Cutaneous leishmaniasis (CL) is endemic in more than 70 countries worldwide. Approximately 0.7 to 1.2 million CL cases occur each year. It can be classified according to reservoir (anthroponotic or zoonotic CL) or geographic distribution (New World or Old World CL). Leishmania major is responsible for zoonotic Old World CL. We reported a cluster of L major leishmaniasis in four travelers returning from Turkmenistan.
We report a cluster of cutaneous leishmaniasis due to Leishmania major in four immunocompetent travelers returning from Western Turkmenistan and having atypical and/or multiple lesions. Treatments with pentamidine or fluconazole were effective. Physicians should be aware that some virulent strains of L major currently circulate in Central Asia.
An immunocompetent 39-year-old French woman was admitted in Bégin Hospital for papulonodular skin lesions. Two weeks earlier, she returned from Western Turkmenistan where she participated in archeological excavations in a semi-arid desert near Bugdayly with three other persons from mid-September to mid-October 2012. They spent considerable time outdoors and slept in a house without protection against arthropod bites.
At admission, lesions were present for 3 weeks. Fifteen painless, ulcerated and necrotic lesions covered with scabs were located on her forearms, arms, and nose (Figure 1). Direct microscopic examination of smears obtained by skin biopsies and stained with May-Grunwald-Giemsa showed numerous intra- and extra-cellular amastigote forms of Leishmania.
Cases 2 + 3
Patient 2, a 63-year-old English man, and patient 3, a 33-year-old French woman, who both participated in this archeological mission, were invited to consult at the same hospital. They presented smaller lesions than those seen in patient 1. Patient 2 had about 10 lesions on his back, right buttock, and left wrist, and also two erysipeloid lesions on the right foot without phlebitis or lymphadenitis. Patient 3 had three erythematous infiltrations on her feet. Microscopic examination of biopsies obtained from both patients confirmed the diagnosis of leishmaniasis.
For these three patients, parasitological diagnosis was confirmed by polymerase chain reaction (PCR) using the method described by Foulet et al. Promastigote forms of Leishmania were also isolated on a mix of heat-inactivated fetal calf serum and RPMI supplemented with antibiotics (vancomycin and amikacin). The species was identified as L major by the French leishmaniasis reference center (Montpellier, France).
Three 4-mg/kg intramuscular injections of pentamidine base were administered every 48 hours to patients 1 and 2 during hospitalization. Patient 3 received only two doses because of the low number of lesions. A second cure of pentamidine isethionate (two 4 mg/kg doses on alternate days) was administered 6 weeks later to the three patients because of a lack of response to treatment. The clinical tolerance was good. Particularly, no hyperglycemia or rhabdomyolysis was noticed.
Patient 4, a 42-year-old man, consulted the Geneva University Hospitals. He presented about 40 reddened papular lesions covered with scabs on his back, limbs, and face. He also complained of arthromyalgia.
Microscopic examination showed rare Leishmania. Serology with ImmunoFluorescence Antibody Test was doubtful. Species identification by PCR at the Swiss Tropical and Public Health Institute (Basel, Switzerland), following a two-step method described by Marfurt et al. revealed L major.
He was started on fluconazole 200 mg daily. The evolution was marked by the appearance of cellulitis of the right foot treated by amoxicilin and clavulanic acid then clindamycin and ciprofloxacin. Because of the lack of improvement of existing lesions and the appearance of new ones, fluconazole dosage was increased after 2 weeks to 400 mg daily for 6 weeks and imiquimod cream was applied on the facial lesion. In addition, cryotherapy was applied on a few slow-evolving lesions on the right upper limb. No hepatotoxicity or hematotoxicity was noticed. On week 5, a thrombophlebitis of the right soleal vein was found, requiring anticoagulation for 6 weeks.
The lesions regressed completely for all patients at fourth month, leaving behind hyper pigmented scars.
Between 2000 and 2009, 1,562 cases of CL have been reported in Turkmenistan, mostly in the southern and eastern parts of the country bordering Iran and Afghanistan, where there is currently a large outbreak. No data on leishmaniasis in the western part of Turkmenistan are currently available. Three species have been reported in Turkmenistan: L major, Leishmania tropica, and Leishmania infantum. In Afghanistan, zoonotic CL occurs from August to January with a peak in mid-October, and the incubation period is 8 to 12 weeks. In this geographic area, the principal vector of L major is the sand fly Phlebotomus papatasi and the main animal reservoir is the great gerbil, Rhombomys opimus.
CL is known for its clinical diversity that depends on several factors, including the virulence of the causative Leishmania strain. Travelers with CL due to L major usually have one to seven lesions and can present papules, nodules, ulcers, or erythemato-squamous plaques. In contrast, patient 1 had numerous wet and ulcerated lesions and patient 4 exhibited about 40 lesions. This unusual clinical picture, the short incubation period, and the 100% attack rate in the archeological mission suggest the involvement of a highly aggressive isolate of L major, as described in Afghanistan and Uzbekistan.[5, 7] This strain is responsible for disseminated CL with nodular lymphangitis and superinfections. Without specific treatment, lesions persist for 3 to 8 months and are generally self-healing with definitive keloid scars. However, it is impossible here to incriminate this strain without further molecular studies.
The high number of lesions could be caused by multiple sandfly bites in these unprotected individuals. High density of sandflies due to a local proliferation induced by ecological factors may have occurred but is likely to be seasonal as suggested by the absence of cases among members of the previous archeological missions. The clinical polymorphism can also be explained by the variable susceptibility of each patient.
Although administration of pentavalent antimonials is considered to be the first-line treatment of Old World CL, no study has compared their efficacy with pentamidine isethionate or imidazoles. Antimonials are toxic, inconvenient, and relatively expensive. In addition, the virulent strain of L major is associated with delayed or poor response to treatment with sodium stibogluconate, as well as miltefosine.
Fluconazole, used for patient 4, is the imidazole of choice for treatment of L major infections. Imidazoles have the advantage of oral administration and good tolerance. A randomized clinical trial in Iran showed that high dose fluconazole (400 mg/day) was more effective than the low-dose regimen (200 mg/day).
Pentamidine is recommended as first-line treatment of Leishmania guyanensis CL in French Guyana. It is also a second-line treatment of Old World CL after failure of antimonials or fluconazole. Considering the lack of clear consensus, the toxicity of antimonials and the extensive experience of using pentamidine in patients returning from French Guyana, the first three patients were treated with pentamidine isethionate. The favorable outcome suggests that pentamidine is effective for Old World CL. In an open-label study of 11 cases of imported Old World CL with large and chronic lesions, three 4-mg/kg intramuscular injections of pentamidine base given every 48 hours as first-line treatment yielded a success rate of 73%. Tolerance is good with the therapeutic regimens used.[11, 12]
Physicians should be aware of these CL due to virulent strains from Central Asia. Molecular biology-based studies are needed to identify factors of virulence of these strains and their pathogenicity. Pentamidine isethionate and fluconazole appear as potential first-line treatments for these CL. Nevertheless, well-designed randomized controlled trials are needed before making any definitive recommendation.
Declaration of Interests
The authors state that they have no conflicts of interest.