Treatment of Cutaneous Leishmaniasis in Travelers 2009
Search strategy and selection criteria: The bibliographic search was done in the Medline/PubMed database and in the collection of documents in the author’s files that included publications and reports in English, French, German, Portuguese, and Spanish written over the past 5 years. Search terms were treatment and CL.
Johannes Blum, MD, DTM&H, Medical Department Swiss Tropical Institute, Socinstrasse 57, CH 4002 Basel, Switzerland. E-mail: firstname.lastname@example.org
Leishmaniasis is an infection caused by intracellular protozoan parasites of the genus Leishmania and it is transmitted by various species of sand flies. Apart from disseminated visceral leishmaniasis (kala azar), nodules, patches/plaques, ulcerative skin lesions, and destructive mucosal inflammation comprise the wide range of clinical manifestations. With regard to cutaneous leishmaniasis (CL) and mucosal leishmaniasis (ML), the parasite species are divided into Old World (Southern Europe, the Middle East, Asia, and Africa) and New World leishmaniasis (Latin America). While most of the Old World species cause benign cutaneous disease, a variety ranging from mild cutaneous disease to severe mucosal lesions is seen among the American species.
CL is one of the 10 leading presentation diseases among tourists from tropical countries with skin diseases and was found in 3% of travelers with skin disorders.1 Because of the broad clinical spectrum of CL and resemblance with common skin diseases such as bacterial or fungal infections and tumors, the correct diagnosis is initially often missed. However, a delayed diagnosis may lead to mucosal spread. Furthermore, treatment of the various species may be different and a suboptimal treatment may cause a prolonged course of the disease and may be associated with disfiguring scars.2,3
The broad availability of polymerase chain reaction (PCR) allows a rapid determination of species. A species-specific treatment approach has been evaluated for many species and is widely applied in many centers.4–9 These treatment options need to be regularly adapted integrating new knowledge and data. This manuscript focuses on new aspects of established compounds and on new drugs such as miltefosine and the combination of traditional compounds with immunomodulators. Recent data focusing on genetic differences of individual species between regions are integrated and region-specific treatment recommendations for Leishmania braziliensis10,11 and Leishmania guyanensis12 CL are given.
In many cases of Old World CL, topical treatment can be used as first-line treatment. In most New World CL, systemic treatment is indicated because of the risk of mucosal spread. The criteria for the use of systemic treatment respecting the aspect of the lesion and the species is summarized in Table 1. The different treatment options for CL and ML according to species, their application mode, dosage schedule, adverse effects, and management are summarized in Tables 2 and 3.
Table 1. The indications for systemic treatment7
|Most species of New World leishmaniasis (Table 2)|
|Mucosal leishmaniasis, longer duration of treatment (30 d)13|
|Established metastatic spread to lymph nodes|
|Localization in the face (nose, eyelids) or close to joints|
|Lesions measuring more than 5 cm in diameter or multiple lesions|
|No response to topical treatment|
|Chronic ear infection of Leishmania mexicana (chiclero ulcer)|
Table 2. Drugs and follow up for treatment of CL
|Pentavalent antimonials||Cardiac toxicity with reversible ECG alterations is seen in 30%–60%||One to two ECG checks every week; interruption of treatment if|
| || Repolarization alterations affecting T wave and ST segment;|| significant arrhythmias|
| || Prolongation of the corrected QT interval|| QTc longer 0.5 s|
| ||Fatal arrhythmias have not been documented with the usual dose ≤20 mg Sb/kg13–16|| QTc longer than 0.45 s: monitoring/dose reduction|
| || Concave ST segment|
| ||Hepatotoxicity seen in 50%, reversible||Transaminases weekly, treatment interruption if transaminases >5 × ULN17|
| ||Hematotoxicity (anemia, leukopenia, and thrombopenia)18||Hemoglobin, leukocytes, and platelets weekly|
