Tropical medicine rounds

Blackwell Oxford, International IJD 0011-9059 XXX 2007 The UK Publishing International Journal Ltd of Dermatology Society of Dermatology

Indigenous leishmaniasis in Taiwan: report of a case

Indigenous Wang TROPICAL et al. leishmaniasis MEDICINE in ROUNDS Taiwan

Jia-Ru Wang1, MD, Sho-Tone Lee2, PhD, Wei-Hsin Juan1, MD, Wei-Lin Chuang2, MS, Shuen-Iu Hung3, PhD, Wen-Hung Chung1, MD, and Hong-Shang Hong4, MD, PhD

From the 1Department of Dermatology, Chang Gung Memorial Hospital, Taipei, 2Institute of Biomedical Sciences, Academia Sinica, Taipei, 3Institute of Pharmacology, National Yang-Ming University, Taipei, 4Chang Gung University, Kwei-Shan Tao-Yuan, Taiwan Correspondence Yue-Zon Kuan, MD Department of Dermatology Chang Gung Memorial Hospital 199, Tun Hwa North Road Taipei Taiwan E-mail: derma0006@adm.cgmh.org.tw

Abstract
Taiwan is not considered an endemic area of leishmaniasis. Imported cases are encountered infrequently, and only two cases of indigenous cutaneous leishmaniasis have been reported.1 We found one new case in the past 20 years. The patient presented with erythematous plaques on the nasal bridge and right thumb. Skin biopsy specimens from both sites revealed numerous LeishmanDonovan bodies in macrophages. There was no history of travel outside the country, and the diagnosis of indigenous cutaneous leishmaniasis was made. Polymerase chain reactions (PCR) identied the species as Leishmania tropica. The route of infection in this patient is unclear. Because pentavalent antimony, the drug of choice for leishmaniasis, is not available in Taiwan, the patient was treated with levamisole and potassium iodide, with an excellent response.

Introduction Leishmaniasis is a protozoan disease caused by the parasite Leishmania and transmitted by infected phlebotomine sand flies. The parasite has a digenetic life cycle shuttling between a flagellated promastigote in the gut of a sand fly and an intracellular amastigote in mammalian macrophages, which are the obligate hosts of the parasite. The term leishmaniasis includes cutaneous, mucocutaneous, and visceral types.2 Case Report In May 2005, a 57-year-old woman presented with a 1-month history of an erythematous plaque on the nasal bridge (Fig. 1), and a 1-week history of a papule involving her right thumb. The lesions were mildly pruritic but not painful. The patient had chronic diabetes mellitus and Graves disease. She has worked as a fruit farmer on Mount Takuan in northern Taiwan, but she had not contacted exotic fruit or traveled outside the country. There was no history of trauma or insect bite. She had an apparently healthy dog and previously had a dog that died from an unknown disease. The skin lesions measured 1.2 cm and 0.5 cm in diameter, respectively. There was no nasal deformity, lymphadenopathy, or hepatosplenomegaly. Biopsy was obtained from the nasal bridge lesion, and the papule of the right thumb was excised completely. Histologic examination of both lesions revealed multiple small granulomas on a background of heavy lymphoplasmacytic dermal infiltrates (Fig. 2a). There were numerous small organisms in histiocytes, compatible with
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LeishmanDonovan bodies on Giemsa-stained sections (Fig. 2b). Because the history was negative for travel outside the country, a diagnosis of indigenous cutaneous leishmaniasis was made. Western blot analysis, using the patients serum as an immuno-probe, showed strong reactivity to Leishmania tropica (BTO11) and Leishmania infantum (Bman), but not to Leishmania donovani (Jeddah) and Leishmania major (LH32) (Fig. 3). Total DNA was extracted from a fresh nasal skin biopsy specimen. PCR primers [5 LITSR (5-CTGGATCATTTTCCGATG-3) and 3 L5.8S (5-TGATACCACTTATCGCACTT-3)] were designed to amplify a 300350-bp region in the ribosomal internal transcribed spacer 1 (ITS1) flanking between the genes coding for SSU and 5.8S rRNA gene. Amplification reactions were performed in 50 L containing the following: 1.5 mm MgCl2; 200 m each of dNTPs; 500 nm primers; and 2 units of Taq DNA polymerase. Amplification was performed by a GenAmp PCR System 9700 (Applied Biosystems) with an initial step of denaturation for 3 min at 96 C, followed by 35 cycles, with each cycle consisting of 30 s at 94 C, 1 min at 53 C, and 2 min at 72 C, and finally, a final extension for 5 min at 72 C. PCR products were analyzed by DNA gel electrophoresis on a 2% (wt/vol) agarose gel, stained with ethidium bromide, and visualized on a UV transilluminator (Fig. 4). The sequencing result was comparable with the ITS1 region of L. tropica deposited in GenBank (accession no. AJ000301 to AJ000302). Ketoconazole 400 mg daily for 8 weeks was prescribed because pentavalent antimony, the drug of choice for leishmaniasis, was not available in Taiwan. After a poor clinical
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Figure 1 A poorly demarcated, indurated erythematous plaque

