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Cutaneous Larva Migrans

Article  in  Recent Patents on Inflammation & Allergy Drug Discovery · January 2017

DOI: 10.2174/1872213X11666170110162344

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Recent Patents on Inflammation & Allergy Drug Discovery 2017, 11, 2-11
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Cutaneous Larva Migrans

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Recent Patents on Inflammation & Allergy Drug Discovery

Alexander K.C. Leung1,*, Benjamin Barankin2 and Kam L.E. Hon3

1
Department of Pediatrics, The University of Calgary, Alberta Children’s Hospital, Calgary, Alberta, Canada; 2Toronto
Dermatology Centre, Toronto, Ontario, Canada; 3Department of Paediatrics, The Chinese University of Hong Kong,
Shatin, Hong Kong

ARTICLE HISTORY
Received: December 20, 2016
Revised: January 1, 2017
Accepted: January 9, 2017
DOI:
10.2174/1872213X11666170110162344
Keywords: Ancylostoma braziliense, Ancylostoma caninum, cats, dogs, hookworm, pruritus, serpiginous track.
Abstract: Background: Cutaneous larva migrans is one of the most common skin diseases reported in
travelers returning from tropical regions. Western physicians, however, are often not familiar of this
condition.
Objective: To review in depth the epidemiology, pathophysiology, clinical manifestations, complica-
tions, and treatment of cutaneous larva migrans.
Methods: A PubMed search was completed in Clinical Queries using the key term “cutaneous larva
migrans”. The search included meta-analyses, randomized controlled trials, clinical trials, and reviews.
Patents were searched using the key term “cutaneous larva migrans” from www.google.com/patents,
www.uspto.gov, and www.freepatentsonline.com.
Results: Cutaneous larva migrans is a zoonotic infestation caused by penetration and migration in the
epidermis of filariform larva of different kinds of animal hookworms through contact with feces of
infected animals. Cutaneous larva migrans is endemic in tropical and subtropical regions. Clinically,
cutaneous larva migrans is characterized by an intensely pruritic erythematous migrating tortuous or
serpiginous, slightly raised track. The diagnosis is mainly clinical, based on the history of travel to an
endemic area and exposure to contaminated soil/sand and the characteristic serpiginous track. Treat-
ment options as well as recent patents related to the management of cutaneous larva migrans are also
discussed. Compared with oral antihelminthics, topical treatment over the affected area is less effec-
tive. Oral ivermectin is the treatment of choice.
Conclusion: The pruritic serpiginous track is pathognomonic. Oral ivermectin is the treatment of choice.

1. INTRODUCTION
Cutaneous larva migrans is a zoonotic infestation caused
by penetration and migration in the epidermis of filariform
larva of different kinds of animal hookworms through con-
tact with feces of infected animals, mostly dogs and cats [1-
3]. Clinically, cutaneous larva migrans is characterized by a
pruritic erythematous migrating tortuous or serpiginous,
slightly raised track [1]. The condition was first described by
Lee, a British physician, in 1874 [3]. The term "cutaneous
larva migrans" was coined by Crocker in 1893 [4]. Syno-
nyms include creeping eruption, sandworm disease, beach
worm disease, ground itch, linear serpiginous dermatitis,
dermatitis serpiginosus, migrant helminthiasis, migrant linear
epidermatitis, epidermatitis linearis migrans, creeping ver-
minous dermatitis, duck hunter's itch, and plumber's itch
[5-7]. Although some authors use the term "cutaneous larva
migrans" and "creeping eruption" interchangeably, Caumes
et al. rightly pointed out that cutaneous larva migrans is a
syndrome whereas creeping eruption is a clinical sign which
can be caused by various parasites [8]. Suffice to say, hook-
worm-related cutaneous larva migrans is the most common
cause of a creeping eruption [9].
Cutaneous larva migrans is one of the most common skin
diseases reported in travelers returning from tropical regions
[10]. Western physicians, however, are often not familiar of
this condition. As a matter of fact, the initial diagnosis is
only correct in less than 55% of cases. Misdiagnosis of
course leads to inappropriate or delayed treatment. A review
of the topic is therefore in order and is the purpose of the
present communication.

*Address correspondence to this author at The University of Calgary, Al- 2. EPIDEMIOLOGY

berta Children’s Hospital, #200, 233 – 16th Avenue NW, Calgary, Alberta,
Canada T2M 0H5; Tel: (403) 230 3300; Fax: (403) 230-3322;
Cutaneous larva migrans affects millions of people
E-mail: aleung@ucalgary.ca worldwide [11]. The condition is common in individuals

2212-2710/17 $100.00+.00 © 2017 Bentham Science Publishers

Cutaneous Larva Migrans Recent Patents on Inflammation & Allergy Drug Discovery 2017, Vol. 11, No. 1 3
residing in tropical and subtropical regions, especially in
developing countries [9]. In a rural community in Brazil,
approximately 4.4% of the general population and 15% of
children have been found to be infested [9, 12].
