Not to Be Missed! Differential Diagnoses of Common Dermatological Problems in Returning Travellers

Home , African tick bite fever, Cutaneous larva migrans, Dirofilariasis, Dracunculiasis, Filariasis, Gnathostoma

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Travel Medicine and Infectious Disease (2013) 11, 337e349

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INVITED SUBMISSION Not to be missed! Differential diagnoses of common dermatological problems in returning travellers

Andreas Neumayr a,b, Christoph Hatz a,b, Johannes Blum a,b,* a Swiss Tropical and Public Health Institute, Socinstrasse. 57, 4051 Basel, Switzerland b University of Basel, Basel, Switzerland

Received 13 June 2013; received in revised form 20 September 2013; accepted 25 September 2013 Available online 6 October 2013

KEYWORDS Summary After systemic febrile illnesses and diarrhoea, dermatological disorders are the Travel; third most frequent health problem of returning travellers consulting travel clinics. While most Skin; travel-related dermatological problems are mild, self-limiting and rather harmless, the chal- Creeping eruption; lenge is to pick up on dermatological clues to potentially severe or even life-threatening dis- Chancre; eases. This article provides an overview of the most common and the ‘not to be missed’ Eschar dermatological diagnoses in international travellers. ª 2013 Elsevier Ltd. All rights reserved.

Introduction dermatological diagnoses in travellers is broad and domi- nated by insect bites, bacterial skin infections, creeping The three most common reasons for returning travellers to eruptions and allergic skin reactions (Table 1). seek medical help are systemic febrile illnesses, acute or This article addresses the most frequent dermatological chronic diarrhoea and dermatological disorders [1]. Various disorders and their differential diagnoses in returning studies have recently reviewed the spectrum and the fre- travellers, and highlights the dermatological clues to severe quencies of travel-related dermatological disorders and potentially life-threatening diseases, which should not observed in travel clinics [1e4]. The spectrum of be missed: ‘When you hear hoofbeats, think horses, not zebras’. but make sure not to miss out on zebras. (Those dermatological disorders that are not conﬁned to d * Corresponding author. Swiss Tropical and Public Health Insti- travelling e.g. herpes zoster, pityriasis rosea, syphilis d tute, Socinstrasse. 57, 4051 Basel, Switzerland. Tel.: þ41 61 284 and sun- and heat-related skin pathologies also 8111; fax: þ41 61 284 8101. frequently occur in travellers, but are beyond the scope of E-mail address: [email protected] (J. Blum). this review).

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Table 1 Spectrum and frequency of travel-related dermatological disorders. Setting Herbinger 2011 Lederman 2008 Ansart 2007 Freedman 2006 Travel clinic in GeoSentinel Travel clinic in GeoSentinel Munich, Germany surveillance network Paris, France surveillance network (1997e2006) (1996e2004) Number of cases (n Z 4158) % (n Z 4594)% (n Z 165)% (n Z 2947) % Ectoparasites Arthropod/insect bite 16.8 8.2 9.7 18.7 Scabies 2.3 e 10 2.2 Myiasis 0.8 e 7.2 3.5 Tungiasis 0.6 e 4 e Tick bites 0.6 eee Bacteria Bacterial skin infectionsa 21.6 14.5 21.2 12.4 Rickettsial disease 1.3 e 0.6 e Leprosy ee 2.4 e Helminths Larva cutanea migrans 7.9 9.8 4.8 12.9 Schistosomiasis 0.6 e 0.6 e Filariasis (Loiasis) 0.7 e 5.5 e Gnathostomiasis ee 1.8 e Protozoa Cutaneous leishmaniasis 2.4 3.3 e 3.8 Virus infection 5.7 3.4 7.2 e Fungal infection 4.0 4.0 6.1 5.6 Allergic reaction/urticaria 5.4 5.5 4.8 11.3 Phototoxic 0.8 eee Chemical, toxic 0.5 e 3.6 e Injuries 1 eee Terrestrial animal bites 0.4 4.3 e >4.7 Maritime animals 0.7 eee Pruritus of unknown origin ee 9.1 e Unknown skin disorder 16.3 5.5 e 6.6 a including skin abscesses, impetigo, erysipelas, superinfected insect bites, etc.

Methods picture may include ecchymoses or vesicles and severely allergic patients may develop haemorrhagic bullae, necroses This review is based on the most frequently reported skin or ulcers that heal with residual scarring [7]. In a few cases, pathologies in travellers (see Table 1), on the relevant insect bites may cause systemic symptoms like generalised literature and on personal experiences from daily practice urticaria, angioedema, anaphylaxis or the rare ‘Skeeter at our travel clinic. syndrome’ (a large local inflammatory reaction accompanied by fever, which can be differentiated from cellulitis by its peracute onset within hours) [8e10]. Sequelae of insect Ectoparasites bites include bacterial superinfection, post-inflammatory changes in pigmentation, prurigo simplex-like lesions, pru- Insect bites rigo nodularis and atrophic scarring [5,7]. Diagnosis Consultations for insect bites are frequent and the clinical Diagnosis is based on the patient’s history and clinical presentations vary widely. One insect may cause different picture. types of skin lesions and each type of skin lesion may be caused by different kinds of insects, thus it is difficult and Treatment often impossible to infer from a skin lesion the causative Insect bites are primarily treated with topical steroids and insect. However, in some cases, the clinical aspect and the oral antihistamines. Patients suffering from agonising distribution of the skin lesions may be suggestive: for nocturnal pruritus may benefit from the use of older, example, pruritic lesions caused by fleas and bed bugs are sedative antihistamines. In severe, disseminated or re- more frequently papular and typically clustered or linearly fractory cases, the oral intake of steroids may be required. grouped, which is rarely seen with mosquito bites [5e7]. The typical evolution of insect bites is the initial formation of wheals and flares (with a peak within 20 min), a delayed Myiasis reaction manifesting as itchy indurated erythematous papules (with a peak at 24e36 h) and the gradual resolution of The maggots/larvae of various flies (mostly Dermatobia the lesions within days to weeks [8]. However, the clinical hominis [human bot fly e Central and South America] and Author's personal copy

