significant response 2–4 weeks after being given a single dose of 200 µg/kg of body weight [22].

Albendazole: A retrospective study that included 78 patients with cutaneous larva migrans found that, after being given 1×400 mg/daily of oral albendazole, all patients healed after 7 days. Two patients reported nausea or increased pruritus related to the drug [23]. Other published case series and retrospective analyses have reported different dosages and treatment durations. Three days of 800 mg/daily reportedly led to healing in 100% of patients; 400 mg/daily led a few treatment failures [24], [25]. At a dosage of 800 mg/daily, the rate of side effects is higher (usually gastrointestinal complaints) than with ivermectin [26].

For topical albendazole therapy, we found a case report [15] and a recommendation in the framework of a review [11]. In one case report, topical albendazole was given to 2 children, and led to recurrence-free healing 1 week after treatment [15]. Other than this case report, there are insufficient data on skin penetration, effectiveness, and tolerability. The authors of the present guidelines have also successfully treated individual patients with topical application of 10% albendazole. The recommendation to generously apply albendazole 10% in a lipophilic base 3 times daily for 7–10 days arose analogous to the thiabendazole-based formulation that was formerly used and according to the published case report. The size of the area of application is based on the knowledge that the larvae often migrate several centimeters farther than the inflammation.

Corticosteroids: There is no direct evidence of the effectiveness of accompanying local treatment with corticosteroids to alleviate the inflammation and itching in patients with larva migrans.

Notes

Validity

The present guidelines are valid until April 2017. The need for an update will be decided on by the authors. Date created: May 2013.

ICD Code (ICD 10)

B76.9

AWMF registry number

013/087

Conflicts of interest

See Attachment 1 [Att. 1].

Financing

The guidelines were financed solely by the authors. No funding was received and there was no outside influence on the contents of the guidelines.

Permissions

Authorized by Deutsche Dermatologische Gesellschaft (DDG).

Authorized for electronic publication: AWMF online.

Publication in GMS ID has been permitted by John Wiley & Sons Ltd in the context of the inderdisciplinary compilation of these guidelines in cooperation with the PEG (originally published in Journal der Deutschen Dermatologischen Gesellschaft 2014 [27]).

Cooperating professional associations and their representatives

• The German Society of Dermatology (DDG)/Working Group on Dermatological Infectious Diseases and Tropical Dermatology (ADI-TD): E. von Stebut-Borschitz, H. Schöfer, M. Mempel, D. Reinel, V. Meyer, A. Nast, C. Sunderkötter
• German Society for Tropical Medicine and International Health e.V. (DTG): G.-D. Burchard, D. Reinel
• Society for Dermatology in the Tropics: D. Reinel
• Paul-Ehrlich-Gesellschaft: C. Sunderkötter

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References

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[27] Sunderkötter C, von Stebut E, Schöfer H, Mempel M, Reinel D, Wolf G, Meyer V, Nast A, Burchard GD. S1 guideline diagnosis and therapy of cutaneous larva migrans (creeping disease). J Dtsch Dermatol Ges. 2014 Jan;12(1):86-91. DOI: 10.1111/ddg.12250

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Attachments

Attachment 1	Conflicts of interest (in German) (Anhang1_id000011.pdf, application/pdf, 119.14 KBytes)