Cutaneous larva migrans is the most common ectoparasi-
tosis acquired by travelers returning from tropical and sub-
tropical regions [6]. In one study, cutaneous larva migrans
accounted for approximately 10% of dermatological diagno-
ses in sick travelers returning from tropical regions [13]. In
another study, 1463 of 13,300 patients who attended a travel-
related-disease clinic during a period of 4 years had skin
symptoms [14]. Of the 1463 patients, 98 (6.7%) patients had
cutaneous larva migrans [14]. Prevalence is high in geo-
graphic regions with a warm and humid climate where indi-
viduals tend to walk barefoot and come in contact with feces
of dogs and cats [15]. This is especially so in rainy season
when the risk of infestation may be 15 times higher [9, 16].
Cutaneous larva migrans is endemic in Central and South
America, Mexico, Caribbean, Africa, Southeast Asia, Medi-
terranean regions, the southeastern parts of the United States,
and other tropical areas [15-18]. The exact prevalence among
returning travelers is not known, but it is bound to increase
in parallel with the popularity of travel to subtropical and
topical areas. The disease is very rarely acquired in temper-
ate areas [16]. Notwithstanding this, autochthonous cases in
persons without a history of foreign travel have rarely been
reported in European countries such as the United Kingdom,
Germany, France, and Italy, presumably because of global
warming [19-26].
There is no racial or sex predilection because the disease
depends on exposure [13]. The condition is more common in
children than in adults [13, 18, 27]. Individuals whose hob-
bies and occupations bring them in contact with contami-
nated soil or sand are at risk for cutaneous larva migrans;
these individuals include travelers, swimmers, sunbathers,
hunters, plumbers, miners, carpenters, farmers, gardeners,
fishermen, and pest exterminators [18]. Poor hygiene and
poor sanitation are important predisposing factors [11, 27].
3. CAUSATIVE ORGANISMS
Cutaneous larva migrans is caused by the filariform lar-
vae of animal (notably dogs and cats) hookworms. The most
common causative larva is Ancylostoma braziliense (hook-
worm of wild and domestic dogs and cats) followed by An-
cylostoma caninum (dog hookworm) [7, 18]. Other causative
larvae are Uncinaria stenocephala (dog hookworm),
Bunostomum phlebotomum (cattle hookworm), and Ancy-
lostoma ceylonicum (dog and cat hookworm) [2, 7, 28-30].
Ancylostoma caninum and Uncinaria stenocephala have,
occasionally, been isolated from foxes [28].
The adult hookworms infest the intestines of the definite
host animals [29, 31]. Their eggs are excreted in their feces
and contaminate the surrounding soil or sand. Under optimal
environmental conditions (moisture, shade, and warmth), the
embryonated eggs hatch in the superficial layer of the soil
within two days [31, 32]. The released rhabditiform larvae
feed on the bacteria in the soil and/or feces [31, 32]. These
larvae mature and molt twice in 5 to 10 days to become fi-
lariform larvae which are infective [18]. The filariform lar-
vae can survive a few weeks to even a few months under
optimal conditions [9, 10, 18]. The larva of Ancylostoma
braziliense, the most common causative larva, on average,
measures approximately 6.5 mm long and has a diameter of
0.5mm [33-35].
4. DISEASE TRANSMISSION
Humans are accidental hosts and become infected when
the filariform larvae come into direct contact and penetrate
the stratum corneum. The larvae usually live in the superfi-
cial layer of the sand/soil, within inches of where the eggs
are deposited [27]. Beaches are a common reservoir for the
filariform larvae. Human infection typically occurs after
walking barefoot or with open-type shoes or lying undressed
on the sand/soil, especially sandy beaches, contaminated by
feces of infected dogs and cats [29, 36]. The larvae can also
be found in sandpits, and loose soil at construction sites, gar-
dens, fields, or under houses [30, 37]. Simultaneous infesta-
tion with larvae of other hookworm species may also occur
[15].
5. PATHOPHYSIOLOGY
Because of the proteases and hyaluronidase that they
secrete, the filariform larvae can penetrate fissures, hair fol-
licles, sweat glands and even intact skin by digesting the
keratin in the epidermis [29-31]. After penetrating the skin,
the filariform larvae shed their cuticle [38]. Until then, the
larvae do not have functioning mouth parts [38]. After the
cuticle has been shed, the larvae start migration in approxi-
mately 7 days [39]. The larvae lack the collagenase enzyme
and therefore cannot penetrate the basement membrane to
invade the dermis and reach blood or lymphatic vessels to
ultimately reach the intestine and complete their life cycle, as
they would do so in an appropriate animal host [9]. As such,
the larvae remain confined to the epidermis. The larvae creep
or wander aimlessly within the epidermis in a serpiginous
route at a rate of 2mm to 2cm per day [7, 18]. The speed of
migration varies depending on the species of the larva, but
generally does not exceed 1cm a day [15, 18, 35, 40, 41].
The larvae usually die in the subcutaneous tissue in 2 to 8
weeks without being able to complete their life cycle in the
human body [18, 32, 35, 36, 42]. In other words, humans are
a dead-end host for the larvae. In spite of this, migration to
internal organs has, very rarely, been reported [29, 43, 44].
6. CLINICAL MANIFESTATIONS
A stinging or tingling sensation may be experienced
within 30 minutes of the larva penetrating the skin [6, 30]. A
few hours later, an itchy reddish-brown papule or nonspe-
cific eruption may be noted at the site of penetration [6, 45].