Diagnoses of common dermatological problems in returning travellers 339

Cordylobia anthropophaga [tumbu/mango/putzi fly e Sub- hygiene standards are low and acquired by direct contact with saharan Africa]) can cause infection in humans [76]. African infected individuals. Scabies mites (0.5 mm) burrow a tumbu flies lay their eggs in faecal-contaminated soil or on mostly invisible S-shaped tunnel of up to 4 mm into the su- damp clothing hanging to dry. Direct contact activates the perficial layer of the epidermis, where they live and lay eggs hatched larvae to penetrate the skin. American human bot [77]. The resulting skin lesions (Fig. 3) are most commonly flies attach their eggs to the body of captured mosquitos, to found on the fingers, especially in the web spaces, anterior reach the human host. wrists, upper limbs, axillary lines, the periumbilical region, external genitalia and buttocks [78]. As a result of a hyper- Diagnosis sensitive reaction to mite proteins, patients typically Diagnosis is based on the pathognomonic clinical picture, complain about intense itching, typically worst at night while which is characterized by itchy, slowly enlarging (Ø 1e3 cm) in the warm bed. Scratching itchy areas may result in bacterial subcutaneous furuncular (boil-like) skin lesions. On close superinfection. Diagnosis is frequently delayed, as the lesions inspection, a central aperture, permitting the maggot to are mistaken for eczema, tinea, or atopic dermatitis [79]. breathe and to drain waste products, is visible (Fig. 1). Diagnosis Treatment Diagnosis is mainly based on the clinical picture. The lesions The maggots can be removed by gently squeezing the boil, are best identified by a handheld dermatoscope. assisted by first covering the aperture with a layer of paraffin oil or petroleum jelly to stop the oxygen supply. Treatment While mature larvae are easily extracted by these mea- For practical reasons, although possibly less effective, oral sures, early lesions are best left to develop for a few days, ivermectin has largely replaced the cumbersome topical as immature maggots are reluctant to emerge. If surgical treatment with permethrin, benzyl benzoate, crotamiton removal is applied, rupture of the larvae has to be avoided, or lindane as the first-line treatment [78e80]. The as this can lead to a severe inflammatory reaction. currently recommended treatment regimens are two ap- plications (overnight) of topical permethrin 5%, 1e2 weeks Tungiasis (‘Sand flea’, ‘Jigger’) apart or oral ivermectin (200 mg/kg body weight) OD on day 1 and after 1e2 weeks [78]. Tungiasis is endemic in parts of Africa, Central and South America, and India. Tunga penetrans is the smallest of all Pitfalls/not to be missed fleas, measuring around 1 mm in length, and lives in the soil Non-healing or progressively ulcerating insect bites near pigsties and cattle sheds [77]. The female T. penetrans persisting over weeks or months should raise suspicions flea burrows into the soft skin regions of suitable hosts of cutaneous leishmaniasis (see below) (humans and various animals) and remains there for up to Consider Myiasis or Tungiasis in lesions showing a cen- five weeks, during which time it feeds on blood, matures, tral orification and produces and releases eggs, before finally dying [76]. Scabies may present a wide range of clinical pictures Erythema chronicum migrans in Lyme borreliosis Diagnosis Rickettsioses (see below) The lesions are commonly located at the feet and the clinical African/South American trypanosomiasis/sleeping picture is pathognomonic: the flea’s round whitish abdomen sickness (see below) shines through the overlying dermis around a central aperture (Fig. 2). The lesions may be pruritic and painful. Bacterial skin infections

Treatment Bacterial infections are the most frequent skin disorder in Extraction of the parasite after removal of the overlaying travellers returning from tropical and subtropical countries. skin is straightforward. The majority of these cases concern superinfected insect bites, with staphylococci and streptococci being the pri- Scabies mary causative pathogens. While most cases of ecthyma, erysipelas and cellulitis are caused by streptococci, impe- Scabies, caused by the mite Sarcoptes scabiei, is a cosmo- tigo, folliculitis and abscesses are rather caused by staph- politan ectoparasitic disease, most commonly seen where ylococci [11]. While methicillin-resistant Staphylococcus

Figure 1 Myiasis left: South American myiasis; middle: African myiasis; right: removed maggot. Author's personal copy