| ||Hyperamylasemia tended to occur very early in therapy and to decline despite continued treatment with antimonials||Amylase daily during the first week, then twice weekly. Treatment interruption if serum amylase levels became more than four times the ULN, regardless of symptoms. Therapy can be resumed once these values tend significantly toward normal19,20|
| ||Subjective complaints: musculoskeletal symptoms, headache, gastrointestinal complaints, and pain at the injection site|| |
| ||Rare complications: glomerulonephritis, acute renal failure,21 peripheral neuritis,22 exfoliate dermatitis, and herpes zoster23||Weekly examination of urine and creatinine|
|Pentamidine||Aseptic abscess (accidental contact of pentamidine with the subcutaneous tissue)||Pentamidine has to be injected slowly and strictly intramuscular with a long needle (50 mm) or preferably given as short infusion|
| ||Diabetes, hypoglycemia, and proteinuria||Fasting glycemia and urine for proteinuria and glycosuria have to be checked before every injection and 3 wk 2 mo after the last injection24|
| ||Rhabdomyolysis25,26||Creatinine kinase and kidney function before each application|
| ||Hypotension27,28||The blood pressure and heart rate have to be measured before and after the injection (every 15 min for 1 h)24|
| ||Subjective complaints: myalgia, nausea, headache, pain at the injection side, and abdominal pain27|| |
|Miltefosine||Subjective complaints: nausea (36%), motion sickness (29%), headache (27%), diarrhea (6%–16%), and vomiting (32%–38%)29,30|| |
| ||Impaired renal function: creatinine increase 32% above the ULN (31% <1.5 times the ULN; 1% between 1.5 and 3 ULN)||Creatinine weekly|
| ||Hepatotoxicity: aspartate aminotransferase elevated in 8% alanine aminotransferase in 10% but <2.5 × ULN30||Transaminases weekly, treatment interruption if transaminases >5 × ULN|
|Ketoconazole||Hepatotoxicity reversible, usually mild31||Transaminases weekly, treatment interruption if transaminases >5 × ULN|
| ||Diminution of testosterone values (70%), but without diminution of libido or beard growth31||Reversible, no controls needed|
| ||Subjective complaints: abdominal pain, headache, nausea, fever, and malaise31|| |
|Fluconazole||Hepatotoxicity||Transaminases weekly, treatment interruption if transaminases >5 × ULN|
| ||Allergic skin reactions|| |
| ||Hematotoxicity (anemia, leukopenia, and thrombopenia)||Hemoglobin, leukocytes, and platelets|
| ||Subjective complaints: headache and gastrointestinal complaints|| |
Table 3. Treatment by species
| Leishmania mexicana||Local: ointment with 15% paromomycin plus 12% methylbenzethonium chloride||Twice daily during 20 d||B32,33||+|
| ||Ketoconazole||600 mg daily for 28 d||B34||++|
| Leishmania panamensis||Ketoconazole||600 mg daily for 28 d||B31||++|
| ||Pentavalent antimonials or||20 mg of Sb/kg/d for 20 d||A35,36||+++|
| ||Pentavalent antimonials and in addition||20 mg of Sb/kg/d for 15 d||B37,38|| |
| ||Allopurinol||20 mg/kg/d given in four doses for 15 d|| |
| ||Miltefosine||2.5–3 mg/kg/d for 28 d||B10||++++|
| Leishmania guyanensis: French Guyana, Surinam, and Brazil||Pentamidine isethionate||Three to four short infusions of 4 mg/kg/d every other day or weekly||C27,39,25,40,41||++|
| L guyanensis: Peru||Pentavalent antimonials||20 mg of Sb/kg/d for 20 d||C42||+++|
| Leishmania braziliensis||Pentavalent antimonials||20 mg of Sb/kg/d for 20 d||A13,34,43||+++|
| L braziliensis: Bolivia and Columbia||Miltefosine||2.5–3 mg/kg/d for 28 d||B44||++++|
| Leishmania amazonensis, Leishmania peruviana, and Leishmania venezuelensis||Treatment as for L braziliensis|| |
| L major||15% paromomycin/12% methylbenzethonium chloride ointment||Twice daily during 20 d||A45–47||+|
| ||Localized heat or||Two sessions with localized heat (55°C during 5 min)||C48||+|
| ||Cryotherapy||Two to three sessions of topical application of liquid nitrogen||B49–51|| |
| ||Local infiltration with antimonials||Sodium stibogluconate, meglumine antimoniate; complete blanching of lesion has to be achieved; upper limit of 5 mL per infiltration and 20 mg of Sb/kg; one to two times weekly; one to five infiltrations||A52–54||+|
| ||Fluconazole||200 mg daily for 6 wk||A55||++|