The incubation period is about 5 to 15 days, with a range of a
few minutes to 165 days; during which time the larvae lie
dormant [39, 40, 46-49]. After the incubation period, the
larva start migrating and wandering freely in the epidermis,
resulting in the formation of an erythematous, slightly raised,
tortuous, winding, serpiginous or, less often, linear track
extending from the reddish-brown papule - the site of larval
penetration [28, 39]. The pruritic serpiginous track is
pathognomonic (Fig. (1)) [15]. Papular and vesicular lesions
may be present in conjunction with the track [41]. The width
of the track ranges from 1 to 4mm [1, 50]. The length is
4 Recent Patents on Inflammation & Allergy Drug Discovery 2017, Vol. 11, No. 1
Fig. (1). A 35-year-old man with cutaneous larva migrans on the
left leg. Note the serpiginous tracks.
highly variable and may reach 20cm in length [10, 16, 40].
The lesion is intensely pruritic [42]. The track created by the
migrating larva desiccates with time after the death of the
parasite and is covered with a scab [10].
Sites of predilection include the ankles, feet, legs, but-
tocks, and thighs [1, 2, 35]. Basically, any part of the body
which has direct contact with the contaminated soil/sand can
be affected. Unusual sites include the face [51], scalp [5],
upper extremities [52], trunk [52], abdomen [11, 42], breast
[30], oral cavity [30], genitalia [1, 7, 53], and the perineal
areas [54]. Lesions are usually unilateral and solitary [35],
but may be bilateral and multiple [30]. Most affected indi-
viduals have one to three lesions [18]. Rarely, affected indi-
viduals have hundreds of lesions [27].
Follicular cutaneous larva migrans, also known as hook-
worm folliculitis, is a clinical variant and accounts for less
than 5% of cases [18]. In contrast to the classical form, this
variant is more common in adults than in children [50]. The
condition is characterized by numerous (20 to 100), intensely
pruritic, erythematous, follicular papules that are sometimes
surmounted or topped with vesicles or pustules with or with-
out a serpiginous or linear track [18, 38, 50, 55]. The track, if
present, is usually short [18]. Characteristically, a hair shaft
is generally not seen in the center of the papule [56]. Nodular
lesions have also been described [50, 57, 58]. Sites of predi-
lection include the buttocks, inguinal regions, forearms, ab-
domen, back, flanks, and thighs [10, 29, 50]. It is believed
that the condition is due to invasion of the larva through the
hair follicular canal and the folliculitis results from an aller-
gic reaction to the larva [55, 59]. Follicular cutaneous larva
migrans is more resistant to treatment because the larva is
located deep in the hair follicle [50, 60].
Leung et al.
Bullous cutaneous larva migrans is another clinical vari-
ant which is quite rare [6, 61-64]. The bulla occurs along a
track, contains a clear serous fluid, and may reach several
centimeters in diameter [50, 61, 63]. Presumably, bullae may
result from a delayed hypersensitivity or contact dermatitis
(be it irritant or allergic) to larval antigens or lytic enzymes
released by the larva [6, 62, 63].
7. DIAGNOSIS
The diagnosis is mainly clinical, based on the history of
travel to an endemic area and exposure to contaminated
soil/sand and the characteristic serpiginous track. Unfortu-
nately, the initial diagnosis is correct in less than 50% of
cases [65, 66].
8. DIAGNOSTIC STUDIES
The diagnosis can be aided by dermoscopy which typi-
cally shows translucent, brownish, structureless areas in a
segmental arrangement corresponding to the body of the
larva and red-dotted vessels corresponding to an empty bur-
row [35, 67]. However, dermoscopy fails to identify the
larva in a significant number of cases [33]. Near-infrared
fluorescence imaging of the lesion gives a better yield [33].
Confocal scanning laser microscopy may also be used to
detect the highly refractile larva and a dark disruption in the
normal honeycomb epidermis corresponding to the burrow
[35, 68]. Laboratory investigations such as eosinophil count
in the peripheral blood and serum IgE levels are usually not
helpful in making the diagnosis [29, 56]. Biopsy is usually
not necessary or helpful as the larva is usually 1 to 2cm
ahead of the advancing end of the visible serpiginous track
[18, 35, 42]. Should a biopsy be obtained 1 to 2cm ahead of
the visible serpiginous track and the larva (PAS-positive) be
found, the larva is usually seen residing in a hair follicle, or
more often, in a suprabasalar burrow within the epidermis
along with an eosinophilic infiltrate, spongiosis, and intra-
epidermal vesiculation with necrotic keratinocytes [30, 59,
69]. Suffice to say, a skin biopsy has low sensitivity and it is
difficult to identify the larva in a biopsy specimen [40]. In
one study, the larvae were found in 8 of 300 biopsy speci-
mens [70]. As such, the species of animal hookworm causing
the cutaneous larva migrans in individual cases is usually
unknown.
9. DIFFERENTIAL DIAGNOSIS
The differential diagnosis includes larva currens
(strongyloidiasis), migratory (creeping) myiasis, loiasis, cer-
carial dermatitis, gnathostomiasis, dirofilariasis, dracunculia-
sis, tungiasis, scabies, herpes zoster; tinea corporis, contact
dermatitis, and bacterial folliculitis [2, 45, 71-76].