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Figure 2 Tungiasis left: tunga lesion with visible shed eggs; middle: multiple tunga lesions; right: removed ﬂea. aureus (MRSA) infections were formerly considered to be a sensitivity testing should be performed, if antibiotic problem restricted to healthcare settings (‘hospital ac- treatment of purulent skin lesions is indicated quired’ HA-MRSA), ‘community acquired’ MRSA (CA-MRSA) Bacterial superinfection of cutaneous leishmaniasis is infections have emerged as a global health problem, common and should not distract from performing in- affecting international travellers [12,13]. Swedish surveil- vestigations for leishmania (see below) lance data show that travellers returning from tropical and When symptoms (esp. pain and fever) and clinical subtropical countries have an up to 59-fold higher risk of ﬁndings of skin and soft-tissue infections are dispro- being colonised or infected with MRSA compared to trav- portional, the rare but rapidly life-threatening differ- ellers returning from countries in Western Europe [14]. ential diagnosis of necrotic fasciitis should be ruled out In cases of skin and soft-tissue infections, linked to the before considering other diagnoses rise in medical tourism (cosmetic injections [‘meso- In skin lesions unresponsive to empirical antibiotic therapy’] or plastic surgery) as well as tattoos acquired treatment, cutaneous leishmaniasis, cutaneous tuber- abroad, atypical mycobacteria (e.g. Mycobacterium che- culosis, atypical mycobacteria and leprosy should be lonae, Mycobacterium fortuitum, Mycobacterium absces- considered sus) should be considered [24e27]. Cases of cutaneous diphtheria [15,16], cutaneous bar- Skin manifestations in febrile patients tonellosis/veruga peruana [17], cutaneous melioidosis [18,19], cutaneous tuberculosis [20], cutaneous atypical Fever D generalised rash mycobacteriosis (e.g. buruli ulcer [21]), cutaneous anthrax [22] or leprosy [23] are only exceptional diagnoses in returning travellers. Causes of fever with generalised rash are copious and their discussion is well beyond the scope of this review. In Diagnosis returning travellers, arboviral infections like dengue and Diagnosis is based on the clinical picture and the bacterial chikungunya and rickettsial infections (see below) are the culture of wound swabs. primary infectious causes to consider (Fig. 4). However, cosmopolitan infections like measles, rubella, scarlet fever and acute HIV- and hepatitis B/C infection, as well as drug Treatment hypersensitivity reactions and connective tissue diseases, The selection of the antibiotic treatment regimen depends should not be forgotten in returning travellers presenting on the causative pathogen and should be guided by sus- with fever and rash. ceptibility testing. Fever D insect bite: eschars & chancres Pitfalls/not to be missed With CA-MRSA emerging as a skin pathogen in travel- In febrile patients returning from endemic regions, rick- lers, microbiological work-up with culture and ettsioses are common and, even though rare, the

Figure 3 Scabies (courtesy of Dr. Martin Pletscher, Binningen, Switzerland). Author's personal copy

Diagnoses of common dermatological problems in returning travellers 341 potentially life-threatening cases of African sleeping sick- corroborate the tentative diagnosis. If available, immu- ness/African trypanosomiasis must not be missed. There- nohistochemical detection of rickettsia in a biopsy spec- fore, in febrile patients returning from endemic regions, imen is an option, while the culture of rickettsia is well eschars and chancres should be actively sought after: beyond routine diagnostics and restricted to specialised laboratories. Rickettsioses: ‘eschars’ Treatment Doxycycline is the drug of choice for all rickettsioses. In Rickettsial ‘spotted fevers’ are caused by various Rickettsia general, a seven-day course is given or until the patient has species worldwide and transmitted by ticks or mites. Most been afebrile for at least 48 h. patients present with a mild-to-moderately severe flu-like illness (fever, headache, malaise, myalgia) typically accompanied by a cutaneous rash (maculopapular, vesicu- African trypanosomiasis (sleeping sickness): lar, or petechial), lymphadenopathy and a characteristic ‘chancres’ inoculation eschar at the site of the tick bite [28,29]. Es- chars are morphologically characterised by a dry, dark African trypanosomiasis, a blood protozoal infection, should (grey, brown, black) scab resembling a cigarette burn be considered in safari tourists, hunters and wildlife re- (Fig. 5) and lymphadenopathy of the locoregional lymphatic searchers returning from East Africa and that present with a drainage is common. Most cases are mild, but severe severe febrile illness, once malaria has been ruled out. To complications (e.g. vasculitis, meningoencephalitis, pneu- date, approx. 100 cases of African trypanosomiasis have been monia, myocarditis/pericarditis, nephritis, pancreatitis) reported in travellers, with five cases published in 2012 and multi-organ failure can develop. Only a minority of [32e36]. Five to fifteen days after being bitten by an infected infected travellers can recall a preceding tick bite. Even tsetse fly, a painful circumscribed inoculation chancre may though not all rickettsioses show eschars and the absence develop, characterised by an indurated dusky-red papule of a rash or eschar does not exclude rickettsial infection, 2e5cmindiameter(Fig. 6) [37]. Accompanying regional the finding of an eschar is often indicative. Among travel- lymphadenopathy may be present. The systemic dissemina- lers, ‘African tick bite fever’ caused by Rickettsia africae is tion of the parasite that follows leads to the ‘hemolymphatic the most frequent rickettsiosis [30]. Especially among stage’ of the disease, characterised by fever, headache, fa- travellers to South Africa, the risk of becoming infected tigue, malaise, lymphadenopathy, pruritus, skin rash, and with ‘African tick bite fever’ is reportedly 4e5 times higher gastrointestinal symptoms. Electrocardiography (ECG) may than the risk of contracting malaria [31]. Other rick- show signs of accompanying myopericarditis, which rarely ettsioses regularly seen in travellers are ‘Mediterranean leads to cardiac insufficiency but can lead to cardiac ar- spotted fever’, caused by Rickettsia conorii, and ‘Scrub rhythmias [38]. If diagnosis and treatment is delayed at this typhus’ (‘Tsutsugamushi fever’), caused by Orientia tsut- stage, the parasites may invade the central nervous system sugamushi [30]. and cause the eponymous ‘meningoencephalitic stage’, characterised by neurological (e.g. headache, drowsiness, Diagnosis tremor, seizures) and psychiatric symptoms. With overlapping Intheabsenceofsuggestiveskinmanifestations,the symptoms, neither stage can be clinically differentiated and diagnosis of a rickettsial disease is often difficult as the staging of the disease has to be based on cerebrospinal fluid most commonly applied serological tests are not useful analysis. Neuropsychiatric disorders are only rarely seen in before the end of the first week of illness and PCR diag- travellers and delayed treatment almost always entails multi- nostic (from blood) is often not available (Note: Lacking organ failure and death [39,40]. sensitivity and specificity, the traditionally-used Weil- South American trypanosomiasis (Chagas disease), which Felix [agglutination] test is no longer recommended). In is transmitted by bloodsucking triatomine insects, is only these cases, the fast and universal response of rick- very rarely seen in travellers [41]. Analogous to African ettsioses to doxycycline treatment can help to trypanosomiasis, a chancre (‘chagoma’) may be seen in