| ||Miltefosine||2.5 mg/kg/d for 28 d||B56,57||++++|
| Leishmania tropica and Leishmania infantum||Local infiltration with antimonials||See above (L major)||B58||+|
| ||15% paromomycin/12% methylbenzethonium chloride ointment||Twice daily during 20 d||D||+|
| ||Cryotherapy||Two to three sessions of topical application of liquid nitrogen||C49–51||+|
| ||Localized heat||Two sessions with localized heat (55°C during 5 min)||D|| |
| ||Pentavalent antimonials||20 mg of Sb/kg/d for 10–20 d||D||+++|
| ||Miltefosine||2.5 mg/kg/d for 28 d||D||++++|
| All species||Pentavalent antimonials and pentoxifylline||20 mg of Sb/kg/d for 30 d and 3 × 400 mg for 30 d||C59||+++|
| ||Liposomal amphothericin B days||Dosages between 2–3 mg/kg over at least 20 d||C60,61||+++++|
| ||Miltefosine||2.5–3 mg/kg/d for 28 d||B44||++++|
Pentavalent antimonials [meglumine antimoniate (MA) and sodium stibogluconate] have been used for decades for the treatment of CL of the New World and are the gold standard for other drugs. The biochemical basis for their effectiveness is unknown but may involve inhibition of ATP synthesis. They are still the best documented treatment and are used as first-line treatment for most New World Leishmania species and for patients with severe Old World leishmaniasis in most travel clinics. The dosage is usually given in Sb equivalents (mg/kg). Some centers administer daily ambulatory treatment without substantial rates of complications.62 Laboratory abnormalities such as liver function tests or amylase are very common and should be monitored as shown in Table 1. Reversible electrocardiogram (ECG) alterations are seen in 30% to 60% and may occur without evidence of myocardial damage.13–15 Recent reports on QTc prolongation in a patient with low serum potassium and underlying cardiac disease to 587 msec16 and in a child63 underline the importance of ECG testing before and during treatment (Table 1). Patients with underlying cardiac disease or with risk of electrolyte disorders such as diuretics or diarrhea should be hospitalized for continuous observation.
Pentamidine, an aromatic diamidin, is the first-line treatment of L guyanensis in French Guyana, Surinam, and Brazil and can be used as an alternative to the pentavalent antimonials.
Pentamidine mesylate (Lomidine) was mainly used in the past. Currently, pentamidine isethionate (Pentacarinat) is the only available drug. Unfortunately, the dosage of pentamidine mesylate (Lomidine) is usually given in pentamidine base and the one of pentamidine isethionate (Pentacarinat) in salt; 4 mg of pentamidine isethionate salt correspond to 2.3 mg base. Thus, the previous (base) dosages can only be compared to the recent dosages (salt) after correcting for the base or salt.
For L guyanensis, similar cure rates were found for seven daily injections of 120 mg of pentamidine mesylate (Lomidine) and 300 mg of pentamidine isethionate (corresponding to 173 mg base) weekly for 3 to 5 weeks (87% vs 94%). The respective relapse rates were 10.6% and 10%.40
Recently, an elevation of the creatinine kinase (CK) was observed with much higher doses of pentamidine isethionate (two injections of 7 mg salt/kg = 4 mg base/kg; second course in case of treatment failure). In 85% of these patients, the CK was extensively elevated (>5,000 IU/L, normal value 25–195 IU/L) indicating rhabdomyolysis, but clinical symptoms of rhabdomyolysis such as muscle pain, weakness, or renal failure, were not observed.25 In an additional study with single-dose pentamidine isethionate (7 mg salt/kg = 4 mg base/kg), substantially increased CK elevation (>1,000 U/L, range 1,032–9,312 U/L, normal <160 U/L) was observed in 19 of 26 patients.26 In most studies, CK was not tested. It is not clear if the higher dosage of pentamidine and/or the intramuscular application is the cause of CK elevation or if rhabdomyolysis was overseen because of lack of symptoms and lack of testing in previous studies. Pentamidine isethionate in the dosage of 4 mg/kg (salt) intramuscularly daily for 7 days is the treatment of choice for human African Trypanosomiasis. In a previous and a recent trial with about 200 patients, no rhabdomyolysis was reported.