Larva currens (strongyloidiasis), caused by Strongyloides
stercoralis, is characterized by a rapidly migrating urticarial
or maculopapular, pruritic, linear or serpiginous, eruption
[40]. The eruption usually starts in the perineum and then
spreads to the buttocks and thighs [40]. The larva migrates at
a rate of 5 to 15 centimeters per hour, hence the name "run-
ning" larva [18, 77-79]. In contrast, the dog or cat hookworm
larva seen in cutaneous larva migrans typically migrates
much less quickly at a rate of 2mm to 2cm per day, depend-
ing on the species of the larva [2, 40, 41].
Cutaneous Larva Migrans Recent Patents on Inflammation & Allergy Drug Discovery 2017, Vol. 11, No. 1 5
Migratory (creeping) myiasis is caused by larvae of the
horse (Gasterophilus intestinalis) and cattle (Hypoderma
ovis and Hypoderma lineatum) bot flies [80, 81]. Migratory
myiasis caused by G. intestinalis presents with a superficial
serpiginous track. Compared to cutaneous larva migrans,
migratory myiasis moves more slowly and the serpiginous
track is less widespread [81, 82]. Migratory myiasis caused
by H. ovis and H. lineatum is deeper and presents with tender
subcutaneous nodules in the absence of a serpiginous track
[45, 81].
Loiasis, caused by the filarial nematode Loa loa, is
transmitted to humans through the bites of deerflies of the
genus Chrysops [83]. Clinically, loiasis may present as visi-
ble movement of the adult worm under the conjunctiva of the
eye (hence the name "eye worm") and migratory angioedema
known as Calabar swellings [84, 85]. Calabar swellings, pre-
sumably due to a hypersensitivity reaction to the migrating
larva, occur predominately on the legs and arms and are of-
ten associated with localized and/or generalized pruritus [83,
84]. The swellings can last from hours to several days [78].
Cercarial dermatitis (swimmer's itch) follows penetration
of the human skin by cercariae of nonhuman schistosome
flukes [86]. Clinically, cercarial dermatitis presents as an
intensely pruritic maculopapular rash within hours to a day
after exposure to water contaminated with schistosomes re-
leased from infected snails. Typically, the rash is non-
migratory which helps to distinguish it from cutaneous larva
migrans [45].
Gnathostomiasis, also known as larva migrans profundus,
is caused by the infective third stage larva of Gnathostoma
species, notably G. spinigerum and G. bispidum [32, 87].
Humans acquire the infestation after consuming inadequately
cooked fish, shellfish or amphibians that contain the infec-
tive larvae [32, 88]. The cutaneous variant presents with in-
termittent migratory cutaneous or subcutaneous swellings or
nodules [87]. In contrast to cutaneous larva migrans, the le-
sions are usually deeper and may involve muscles [89].
Dirofilariasis is caused by the zoonotic filarial worms of
the Dirofilaria species, notably D. repens and D. tenuis; the
natural hosts of which are dogs and wild canines [90]. When
mosquitoes feed on the infected animal, the microfilariae are
ingested with the blood meal [91]. Humans acquire the infec-
tion via bites from mosquitoes carrying the infective microfi-
lariae [91]. The larva wanders in the subcutaneous tissue and
produces an asymptomatic, non-migratory, subcutaneous
nodule [90]. Sites of predilection include the extremities,
head, and neck [90].
Dracunculiasis, also known as guinea-worm disease, is
caused by drinking water contaminated with parasite-
infected water-fleas (Cyclops species) that have ingested
guinea-worm larvae (Dracunculus medinensis). After matu-
ration into adult worms and copulation, the male worms die
and the female worms migrate in the subcutaneous tissue
towards the skin surface [92]. Clinically, subcutaneous
dracunculiasis presents as a painful papule, most commonly
on the lower extremities but may occur on the genitalia and
buttocks. Worms may emerge from the papule.
Tungiasis is an ectoparasitic infestation caused by the
penetration of the gravid female sand flea Tunga penetrans
into the skin [93]. Both female and male fleas are hemato-
phagous [93]. The male flea dies after copulation while the
female flea burrows into the human epidermis where it
grows as large as 10mm in diameter as its fertilized eggs
mature. Clinically, the condition presents as a non-migratory
papule or nodule with a central black dot. The latter repre-
sents the ano-genital opening of the female flea through
which she expels feces and passes eggs [93]. The lesion can
be asymptomatic, painful, or pruritic [93, 94]. The majority
of the lesions are located on the feet.
Scabies is a skin infestation caused by the parasite mite
Sarcoptes scabiei var hominis. Clinically, scabies is charac-
terized by burrows, an erythematous papular eruption, and
intense pruritus [76]. Burrows, which are pathognomonic of
the disease, appear as serpiginous grayish, whitish, reddish,
or brownish lines several millimeters long in the upper epi-
dermis [76]. Sites of predilection include the interdigital web
spaces and flexor aspects of wrists.
Occasionally, cutaneous larva migrans, especially the
bullous variant, can mimic herpes zoster [88, 95]. Clinically,
herpes zoster is characterized by a painful, unilateral vesicu-
lar eruption in a restricted dermatomal distribution. Herpes
zoster has a predilection for areas supplied by the cervical
and sacral dermatomes in young children and the lower tho-
racic and upper lumbar dermatomes in adults [72, 73, 75].
On the other hand, the eruption seen in cutaneous larva mi-
grans is intensely pruritic rather than painful, is more com-
mon in the lower extremities and buttocks, does not follow
any dermatome, and progresses in an unpredictable manner
resulting in the formation of a serpiginous track.