Figure 4 Arboviral rashes left: maculopapular dengue rash middle: conﬂuent dengue rash (‘white islands’) right: chikungunya rash. Author's personal copy

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Figure 5 African tick bite fever eschars. acute Chagas disease. This oedematous lesion develops - African/South American trypanosomiasis (sleeping where the vector’s infective faeces enters (is rubbed) into sickness) the skin, which is mostly at or around the bite site. If the insect’s infective faeces is deposited close to or acciden- Cutaneous leishmaniasis tally rubbed into the eye, a pathognomonic unilateral painless periorbital oedema with conjunctivitis (‘Romanã’s Leishmaniasis is caused by various Leishmania parasite sign’) can be seen. A generalised rash may also occur in species, which are transmitted through Phlebotomus (Old acute Chagas disease. World) and Lutzomyia (New World) sandfly bites. The clinical manifestations of leishmaniasis vary widely (visceral-, Diagnosis cutaneous-, mucosal disease) and depend on the causative Diagnosis of trypanosomiasis rests on finding the parasite in Leishmania species. body fluid or tissue by microscopy. All patients diagnosed Cutaneous leishmaniasis (CL) manifests one to several with African trypanosomiasis must have their cerebrospinal weeks after the bite of an infected sandfly with a slow, fluid examined to determine whether there is central ner- progressively growing and ulcerating, granulomatous pla- vous system involvement, since the choice of treatment que (Fig. 7). Due to the high variability of the clinical pic- will depend on the disease stage. Serological tests are also ture and the overall low awareness of general practitioners, available. diagnosis is often delayed. In a few patients, mucosal leishmaniasis (ML), characterised by symptoms related to Treatment the progressive infiltration and ulceration of the mucosal Depending on the causative trypanosoma species and stage membranes of nose and pharynx, may develop concomi- of the disease, pentamidine, eflornithine/nifurtimox, sur- tantly or months to years after the appearance of the CL amin or melarsoprol are the treatment options for African lesion(s). ML is mostly seen in patients infected by New trypanosomiasis. In South American trypanosomiasis, World Leishmania species. As the treatment regimens used benznidazole and nifurtimox are used. in ML differ considerably from the regimens used in CL, an ENT examination (inspection of the oral, pharyngeal and Pitfalls/not to be missed nasal mucosa) should be performed in all CL patients to rule Fever þ generalised skin rash: out concomitant ML. - Arboviral infection (dengue, chikungunya) Imported CL cases among travellers returning from - Acute HIV-, Hepatitis B-, Hepatitis C-infection endemic regions have increased in recent years [42]. For Fever þ insect bite/suspicious skin lesions: international travellers, the risk of contracting CL depends - Rickettsioses on the region visited and is estimated to be 20 times higher

Figure 6 African trypanosomiasis chancres (courtesy of Prof. Denis Malvy, Bordeaux, France [left, middle] and Prof. Joachim Richter, Du¨sseldorf, Germany [right]). Author's personal copy

Diagnoses of common dermatological problems in returning travellers 343 in Central and South America, 10 times higher in Africa, and Consider mucosal involvement (ML) in CL patients with 5 times higher in Asia compared to visiting leishmanial New World leishmaniasis endemic regions of Southern Europe [43]. The incidence PCR diagnosis should be enforced, as species determi- rates of New World CL in travellers have been estimated to nation is crucial for deciding the optimal treatment be between <1/1,000,000 in Mexico and 1/360 in the modality Amazonas region of Bolivia [44].