Because of this risk of rhabdomyolysis, an alternative treatment would be preferable. The only validated alternative treatment for L guyanensis CL would be pentavalent antimony. But its cure rate after 6 months was disappointingly low (26.3%).64 However, in a recent study in Peru, the cure rate after 6 months of pentavalent antimony was much higher (91.7%). A part from study design differences, these differences could be explained by genetic differences within individual species.12
Because of the long lasting good experience in respect to efficacy and safety and because of the lack of a validated alternative, pentamidine has to be considered as first-line treatment of L guyanensis CL in French Guyana, Surinam, and Brazil. In Peru, pentavalent antimony could be used as first-line treatment. Because of the unclear correlation of high-dose pentamidine and CK, repeated doses of pentamidine [three to four doses of 4 mg/kg pentamidine salt (Pentacarinat) on alternate days or weekly as intravenous infusion]40,41 can be proposed, but CK and kidney function have to be controlled before every injection.
Miltefosine, a phosphocholine analog, is a new promising oral agent for visceral leishmaniasis. An increasing number of studies shows its efficacy in Old World and New World CL and ML. The same dose of 2.5 mg/kg/d for 28 days was used for CL and ML.
The most important adverse events are nausea (36%), vomiting (32%–38%), motion sickness (29%), headache (27%), and diarrhea (6%–16%).29,30 However, vomiting lasted less than 3 days in most patients and did usually not lead to a discontinuation of treatment. Creatinine increased above the normal range in 32%, in 31% <1.5 times the upper limit of normal, and in 1% between 1.5 and 3 times the upper limit of normal.30 The aspartate aminotransferase was elevated in 8% and the alanine aminotransferase in 10% but always less than 2.5 times the upper limit of normal.30
Old World CL
Treatment with miltefosine is reported in only a small number of patients with Old World CL. The cure rate (26 of 28 = 92.9%) of miltefosine was superior to the cure rate (25 of 31 = 83.1%) of meglumine antimoniate (20 mg/kg for 14 days) in patients with Leishmania major CL. However, four patients in the miltefosine group stopped treatment because of severe vomiting.56 In a small nonrandomized trial with L major and Leishmania tropica miltefosine (n = 15) had a cure rate of 100% at the end of treatment and 87% after 6 months and was superior to meglumine antimoniate (20 mg/kg for 28 days) with a cure rate of 93% at the end of treatment and 67% after 6 months.57 In the mouse model, four L tropica isolates resistant to meglumine antimoniate from Iran were shown to be sensitive to miltefosine and to paromomycin.65
In L major CL, miltefosine appears to be a valuable option and may be superior to meglumine antimoniate for 14 days. However, the high price and adverse events such as vomiting limit its use. The alternative for oral treatment is fluconazole (Table 3). The limited data do not allow a judgment of the efficacy against Leishmania infantum and L tropica.
New World Leishmaniasis
Miltefosine shows promising effects on Leishmania panamensis (91%–94% cure rate), but only a limited effect against Leishmania mexicana (60%).10,66 It failed to cure L braziliensis infections (33%) in Guatemala.10 Interestingly, the cure rates of miltefosine of L braziliensis infections in Bolivia (88%) were much higher than in Guatemala and similar to meglumine antimoniate (94%),11 but antimony cured more rapidly. It appears that subspecies of L braziliensis respond differently to miltefosine. Thus, this drug needs to be evaluated in different regions.
In New World ML (mainly L braziliensis), the cure rate of miltefosine was 83% in patients with mild disease (ie, nasal mucosa) and 58% in patients with more extensive disease (involving pharynx, larynx, and palate). In a nonrandomized contemporary group with ML treated with amphothericin B (45 injections of 1 mg/kg applied every other day), the cure rate was only 50%.44
Miltefosine is a valuable option for L panamensis. However, the high costs and poor tolerability limit its use. Ketoconazole (Table 2) is a less expensive and better tolerated alternative for oral treatment, even if the efficacy was slightly inferior (76% cure rate).31 For L braziliensis, meglumine antimoniate is still the treatment of choice, but miltefosine can be used as alternative, mainly in patients with ML.