Tinea corporis refers to a superficial fungal infection of
the skin most often caused by Trichphyton rubrum, T. ton-
surans, and Microsporum canis [74]. Typically, tinea cor-
poris presents as a sharply circumscribed, well-demarcated,
annular, erythematous plaque with a raised leading edge and
scaling [74]. The border can be papular, vesicular, or pustu-
lar. The lesion spreads centrifugally and clears centrally to
form the characteristic lesion commonly known as “ring-
worm” [74]. Tinea corporis tends to be asymmetrically dis-
tributed. When multiple lesions are present, they may be-
come coalescent. Mild pruritus is common.
Contact dermatitis results from either exposure to aller-
gens (allergic contact dermatitis) or irritants (irritant contact
dermatitis). Typically, the lesion is eczematous and occurs
only in an area which has been in contact with the irritant or
allergen agent. It does not have a serpiginous appearance.
Follicular cutaneous larva migrans should be differenti-
ated from bacterial folliculitis. Bacterial folliculitis typically
presents as follicular, erythematous, maculopapules and fol-
licular pustules in a hair-bearing area. A hair shaft may be
seen at the center of the lesion. The lesions may be painful,
tender or mildly pruritic. In contrast, follicular cutaneous
larva migrans is intensely pruritic and a hair shaft is not seen
in the center of the lesion [56]. Unlike bacterial folliculitis,
follicular cutaneous larva migrans does not respond to anti-
biotic therapy.
10. COMPLICATIONS
Pruritus may cause sleep disturbance [27, 31]. Repeated
scratching may lead to excoriation and secondary bacterial
6 Recent Patents on Inflammation & Allergy Drug Discovery 2017, Vol. 11, No. 1
infection and eczematization [17, 27, 45]. Localized and/or
generalized allergic reactions are among other complications.
In previously sensitized individuals, erythema multiforme
may occur [29]. The psychosocial consequences can be sig-
nificant and may have an adverse effect on the quality of life
[31, 96].
Rarely, cutaneous larva migrans may be complicated by
optic disease edema and Löffler syndrome [45, 97]. Löffler
syndrome is characterized by migratory pulmonary eosino-
philic infiltrates and peripheral blood eosinophilia [98, 99].
Affected patients may present with fever, malaise, cough,
substernal discomfort, and blood-tinged sputum containing
Charcot-Leyden crystals [98]. Löffler syndrome is consid-
ered as a type 1 hypersensitivity reaction to the larva or its
soluble antigen [45, 64, 98, 99].
11. PROGNOSIS
The prognosis is excellent [17, 41]. The disease is self-
limited and usually resolves in weeks to months even with-
out treatment [18, 41]. Rarely, the larva may persist in the
hair follicle for up to two years [18, 52, 55].
12. MANAGEMENT
Treatment is often necessary to shorten the course of the
disease because of the intense pruritus and potential compli-
cations associated with the disease [17]. Untreated, the pruri-
tus may last for 3 months or even longer [100]. Appropriate
treatment hastens resolution of the lesion and the associated
symptoms and reduces the likelihood of complications.
Compared with oral antihelminthics, topical treatment over
the affected area is less effective since the larva is mobile
and the exact location of the larva is not precisely known
[40, 101].
12.1. Oral Antihelmintic Agents
Oral Ivermectin: Ivermectin (Stromectol, Mectizan,
Revectina, Ivermec), a macrocyclic lactone, is a semisyn-
thetic avermectin derived from the bacterium Streptomyces
avermitilis [99]. William Campbell and Satoshi Omura were
credited for the development of avermectin and ivermectin
and were awarded the Nobel Prize in Medicine in 2015 [102-
104]. The medication works by stimulating excessive release
of neurotransmitters in the peripheral nervous system and
increasing the permeability of cell membrane of the
helminth, resulting in the paralysis and death of the helminth.
Oral ivermectin in a single dose of 12mg in adults (150 to
200mcg/kg in children, maximum 12mg) is the treatment of
choice for cutaneous larva migrans [10, 18, 15, 29, 35]. The
medication should be given on an empty stomach with water.
If a single dose does not result in much improvement, a sec-
ond dose should be given [15]. As follicular cutaneous larva
migrans is more resistant to treatment, adult patients should
be treated with 12mg (150 to 200mcg/kg in children; 12mg,
maximum) of ivermectin twice a day for several days [18,
60]. Side effects include anorexia, nausea, vomiting, ab-
dominal pain, constipation, dizziness, xerosis, burning skin,
flushing, eye pain, red eye, transient tachycardia, and hy-
potension. Oral ivermectin is contraindicated during preg-
nancy, in children under 5 years of age or less than 15kg, and
Leung et al.
in those with hepatic or renal disease [10, 15, 105]. The
medication should be avoided in breastfeeding mothers.
Oral Albendazole: Chemically, albendazole (Eskazole;
Albenza, Andazol, Alworm, Noworm, Alben-G, ABZ, Cida-
zole, Zentel) is methyl 5-(propylthio)-2-benzimidazole car-
bamate. The medication works by causing degeneration in
the intestinal cells of the helminth by binding to the colchi-
cine-sensitive cells of tubulin, thereby preventing its polym-
erization into microtubules [27]. This in turn leads to im-
paired uptake of glucose by the helminth, and ultimately, to
its death [27].