Diagnosis Cutaneous larva migrans syndrome, creeping Diagnosis is based on epidemiology, the clinical picture and eruptions and migratory swellings direct or indirect detection of the parasite in biopsy ma- terial. Polymerase chain reaction (PCR) has a sensitivity of Various helminth parasites can cause ‘cutaneous larva mi- 89e100%, is fast, allows species determination and has grans’ syndrome or ‘creeping eruptions’ (demarcated linear become the diagnostic method of choice, likely to replace or serpiginous tracks beneath the skin) and ‘migratory microscopy (sensitivity 9e77%) and culture (sensitivity swellings’ (less demarcated as the parasite migrates 58e62%) [42,45,46]. through deeper subcutaneous tissues). While Hookworm- related cutaneous larva migrans is always confined to the Treatment skin and shows a characteristic clinical picture, it is Treatment modality (local cryo- or heat-therapy vs. local important to highlight that the clinical differentiation of drug therapy [topical or by injection] vs. systemic drug other parasites (e.g. Strongyloides, Gnathostoma, Loa loa) therapy) and the selection of an anti-leishmanial drug is often not possible. Some parasites may migrate, unre- regimen depends on the causative Leishmania species and stricted, through body tissues and organs, capable of local drug susceptibility, as well as on the number, size and causing severe symptoms and sequelae (e.g. CNS invasion of localisation of the lesion(s). Treatment is complex and Gnathostoma or Angiostrongylus). should be discussed with a specialist or referral centre. Drugs currently in use include pentavalent antimonials (sodium stibogluconate and meglumine antimoniate), Hookworm-related cutaneous larva migrans amphothericin B formulations, pentamidine, miltefosine, (‘ground itch’, ‘sandworm’) paromomycin, imiquimod, azoles (ketoconazole, itracona- zole, fluconazole), allopurinol and adjunct pentoxyphillin Hookworm-related cutaneous larva migrans is caused by and TNF-inhibitors. hookworm larvae from various animals (incl. domestic dogs Various recommendations for treating CL in travellers and cats), with Ancylostoma braziliense being the species have been published at national level [46e50] and a Euro- that most frequently affects humans [51]. Hookworms live pean expert group (‘LeishMan’) is currently working on in the intestines of animals and shed their eggs with the harmonising diagnostic and treatment recommendations host’s faeces; left on the ground the infectious larval stage for CL. develops. Human infection results from larvae penetrating the intact skin on contact with contaminated soil (often Pitfalls/not to be missed sandy beaches). Humans are accidental dead-end hosts and CL should be suspected for skin lesions that: the parasite lacks the enzymatic provisions to penetrate - develop one to several weeks after a suspected insect beyond the human dermis to complete its lifecycle. bite Therefore, the parasite migrates superficially, exclusively - progress in size over days/weeks/months within the dermis, until the parasite eventually dies spon- - persist over weeks/months taneously (within 2e8 weeks). The track is 1e5 mm wide, - do not or only partially* respond to antibiotic treat- extends slowly over days to weeks and classically shows a ment (* bacterial superinfection of CL lesions is well demarcated linear or serpiginous pattern (Fig. 8). common and should not limit investigations for Sensitisation may lead to the formation of papules and Leishmania) vesicles and the (often) intense pruritus tempts patients to - worsen under steroid therapy scratch, which may in turn cause bacterial superinfection.