Liposomal Amphothericin B
The antifungal agent amphothericin B is active against Leishmania species. Its main disadvantage is the high incidence of adverse reactions (hyperpyrexia, severe malaise, hypotension, thrombophlebitis, azotemia, renal tubular damage, hypokaliaemia, anemia, and hepatitis). The development of several amphothericin B lipid formulations with lower toxicities than the free drug has proved to be useful in the treatment of visceral leishmaniasis, but the appropriate doses for CL and ML are still under debate. Liposomal amphothericin B is mainly used in patients with resistance or contraindications for pentavalent antimonials. In ML, good response has been observed with dosages between 2 and 3 mg/kg for at least 20 days.60,61 Even in the absence of a randomized study, there are now sufficient data to support recommendation of liposomal amphothericin B. The high cost limits its use as first-line treatment for ML.
Fluconazole, Itraconazole, and Ketoconazole
The imidazoles and the structurally related triazoles were introduced as antifungal drugs, but also have an antileishmanial activity. They have the advantage of oral administration and few adverse effects.
Fluconazole was well tolerated and showed promising results in L major leishmaniasis in Iran with a cure rate of 36% at day 50 and 88% at day 90 compared to the corresponding cure rates of 10% and 66% in the placebo group.55 Unfortunately, these good responses of fluconazole could not be reproduced: the cure rate of 44% at day 50 was similar to published data of spontaneous healing but was not compared to a placebo group.67 Because of different interpretation of cure rate and different geographic regions, these data do not allow additional conclusions. In the same study, five patients with L infantum lesions had treatment failure with fluconazole.67
The efficacy of itraconazole is doubtful. The clinical cure rates 200 mg of itraconazole daily for 8 weeks (59%) was similar to the placebo group (53%) in patients with L major CL.68
Studies with small patient numbers from the 1980s and early 1990s showed that ketoconazole has an acceptable cure rate for L panamensis (76%),31 for L mexicana (eight of nine patients),34 and for L major (70%).69,70 However, these studies comprised only limited patient numbers and were not confirmed by recent studies.
Fluconazole is the imidazole of first choice for treatment of L major infections and ketoconazole for L panamensis infections.31 Because of only limited data on L infantum with treatment failure in all cases, fluconazole cannot be suggested for treating L infantum leishmaniasis.
The efficacy of azithromycin is limited.71–73 However, it was successfully applied in the dosage of 500 mg daily during 10 days, in three to four cycles every 1 to 2 months in a child (L infantum)74 and in three elderly patients with ML and contraindication to classical drugs.75 Therefore, the use of azithromycin is limited to patients with treatment failure or contraindications for all other options such as small children, pregnant women, or patients with underlying severe disease.
Combination of Pentavalent Antimony With Topical Application of Immunomodulators
Topical immunomodulators are ineffective given alone but may improve the efficacy of a standard treatment such as meglumine antimoniate if given in combination.
Imiquimod (1(2methylpropyl)-1H-imidazo(4,5-c)quinolin-4-amine) is widely used against genital warts caused by the human papillomavirus. It acts as an immune response modifier through stimulation of a local immune response at the site of application on the cutaneous genital warts, resulting in wart regression and resolution. It has no direct activity against leishmaniasis but was shown to improve the efficacy of pentavalent antimonials.
With CL (L peruviana) 12 patients resistant to MA responded to the combination of MA plus imiquimod (5% cream topically, applied every other day for 20 days).76 Seven patients with New World leishmaniasis (species unknown) all had a clinical cure, whereas only four of seven patients in the placebo group were cured.77 The addition of imiquimod to MA did not improve the cure rate but induced a more rapid healing in 40 patients suffering from L peruviana or L braziliensis CL.78
However, in Old World leishmaniasis due to probably L tropica, the addition of imiquimod did not improve the cure rate of meglumine antimoniate for 14 days.79
Human granulocyte–macrophage colony-stimulation factor (GM-CSF) is commercially available (molgramostim). It has to be diluted to a final concentration of 10 μg/mL and to be applied on the ulcer as follows: ulcers are cleansed with 0.9% sodium chloride solution and are sprinkled with 1 mL of GM-CSF working solution, providing a final dose between 1 and 2 μg/cm2 of ulcer area. A nonadhesive hydrophobic wound compress is secured over the area with a cotton bandage and a short stretch compression bandage. The application of 200 μg of GM-CSF into the lesion at enrollment and 1 week later decreased the time of healing significantly and was—apart from minor local reactions—well tolerated.80 The mean healing time was shorter (43 days) in the GM-CSF (three applications per week for 3 weeks) group than in the placebo group (104 days).81 Five patients who had received three or more courses of antimony without success could be healed with 1 to 2 mL of the GM-CSF solution (10 μg/mL) associated with standard parenteral antimony.82
The addition of an immunomodulating topical treatment to antimonials appears to be promising, but additional studies with other Leishmania species are needed. The additional workload of local application and bandages is compensated by a quicker achievement of healing, a better cure rate and cure in patients with lesions refractory to MA. The data are insufficient to compare imiquimod and GS-CFS. In patients with refractory lesions or lesions needing a quick treatment (face), the addition of an immune modulator may be tried.