In case oral ivermectin is not available, not tolerated, or
ineffective, oral albendazole is a treatment option [100]. The
medication is usually given at a dose of 10 to 15mg/kg (800
mg, maximum) divided into 2 doses for 3 to 5 days [18, 35,
100]. The optimal duration of treatment has not been estab-
lished as 1 to 7 days of treatment has also been recom-
mended [10, 28]. Some authors suggest a 7-days course of
treatment for patients with multiple and extensive lesions
and for those with Löffler syndrome [35, 106]. The medica-
tion should be taken with meals. Side effects include nausea,
vomiting, abdominal pain, dizziness, headache, reversible
thinning of hair or hair loss, fever, rash, increased intracra-
nial pressure, bone marrow suppression, and hepatic dys-
function. Oral albendazole is contraindicated during preg-
nancy and in those with hematologic or hepatic disease [15,
104]. The medication should be avoided in breastfeeding
mothers.
In an open study, Caumes et al. compared the efficacy of
single doses of oral ivermectin (12mg) and oral albendazole
(400mg) for the treatment of cutaneous larva migrans [107].
Twenty one patients were randomized to receive ivermectin
(n = 10) and albendazole (n = 11). The authors found that the
all 10 patients who received oral ivermectin responded and
none relapsed. On the other hand, 10 of the 11 patients who
received oral albendazole responded, but 5 of the 10 patients
who responded to oral albendazole relapsed after a mean of
11 days (range, 3 to 35 days). Caumes et al. concluded that a
single oral dose of 12mg of ivermectin is more effective than
a single oral dose of 400mg of albendazole for the treatment
cutaneous larva migrans.
Oral Thiabendazole: Thiabendazole (Mintezol) is a
benzimidazole derivative with antihelminthic property.
Thiabendazole works by inhibiting the helminth-specific
mitochondrial enzyme fumarate reductase, thereby inhibiting
the citric acid cycle, mitochondrial respiration and subse-
quent production of ATP, ultimately leading to the death of
the helminth. Oral thiabendazole at doses of 25 to
50mg/kg/day (2.5g/day, maximum) given twice daily for 2 to
5 days is effective in the treatment of cutaneous larva mi-
grans [27, 29, 79]. The tablet formulation must be chewed
before swallowing and taken after meals. Side effects are
common and include anorexia, nausea, vomiting, abdominal
cramps, diarrhea, blurred vision, dizziness, and headaches
[10]. The medication is contraindicated during pregnancy.
Because of the high incidence of side effects and poor toler-
ance, the medication is no longer recommended for the
treatment of cutaneous larva migrans [10, 29, 31]. The medi-
cation has been taken off the market in many countries in-
cluding Canada and the United States.
Cutaneous Larva Migrans Recent Patents on Inflammation & Allergy Drug Discovery 2017, Vol. 11, No. 1 7
12.2. Topical Antihelmintic Agents
Topical Albendazole: Topical albendazole 10% in a
lipophilic base applied under occlusion three to four times a
day for 5 to 10 days may be considered for patients with lo-
calized lesion in whom oral antihelminthics are contraindi-
cated or not tolerated [10, 15]. It is a reasonable alternative
for young children and pregnant women. Side effects include
irritant contact dermatitis and skin ulceration.
Topical Thiabendazole: Topical thiabendazole 10 to
15% in a lipophilic base applied under occlusion three to
four times a day for 5 to 10 days may be considered for pa-
tients with localized lesion in whom oral antihelminthics are
contraindicated or not tolerated [10, 15]. It is a reasonable
alternative for young children and pregnant women. Side
effects include irritant contact dermatitis and skin ulceration.
12.3. Cryotherapy
Prior to the availability of antihelminthics, cryotherapy
with liquid nitrogen was at one time used for the treatment of
cutaneous larva migrans. Cryotherapy is not very effective as
the location of the larva is not precisely known; the larva is
usually found a few centimeters ahead of the advancing visi-
ble end of the lesion. Also, it has been shown that the larva
can survive temperatures as low as -21ºC for more than 5
minutes [27, 31]. In addition, the procedure is painful. As
such, cryotherapy is no longer routinely recommended for
the treatment of cutaneous larva migrans except for patients
in whom oral antihelminthics are contraindicated (e.g., preg-
nancy) or not tolerated [29].
12.4. Fractional Carbon Dioxide Laser
Recently, it has been shown that a single session of 1 to 4
passes of fractional carbon dioxide laser up to 1 to 2cm pe-
rimeter around the erythematous portion of the serpiginous
track is effective in the treatment of cutaneous larva migrans
[108]. In one study, ten cases (eight patients) with cutaneous
larva migrans were treated with one session of carbon diox-
ide laser treatment and followed up daily for the first week
with photographic documentation and then weekly for the
next 3 weeks to complete a 4 week follow-up period. The
first case received one to two passes of fractional CO2 laser,
experienced further larval migration for 2 to 3 days, after
which no more progression was noted. For the next seven
cases, the authors increased the number of CO2 laser passes
to 3 to 4, and noted no further larval migration. At the end of
the 4-week follow-up period, all CO2 laser-treated areas were
completely healed [108].
Confocal scanning laser microscopy can be used to detect
the larva, thereby increases the success rate of fractional car-
bon dioxide laser. Fractional carbon dioxide laser works ei-
ther by destroying the larva directly or that the microthermal
zones produced by the laser halt the migration of the larva
[108]. The ideal number of passes of fractional carbon diox-
ide laser required to effectively control cutaneous larva mi-
grans has to be determined.