Figure 7 Cutaneous leishmaniasis. Author's personal copy

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Diagnosis untreated, for many (up to 10e12) years through the pa- Hookworm-related cutaneous larva migrans can almost al- tient’s body [60]. The symptomatic episodes commonly last ways be differentiated from other creeping eruptions by its several days to weeks and the migratory swellings/creeping distinct clinical picture and without the need for additional eruptions may be accompanied by pruritus, local pain and/ diagnostic investigations [52]. or inflammation. In most cases, only one single migratory lesion is present at a time. Although most symptomatic Treatment infections are confined to the skin and subcutaneous tissue, Oral ivermectin and albendazole are the two first-line drugs severe manifestations due to visceral migration and inva- for Hookworm-related cutaneous larva migrans, as thia- sion of the central nervous system may occur [61]. bendazole is no longer marketed. Ivermectin is taken as a single dose (200 mg per kg body weight; usually 12 mg in an Diagnosis adult), is well tolerated and highly efficacious, with cure Diagnosis is mostly based on the patient’s history (ingestion rates of 94%e100% [53]. After ivermectin intake, symptoms of raw or undercooked fish dishes), the clinical picture, disappear within one week: Ø 3 (1e20) days for pruritus, blood eosinophilia (which is often, but not always, present) and Ø 7 (1e30) days for creeping dermatitis [54]. Treatment and positive serology (Western blot). If the parasite mi- failure or relapse cases usually respond well to 1e2 addi- grates very superficially, skin biopsy can be both diagnostic tional courses of ivermectin [55]. In the absence of a and therapeutic. consensual optimal treatment regimen, oral albendazole is mostly recommended at a dose of 400 mge800 mg/day Treatment (according to weight) for 3e5 days [56]. Cryptherapy is Oral albendazole and ivermectin are the drugs of choice for obsolete, as the larva is usually located several centimetres gnathosotomiasis. Albendazol has shown an efficacy of beyond the visible end of the track and larvae are capable around 94% and is mostly given in a dosage of 400 mg BID for of surviving temperatures as low as 21 C for more than 21 days [62]. Ivermectin is given as single dose (200 mg per 5 min [53]. Additionally, the procedure is painful and may kg body weight; usually 12 mg in an adult) for two days and lead to scarring. shows similar results as albendazole [63e65]. In case of persisting symptoms, re-treatment with either drug or Gnathostomiasis sequential treatment with both drugs has been shown to be successful. Normalisation of the blood eosinophil count has proven to be a useful parameter for monitoring effective Gnathostoma is a helminthic parasite of dogs, cats and treatment [63]. Gnathostoma larvae tend to migrate out- other (mostly fish-eating) mammals, with a complex life- ward as a result of albendazole treatment, which some- cycle (involving copepods, freshwater fish and a wide range times facilitates excisional biopsy or removing the parasite of potential paratenic hosts). Humans are accidental dead- by picking with a needle [66]. end hosts and usually become infected by ingesting raw or inadequately cooked freshwater fish infected with the 3rd stage larva of the parasite. Gnathostomiasis is endemic to Strongyloidiasis (‘Larva currens’) some regions of Asia and South America where raw fish is consumed as part of the local food tradition (e.g. ‘sushi’ in Strongyloidiasis is a human gastrointestinal helminthic Asia and ‘ceviche’ in Central and South America). With parasite with global distribution. The prevalence is highest increasing numbers of international travellers, gnathosto- in tropical and subtropical regions and is related to poor miasis has become recognised as an emerging parasitic hygienic conditions. Humans become infected by contact disease in travellers returning from endemic regions with soil containing infectious larvae. The larvae penetrate [57e59]. the intact skin and symptoms (e.g. pulmonary [‘Lo¨ffler’s Cutaneous gnathostomiasis may manifest as intermittent syndrome’], gastrointestinal [abdominal pain, diarrhoea]) migratory swelling or subcutaneous creeping eruption, accrue from the parasite’s migration through the host’s varying in size and duration (Fig. 9). The migratory tracks body, including the skin. are often wider than 5 mm. The larvae are capable of There are two types of skin manifestations in strongy- migrating with a speed of up to 1 cm per hour and, if left loidiasis. One is a pruritic linear or serpiginous creeping eruption (mostly around the anus and anywhere on the trunk), which moves rapidly (2e10 cm per hour) and disappears within a few hours, hence the name ‘larva currens’ (Fig. 10) [67]. In most cases, the skin eruption has already completely disappeared when the patient is finally seen by the physician. The second form is an urticarial rash in an individual who has already been sensitised. This urticarial rash occurs predominantly in the buttocks and around the waist, lasts 1e2 days and may recur at regular intervals [67]. An important feature of Strongyloides stercoralis is the Figure 8 Hookworm-related cutaneous larva migrans left: parasite’s unusual ability to complete its lifecycle within the classical clinical picture; right: pronounced inflammatory, the human body, leading to continuing cycles of autoin- bullous form. fection [68]. This is especially important as chronic or Author's personal copy

Diagnoses of common dermatological problems in returning travellers 345

Figure 9 Gnathostomiasis left: migratory swelling (thigh); middle: creeping eruption; right: Gnathostoma 3rd stage larva (3 mm long). persistent infection may remain asymptomatic over de- loa microfilariae exhibit a diurnal periodicity in the pe- cades and culminate in severe and potentially life- ripheral blood, the optimal time for taking a blood sample threatening Strongyloides hyperinfection syndrome once is around noon, when the concentration of microfilariae in an individual sustains immunosuppression (e.g. chemo- blood samples is highest [73]. However, the absence of therapy, organ transplantation, high dose steroid- or any microfilaremia does not rule out the diagnosis; in a study other immunosuppressive therapy) [68,69]. comparing the clinical symptoms in endemic and nonendemic populations, microfilaremia was present in 90% Diagnosis and Calabar swellings in only 16% of the endemic patients. Diagnosis is based on the clinical picture, blood eosinophilia Conversely, only 10% of the expatriates were micro- (which is often, but not always, present), positive serology filaremic, while 95% complained of Calabar swellings [74]. (ELISA), and special stool investigations. Conventional stool microscopy is insufficient for diagnosing strongyloidiasis Treatment because the parasite load is generally low and the larval The drugs used to treat loa loa are diethylcarbamazin output irregular. Therefore, specific stool concentration (DEC), ivermectin and albendazole, but only DEC is effec- methods (e.g. ‘Baermann’) or stool culture techniques (e.g. tive against adult worms and microfilariae (ivermectin and HaradaeMori filter paper culture, nutrient agar plate cul- albendazole are microfilaricidal only). Therefore, a defini- ture) have to be applied [70]. A novel, promising diagnostic tive cure requires DEC therapy. As 20e60% of the adult tool is stool PCR [71]. worms survive the three-week DEC therapy, repeated courses of DEC may be necessary [75]. Because treatment is Treatment complex and may cause severe complications (potentially Oral ivermectin is the drug of choice for strongyloidiasis, fatal encephalopathy) in patients with high levels of and is more effective than albendazole (400 g BID for 7 microfilariae in the blood, therapy should be discussed with days) [72]. A single dose of ivermectin may not completely a specialist or referral centre. clear the infection, thus the recommended regimen is 200 mg/kg body weight OD for 2 days [72]. Other parasites causing creeping eruptions