involving the nasal bridge

response to ketoconazole, subtotal excision of the nasal lesion was performed, and systemic fluconazole 150 mg daily for 8 weeks was prescribed. However, the nasal lesion enlarged. Levamisole hydrochloride 50 mg t.i.d. for 3 days every 2 weeks and potassium iodide 300 mg orally t.i.d. were then prescribed. In 1 month, the lesion appeared smaller, softer, and less erythematous. Discussion In 1903, Leishman and Donovan, working separately, described the protozoan Leishmania. Leishmaniasis is a collective term used to describe the diseases caused by 20 Leishmania species pathogenic to mammals. Worldwide, approximately 12 million people have leishmaniasis, with 1.52 million new cases reported each year.3 Leishmaniasis is widespread in 22 countries in the New World and in 66 countries in the Old World. The disease is not found in Southeast Asia, except in Vietnam; kala-azar was diagnosed in three HIV-positive women in Vietnam in 2002.4 Leishmaniasis is transmitted by the female phlebotomine sand fly. Thirty out of 500 phlebotomine species have been identified as vectors of the disease. Leishmaniasis is an important infectious disease in mainland China, especially the regions north of the Yangtze River, such as Xinjiang, Sichuan, Gansu, Shanxi, Shaanxi, Neimenggu, and Shandong.5 Taiwan is not considered to be an endemic area, and leishmaniasis was not seen in Taiwan prior to World War II. About 100 imported cases of kala-azar were observed in civilians and military personnel from
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Figure 2 (a) Multiple small granulomas embedded in a dense lymphoplasmacytic infiltrate, and numerous small cellular organisms within histiocytes (hematoxylin and eosin, 100). (b) Giemsa-stained section demonstrates the intracellular organisms consistent with Leishman-Donovan bodies (400)

Figure 3 Western blot result. Serum of the patient showed no reactivity to L. amazonensis (Promastigote) (1), L. amazonensis (Amastigote) (2), L. major (3) and L. donovani (4) while strong reactivity to L. tropica (5) and L. infantum (6)
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Tropical medicine rounds Indigenous leishmaniasis in Taiwan

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Table 1 Treatment of leishmaniasis

Species Old World L. tropica L. ethiopica

Category Local treatment Physical

Type of treatment Cryotherapy11 Local heat12 Surgery Paromomycin Paromomycin with methylbenzethonium Imiquimod16 Pentavalent antimony

New World L. brasiliensis

Ointment

L. major13

L. mexicana14 L. panamensis15 L. mexicana

Local inltration Photodynamic therapy Intravenous

Systemic treatment

Pentavalent antimony (Sodium stibogluconate)

L. major17 L. tropica18 L. donovani19 L. major L. tropica L. donovani

Oral

Pentamidine Amphotericin B1 Ketoconazole Fluconazole Other: Rifampin26; Dapsone1; Allopurinol1; Pentoxiline27; Miltefosine28 Vaccination29 Interferone-30 Sitamaquine (WR6026)31 Phytotherapy32