12.5. Miscellaneous
Systemic antihistamines and topical corticosteroid may
be considered to provide symptomatic relief of itchiness
[15]. Secondary bacterial infection may require treatment
with appropriate antibiotics.
13. PREVENTION
In endemic areas, preventative measures include periodic
deworming of dogs and cats and banning them from beaches
and playgrounds, disposing the waste products of dogs and
cats properly, wearing proper footwear while walking on the
beach, using towels, mattresses and deckchairs on the beach,
and avoiding lying or sitting directly on the sand/soil [29,
79]. Sandpits that children play with should be protected
from dogs and cats [27]. Gloves should be worn when
soil/sand is handled.
CURRENT & FUTURE DEVELOPMENTS
Current methods for diagnosis of hookworm infections
primarily involve microscopic examination of fecal samples,
either directly in fecal smears or following concentration of
ova by flotation in density media. Despite this procedure is
popular and in common use, the methods have significant
shortcomings. These microscopic methods are time-
consuming, are unpleasant, require specialized equipment,
and can have low specificity having have to rely heavily on
the skill and expertise of the operator. Geng and Elsemore
disclosed methods, devices, kits and compositions for detect-
ing more accurately the presence of hookworm such as Ancy-
lostoma caninum and Ancylostoma braziliense in a fecal
sample by using one or more antibodies that specifically bind
to a polypeptide present in hookworm coproantigen [109].
These methods would allow early diagnosis and treatment of
the infected animal and efficient follow-up to determine
whether the animal has been rid of the infestation after
treatment has been initiated, thereby minimizing the risk of
cutaneous larva migrans.
The drugs currently used against hookworms have limita-
tions as they are contraindicated during pregnancy, in very
young children, and in those with certain systemic diseases,
making new drugs highly desirable. Eickhoff et al. patented
an invention comprising of pyrazolo-triazine derivatives
and/or pharmaceutically acceptable salts thereof for the
treatment of infectious diseases including cutaneous larva
migrans [110]. The pharmaceutical compositions or formula-
tions comprise at least one compound as an active ingredient
together with at least one pharmaceutically acceptable (i.e.
non-toxic) carrier, excipient and/or diluent. The preferred
preparations are adapted for oral administration. Spangen-
berg disclosed an invention comprising of azepanyl deriva-
tives for the treatment of parasitic diseases including cutane-
ous larva migrans [111]. Pharmaceutical formulations ac-
cording to the invention can be adapted for oral as well as
topical administration. Levine et al. disclosed a method of
treating or ameliorating skin lesions as may result from cuta-
neous larva migrans by periodically applying to the skin a
composition comprising: an effective amount of an appropri-
ate composition of herbal bioactive comprising active(s) of
one or more of Sambucus nigra, Centella asiatica or Echina-
cea purpurea, and an effective amount of a quaternary am-
monium surfactant [112]. At the moment, it is not sure
whether these new medications have the same contraindica-
tions as the existing ones. Also, their efficacy and adverse
8 Recent Patents on Inflammation & Allergy Drug Discovery 2017, Vol. 11, No. 1
effects are not known. Comparative studies on the effective-
ness of drugs in the treatment of cutaneous larva migrans are
few and they are not randomized, double-blind, and placebo-
controlled. It is hoped that future well-designed, large-
scaled, randomized, double-blind, and placebo-controlled
studies will provide us with more information on the efficacy
and optimal regimen of the various antihelminthics including
the present ones and those in development.
The cost of antihelminthics may, to certain extent, limit
its access to patients especially those in developing coun-
tries. By bringing the production cost down, the medication
would be made available to more patients. Traditionally, in
the preparation of albendazole, 2-nitroaniline is thiocyanated
to obtain 2-nitro-4-thiocyanoaniline, then alkylated with n-
propylbromide in the presence of n-propanol and methyl
tributyl ammonium chloride or the tetrabutyl ammonium
bromide as the phase-transfer catalyst and an alkali metal
cyanide or alkaline metal cyanide to generate 4-propylthio-2-
nitroaniline. 4-Propylthio-2-nitroaniline is reduced by so-
dium sulphide monohydrate in the presence of water to ob-
tain 4-propylthio-O-phenylenediamine. This diamine is fur-
ther reacted with sodium salt of methyl-N-cyano carbamate
to obtain the albendazole. In this process, phase transfer cata-
lyst as well as an alkali metal cyanide or alkaline metal cya-
nide is used for condensation of 2-nitro-4-thiocyanoaniline
with n-propylebromide, which adds to the cost of production,
increases the organic material content in effluent and may
facilitate the formation of impurity and uses toxic cyanide
compound. The reduction of 4-propylthio-2-nitroaniline is
done in the presence of water as a solvent which makes the
reaction sluggish. Thus it is highly desirable to develop a
process which overcomes most of the drawbacks of the prior
process. Rane et al. disclosed a novel, cost-effective and
environment friendly process for preparation of albendazole
which overcomes most of the above stated drawbacks [113].