Loa loa/loiasis (‘eye worm’) Other parasites able to cause creeping eruptions include dracunculiasis, dirofilariasis, fasciola, paragonimiasis, Loa loa is a filarial disease (helminthic parasite) trans- sparganosis, lagochilascariasis and migratory myiasis. mitted by bloodsucking flies in West- and Central Africa. However, these infections are only rarely seen in travellers. The classical symptom of an adult worm (3e7cm 0.4 mm) migrating under the conjunctiva of the eye is rarely Pitfalls/not to be missed observed, as the visible passage of the worm only lasts Diagnosis of Hookworm-related cutaneous larva migrans 10e15 min [73]. is unlikely, if: The same applies to the fugitive creeping eruptions - the lesion spontaneously disappears within 2e3 days caused by superficially migrating adult worms (Fig. 11). The most frequent symptoms are recurrent subcutaneous soft- tissue swellings (‘Calabar swellings’) and chronic pruritus. Calabar swellings are painless, non-pitting angio-oedemas, most commonly observed on the hands, wrists and forearms (but possibly anywhere on the body), lasting a few hours to several days [73].

Diagnosis Diagnosis is based on the epidemiological history, the clinical picture, blood eosinophilia (especially common in travellers), positive serology, and the microscopical detection of microﬁlaria in the patient’s blood. Because loa Figure 10 Strongyloidiasis creeping eruption. Author's personal copy

346 A. Neumayr et al.

- the track is subcutaneously located Pitfalls/not to be missed - the track is wider than 5 mm The history of exposure to freshwater is crucial in the dif- - peripheral blood eosinophilia is present ferential diagnosis, as the skin manifestations may other- - the lesion shows almost no migration wise be considered representative of insect bites. Treatment of gnathostomiasis is mandatory, as severe and potentially fatal neuroinvasive disease may develop Allergic skin reactions/urticaria Treatment of strongyloidiasis is mandatory, as the infection may cause severe and potentially life- threatening hyperinfection syndrome in cases of Urticaria is frequently seen in returning travellers and its immunosuppression causes are copious, ranging from food allergies and jellyfish Migrants from regions with high strongyloidiasis preva- contact to parasitic infections. Depending on the travel lence rates should be screened for asymptomatic chronic history, parasitic infections should not be excluded as, in infection before initiating immunosuppressive therapy some cases, acute or chronic urticaria may be the only in- (e.g. chemotherapy, high dose steroid- or any other dicator of infection (e.g. strongyloidiasis, gnathostomiasis, immunosuppressive therapy, organ transplantation) toxocariasis, filariasis, fascioliasis, giardiasis, amoebiasis, Blastocystis hominis) [81]. Other frequently seen travel- related dermal hypersensitivity reactions include contact Swimmer’s itch dermatitis (e.g. poison ivy), phytophotodermatitis (e.g. lime juice), drug induced phototoxic reactions (e.g. by ‘Swimmer’s itch’ (also known as ‘lake itch’, ‘duck itch’, doxycycline, which is used for malaria chemoprophylaxis) ‘cercarial dermatitis’, or ‘Schistosome cercarial derma- and other drug eruptions (Fig. 12). titis’) is a short-term, self-limiting immune reaction caused by penetration through the skin of various species of zoo- Diagnosis notic schistosomatida larvae (cercariae of e.g. Tricho- Diagnosis is based on the patient’s history, the clinical bilharzia spp.), and is observed in patients who have picture and (when indicated) laboratory investigations to bathed in freshwater. These zoonotic schistosomatidae rule out an underlying parasitic infection. must not be confused with the Schistosoma spp. that cause invasive human schistosomiasis/bilharziosis. Zoonotic Treatment schistosomatidae are found worldwide and human infection Depending on the severity, symptomatic treatment with is well documented in Central Europe and North America. antihistamines or glucocorticosteroids (topical or oral) may When the parasites’ larvae penetrate the skin, they causes be considered. If an underlying parasitic infection has been mild itchy spots on the skin. Within hours, these spots identified, specific treatment is indicated. become raised papules, which are intensely itchy. Each papule corresponds to the penetration site of a single larva Not to be missed/pitfalls (cercaria). As the parasites die off spontaneously, the In patients with uriticaria (especially in chronic cases) rule symptoms are self-limiting and rarely last longer than a few out a potential underlying parasitosis by stool examination days. (for intestinal parasites) and serological test (for tissue invasive parasites), respectively. Diagnosis Diagnosis is based on the clinical picture and on the patient’s history of freshwater contact. Fungal skin infections

Treatment Although not conﬁned to travelling, dermatomycoses are Depending on the severity, symptomatic treatment with frequently seen in travel clinics but are almost exclusively antihistamines or glucocorticosteroids (topical or oral) may limited to the superﬁcial tinea (ringworm) and pityriasis be considered. versicolor infections [1,2]. Tinea pedis (athlete’s foot) is

Figure 11 Loa loa left: Loa loa creeping eruptions in a migrant; right: conjunctival passage of the adult worm. Author's personal copy