Combination of Oral Pentoxifylline and Pentavalent Antimony
In mucosal destructive lesions, a paucity of parasites and high levels of tumor necrosis factor (TNF) are observed, and the tissue damage is related to an unmodulated immune response with increased production of proinflammatory cytokines such as interleukin-10. Pentoxyfilline is known to downregulate TNF-α and to decrease leukocyte migration and adhesion. In 10 patients with refractory ML, the combination therapy of pentoxifylline (3 × 400 mg for 30 days) and antimony (20 mg/kg of Sb for 30 days) induced cure.59 Another 11 patients with ML treated with the same combination were cured, whereas 5 of 12 patients (41.6%) in the placebo group (only antimony) required a second course of antimony. The healing time in the pentoxifylline group was 83 days compared with 145 days in the placebo group. No relapses were documented in either group at the 2-year follow-up visit.83 A satisfactory response with quick cure of skin lesions of two patients with New World CL unresponsive to antimonial drugs was observed after treatment with pentoxifylline and antimony.84
The combination of antimony and pentoxifylline was superior to antimony and placebo also in patients with L major CL: complete improvement, partial improvement, and poor response to treatment were 81.3%, 12.5%, and 6.2% in the trial group and 51.6%, 29%, and 19.4% in the control group, respectively.85
The addition of pentoxifylline to MA is well tolerated and only mild adverse effects (gastrointestinal symptoms and arthralgia) were attributed to pentoxyfilline.83,85 The combination of MA and pentoxifylline is superior to MA alone and is suggested for relapsing and severe ML.83 There are no data on the combination of pentoxifylline with other drugs such as amphothericin B and miltefosine.
With a defined antigen combination, clinical cure could be obtained in six patients with refractory ML, but such vaccination is not yet available.86
Local heat treatment with special devices,48,87 cryotherapy,49,88,89 laser treatment,90 or combination of cryotherapy with intralesional meglumine antimoniate91,92 were successfully applied in endemic countries. However, physical treatment was not applied in patients with Old World CL in Germany,93,94 Italy,95 France,96 and the United Kingdom8 probably because the technical methods are not available in these clinics or the physicians have no routine to apply these methods. Cryotherapy was used only in the Netherlands.97 Physical treatment needs some clinical experience and technical assistance and is limited to centers with a high number of CL patients.
Fifteen Percent Paromomycin Plus 12% Methylbenzethonium Chloride
An ointment with 15% paromomycin plus 12% methylbenzethonium chloride appears to be more effective than the combination of 15% paromomycin plus 10% urea but causes more local inflammatory reactions.98 Methlybenzethonium itself has some antileishmanial activity, may cause a local inflammation, and appears to improve the penetration of paromomycin.99 The main problem for this topical treatment is the weak penetration of paromomycin into the intact skin.99 Topical formulations may be applied for open lesions.99
Patient Groups of Special Interest
Pregnancy influences the clinical manifestations of L braziliensis CL. The lesions of pregnant women with CL are larger than in nonpregnant women and in contrast to the typical presentation of a well-demarcated ulcer with raised border, lesions are often of a cauliflower appearance.100 Because pentavalent antimonies are potentially abortogenic, treatment is commonly withheld until delivery and topical treatment is applied.100
In patients with contraindications for the optimal treatment such as small children,74 pregnant women, or patients with underlying severe disease,75 azithromycin can be an option despite its limited efficacy.
Widely available PCR tests to determine the species allow species-specific diagnosis of the causing organism and a species-specific treatment. However, most studies were done in endemic regions and different responses to treatment cannot be ruled out in travelers. Thus, a multinational observational study using a standardized protocol is warranted to assess the pattern of disease and to optimize treatment in travelers.
Declaration of Interests
The authors state that they have no conflicts of interest.