The process comprises a) thiocyanating 2-nitroaniline of
formula VI with ammonium thiocyanated in presence of a
halogen to obtain 2-nitro-4-thiocyanoaniline of formula V; b)
propylating 2-nitro-4-thiocyanoaniline of formula V with
propylbromide in presence of n-propanol and a base in ab-
sence of a phase transfer catalyst to obtain 4-propylthio-2-
nitroaniline of formula III; C) reducing the nitro group of 4-
propylthio-2-nitroaniline prepared in step b) by reacting an
aqueous alkali metal sulphide or an alkaline metal sulphide
to obtain 4-propylthio-O-phenylenediamine of formula II;
and d) condensing 4-propylthio-O-phenylenediamine of for-
mula II with alkali or alkaline earth metal salt of methyl-
cyano carbamate in presence of an acid to form albendazole.
Pruritus due to cutaneous larva migrans can be severe
resulting in sleep disturbance. Currently, systemic antihista-
mines and topical corticosteroid can be used to provide
symptomatic relief of pruritus [15]. Zhang et al. disclosed a
method of treating pruritus, comprising administering a
therapeutically effective amount of 3-[(3aR,4R,5S,7aS)-5-
[(1R)-1-[3,5-bis (trifluoromethyl) phenyl] ethoxy]-4-(4-
fluorophenyl)-1,3,3a,4,5,6,7,7a-octahydroisoindol-2-yl] cy-
clopent-2-en-1-one (serlopitant) or a pharmaceutically ac-
ceptable salt, solvate or polymorph thereof to a patient in
need of treatment [114]. The invention provides a method for
treating chronic pruritus using serlopitant or a pharmaceuti-
cally acceptable salt or hydrate thereof. Serlopitant has pre-
Leung et al.
viously been disclosed as a neurokinin-1 (NK-1) receptor
antagonist, an inhibitor of tachykinin and, in particular, of
substance P. Compositions for oral and topical administra-
tion are available. Ji et al. disclosed a method of treating
pruritus resulting from, but not limited to, cutaneous larva
migrans with superoxide dismuate (SOD) mimetic [115].
The SOD mimetic can be a complex of a metal (e.g., manga-
nese) and an organic ligand, with suitable organic ligands
including porphyrins, polyamines, salens, nitroxides, and
fullerenes. The invention can be given orally, parenterally, or
topically. Kaspar and Speaker disclosed methods of treating
pain and/or itch in a targeted region of a subject [116]. Such
methods include topically administering a therapeutically
effective amount of an mTOR pathway inhibitor to the sub-
ject. An mTOR is a serine/threonine kinase that regulates
translation and cell division. The mTOR inhibitor in this
invention is rapamycin (Sirolimus) or an analogue thereof.
Rapamycin is a macrocyclic lactone produced by the organ-
ism Streptomyces hydroscopicus. The investigators claim
that the invention is effective in the symptomatic treatment
of intense pruritus associated with cutaneous larva migrans.
These new anti-pruritic medications will offer readers and
patients another therapeutic option for the treatment of pruri-
tus.
Worldwide, cutaneous larva migrans affects millions of
individuals. Effective vaccines against hookworms would be
the best way to lower the abundance of hookworm infesta-
tions. Currently no such vaccines exist. Schwarz et al. dis-
closed a method for preventing or treating a hookworm in-
fection in an animal, comprising administering to the animal
a composition comprising either an antigen or a nucleic acid
encoding the antigen, wherein the antigen comprises an
amino acid sequence comprising at least 10 consecutive
amino acids encoded by an open reading frame in any one of
SEQ ID NOS: 1-540 [117]. This invention may be for use in
manufacturing a vaccine. It is hoped that effective hook-
worm vaccines may be available in the future.
CONCLUSION
Cutaneous larva migrans is a zoonotic infestation caused
by penetration and migration in the epidermis of filariform
larva of different kinds of animal hookworms through con-
tact with feces of infected animals, mostly dogs and cats.
Clinically, it is characterized by a pruritic erythematous mi-
grating tortuous or serpiginous, slightly raised track. The
condition is common in individuals residing in tropical and
subtropical regions. It is the most common ectoparasitosis
acquired by travelers returning from those regions. Because
of the increasing incidence of foreign travel, cutaneous larva
migrans is no longer confined to endemic regions. Western
physicians should familiarize themselves with this condition
so that a correct diagnosis can promptly be made and treat-
ment initiated. Clinically, the condition is characterized by a
pruritic erythematous migrating tortuous or serpiginous,
slightly raised track which is pathognomonic.
Compared with oral antihelminthics, topical treatment
over the affected area is less effective since the larva is mo-
bile and the exact location of the larva is not precisely
known. Unfortunately, the two available oral antihelminthics
(ivermectin and albendazole) are contraindicated during
pregnancy and should be avoided in breastfeeding mothers.
Cutaneous Larva Migrans Recent Patents on Inflammation & Allergy Drug Discovery 2017, Vol. 11, No. 1 9
It is hoped that future medications may circumvent these
problems.
CONSENT FOR PUBLICATION
Not applicable.
CONFLICT OF INTEREST
Prof. Leung, Dr. Barankin, and Prof. Hon disclose no
relevant financial relationship.
ACKNOWLEDGEMENTS
Prof. Alexander K.C. Leung is the principal author. Dr.
Benjamin Barankin and Professor Kam Lun Hon are co-
authors who contributed and helped with the drafting of this
manuscript. The authors would like to thank Dr. Kin Fon
Leong for providing them with the photo image on his pa-
tient with cutaneous larva migrans.
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