Diagnoses of common dermatological problems in returning travellers 347

Figure 12 Non-infectious skin disorders left: phytotoxic reaction to lime juice; middle: drug rash to atovaquone-proguanil [Malarone] (malaria chemoprophylaxis); right: phototoxic reaction to doxycycline (malaria chemoprophylaxis). probably the most common dermatomycosis in travellers, place of exposure among ill returned travellers. N Engl J but is rarely seen in travel clinics, as the clinical manifes- Med 2006;354:119e30. tation is well known and most patients will either consult [2] Herbinger KH, Siess C, Nothdurft HD, von Sonnenburg F, their general physician or perform self-treatment with over Lo¨scher T. Skin disorders among travellers returning from the counter products. Dermatomycoses caused by other tropical and non-tropical countries consulting a travel medicine clinic. Trop Med Int Health 2011;16:1457e64. fungi endemic to the tropics and subtropics or cutaneous [3] Lederman ER, Weld LH, Elyazar IR, von Sonnenburg F, manifestations of endemic mycoses (e.g. histoplasmosis) Loutan L, Schwartz E, et al. Dermatologic conditions of the ill are only exceptionally reported in travellers [82]. returned traveller: an analysis from the GeoSentinel surveillance network. Int J Infect Dis 2008;12:593e602. Diagnosis [4] Ansart S, Perez L, Jaureguiberry S, Danis M, Bricaire F, Diagnosis is based on the clinical picture and on microscopy Caumes E. Spectrum of dermatoses in 165 travellers and culture of skin scrapings. returning from the tropics with skin diseases. Am J Trop Med Hyg 2007;76:184e6. Treatment [5] Caumes E, Carriere J, Guermonprez G, Bricaire F, Danis M, Depending on the severity and causative fungus, topical or Gentilini M. Dermatoses associated with travel to tropical countries: a prospective study of the diagnosis and man- systemic antimycotic drugs are applied. agement of 269 patients presenting to a tropical disease unit. Clin Infect Dis 1995;20:542e8. Pitfalls/not to be missed [6] Stibich AS, Carbonaro PA, Schwartz RA. Insect bite re- The diagnosis of fungal skin infections is mostly straight- actions: an update. Dermatology 2001;202:193e7. forward. However, some lesions may mimic other disorders, [7] Kulthanan K, Wongkamchai S, Triwongwaranat D. Mosquito e.g. bacterial skin infections or cutaneous leishmaniasis. allergy: clinical features and natural course. J Dermatol 2010;37:1025e31. Summary [8] Peng Z, Simons FE. Mosquito allergy: immune mechanisms and recombinant salivary allergens. Int Arch Allergy Immunol 2004;133:198e209. Dermatological disorders in travellers returning from tropical [9] Tokura Y, Tamura Y, Takigawa M, Koide M, Satoh T, and subtropical destinations are the daily business of travel Sakamoto T, et al. Severe hypersensitivity to mosquito clinics. Differential diagnoses largely depend on the pa- bites associated with natural killer cell lymphocytosis. tient’s travel history, the geographic background of the Arch Dermatol 1990;126:362e8. journey (local endemicity of certain diseases) and the clin- [10] Simons FE, Peng Z. Skeeter syndrome. J Allergy Clin ical picture, with a focus on the evolution of skin manifes- Immunol 1999;104:705e7. tation(s). When evaluating dermatological pathologies in [11] Monsel G, Caumes E. Recent developments in dermato- travellers, the main objective is to rule out potentially se- logical syndromes in returning travellers. Curr Opin Infect e vere or even life-threatening diseases. In this regard, the Dis 2008;21:495 9. presence or development of extra-cutaneous systemic [12] Zanger P. Staphylococcus aureus positive skin infections and international travel. Wien Klin Wochenschr 2010;122: symptoms (e.g. fever, generalised lymphadenopathy) may 31e3. be suggestive (e.g. trypanosomiasis, rickettsiose, etc.). If [13] Zanger P, Nurjadi D, Schleucher R, Scherbaum H, Wolz C, the pathologies are restricted to the skin, the differential Kremsner PG, et al. Import and spread of Panton- diagnoses are best narrowed down by evaluating the pro- Valentine Leukocidin-positive Staphylococcus aureus gression/evolution of the skin manifestation(s) over time through nasal carriage and skin infections in travellers (e.g. cutaneous leishmaniasis, insect bites, etc.). returning from the tropics and subtropics. Clin Infect Dis 2012;54:483e92. Conﬂict of interest [14] Stenhem M, Ortqvist A, Ringberg H, Larsson L, Olsson Liljequist B, Haeggman S, et al. Imported methicillin- resistant Staphylococcus aureus, Sweden. Emerg Infect None. Dis 2010;16:189e96. [15] Sing A, Heesemann J. Imported cutaneous diphtheria, References Germany, 1997e2003. Emerg Infect Dis 2005;11:343e4. [16] de Benoist AC, White JM, Efstratiou A, Kelly C, Mann G, Nazareth B, et al. Imported cutaneous diphtheria, United [1] Freedman DO, Weld LH, Kozarsky PE, Fisk T, Robins R, von Kingdom. Emerg Infect Dis 2004;10:511e3. Sonnenburg F, et al. Spectrum of disease and relation to Author's personal copy

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