L. guyanensis L. panamensis L. brasiliensis L. guyanensis20 L. Mexicana22 L. panamensis23

L. major21 L. major24 (no response to L. tropica25)

Immunotherapy Other

Figure 4 Leishmania PCR result. 1: DNA extracted from skin

lesion of patient, 2: DNA extracted from normal human skin, 3: negative control

mainland China during and after the civil war. The first report of autochthonous leishmaniasis in Taiwan was published in 1985 by John and colleagues.1 They described two native born aboriginal Taiwanese, with cutaneous leishmaniasis,
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who were from the same village in Hsinchu County of northern Taiwan and had never traveled far from home.1 Although a human-bite sand fly species Phlebotomus kiangsuensis had been identified in Taiwan in 1970,6 John and colleagues could identify only the sand fly Phlebotomus iyengari taiwanensis that feeds on animals in the area. No disease was found in other humans, dogs, cats, rodents, birds, reptiles, and amphibians in the region. The infectious route in our patient was not clear. Since the possible species was L. tropica, the source of infection probably did not come from mainland China where kala-azar and post-kala-azar dermal leishmaniasis are caused most commonly by L. donovani.1 Because sand flies have been found in Taiwan, physical transmission by sand flies was possible, with village animals as a reservoir, although serum from the patients dog was negative for leishmania. There probably are unrecognized autochthonous foci, such as wild animals, in the remote mountains of Taiwan. Treatment of leishmaniasis varies according to the infecting species and clinical severity (Table 1). Lesions of Old World cutaneous leishmaniasis may resolve spontaneously. Intervention is necessary only in the following conditions: cosmetically unacceptable lesions, chronic and large lesions, mucosal disease, multiple lesions, worsening lesions, and lesions in immunosuppressed patients.3 Levamisole and potassium iodide were beneficial in our patient. Levamisole is
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a levo-isomer of tetramisole, a potent antihelmintic agent. In 1971, its immunomodulatory effects were documented.7 Levamisole is capable of inducing T-cell differentiation and restoring depressed effector function of peripheral lymphocytes and phagocytes. Potassium iodide is used to treat inflammatory dermatoses such as Sweets syndrome, erythema nodosum, subacute nodular migratory panniculitis, and some cutaneous infection,9 but its mechanism of action is unknown. These drugs also may be useful in other countries where pentavalent antimony is unavailable. More data are needed to establish the roles of levamisole and potassium iodide in the treatment of leishmaniasis. References
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16 Josef S, Saleh D, Johannes P. Transient effect of topical treatment of cutaneous leishmaniasis with imiquimod. Int J Dermatol 2003; 42: 576579. 17 Alkhawajah AM, Larbi E, al GY, et al. Treatment of cutaneous leishmaniasis with antimony: intramuscular versus intralesional administration. Ann Trop Med Parasitol 1995; 91: 899 905. 18 Munir M, Mohammed K, Babkerhyl M. Guidelines for the Treatment and Prevention of Cutaneous Leishmaniasis in Pakistan 2002 Ministry of Health Pakistan; WHO, Health Net International. 19 Gardlo K, Horska Z, Enk CD, et al. Treatment of cutaneous leishmaniasis by photodynamic therapy. J Am Acad Dermatol 2003; 48: 893896. 20 Soto J, Buffet P, Grogl M, et al. Successful treatment of Colombian cutaneous leishmaniasis with four injections of pentamidine. Am J Trop Med Hyg 1994; 50: 107111. 21 Weinrauch L, Livshin R, el-On J. Ketoconazole in cutaneous leishmaniasis. Br J Dermatol 1987; 117: 666668. 22 Navin TR, Arana BA, Arana FE, et al. Placebo-controlled clinical trial of sodium stibogluconate (Pentostam) versus ketoconazole for treating cutaneous leishmaniasis in Guatemala. J Infect Dis 1992; 165: 528534. 23 Saenz RE, Paz H, Berman JD. Efficacy of ketoconazole against Leishmania braziliensis panamensis cutaneous leishmaniasis. Am J Med 1990; 89: 147155. 24 Alrajhi AA, Ibrahim EA, De EB, et al. Fluconazole for the treatment of cutaneous leishmaniasis caused by Leishmania major. N Engl J Med 2002; 346: 891895. 25 Singh S, Singh R, Sundar S. Failure of ketoconazole treatment in cutaneous leishmaniasis. Int J Dermatol 1995; 34: 120121. 26 Choi CM, Lerner EA. Leishmaniasis: recognition and management with a focus on the immunocompromised patient. Am J Clin Dermatol 2002; 3: 91105. 27 Bafica A, Oliveira F, Freitas LAR, et al. American cutaneous leishmaniasis unresponsive to antimonial drugs: successful treatment using combination of N-methilglucamine antimoniate plus pentoxifylline. Int J Dermatol 2003; 42: 203207. 28 Yardley V, Croft SL, De D, et al. The sensitivity of clinical isolates of leishmania from Peru and Nepal to miltefosine. Am J Trop Med Hyg 2005; 73: 272275. 29 Mayrink W, Botelho A, Magalhaes PA. Immunotherapy, immunochemotherapy and chemotherapy for American cutaneous leishmaniasis treatment. Rev Soc Bras Med Trop 2006; 39: 1421. 30 Mahrle G, Schulze HJ. Recombinant interferon gamma (rIFN-gamma) in dermatology. J Invest Dermatol 1990; 95: 132s137s. 31 Wasunna MK, Rashid JR, Mbui J, et al. A phase II dose-increasing study of sitamaquine for the treatment of visceral leishmaniasis in Kenya. Am J Trop Med Hyg 2005; 73: 871876. 32 de Carvalho PB, Ferreira EI. Leishmaniasis phytotherapy. Natures leadership against an ancient disease. Fitoterapia 2001; 72: 599 618.

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