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Andreas Neumayr, MD, DTM&H, MCTM, Swiss Tropical and Public Health Institute, Socinstr. 57, P.O. Box CH-4002 Basel, Switzerland. E-mail: firstname.lastname@example.org
Old World mucosal leishmaniasis is a rare but regularly reported disease in Southern Europe. We report the case of a 64-year-old woman who developed severe hypokalemia under meglumine antimoniate treatment and was successfully treated under second line therapy with miltefosine.
A 64-year-old Swiss woman was referred by her dentist with therapy-refractory painful mucosal lesions in the oral cavity, persisting over the last 6 months. The dental examination revealed multiple mucosal lesions on the hard and soft palate, gingiva, and base of the tongue, with the largest lesion measuring about 15 mm in diameter (Figure 1). Past medical history and physical examination were otherwise unremarkable revealing no history of skin lesions. Routine laboratory investigations—including tests for underlying immunodeficiency—were inconspicuous. Intraoral radiography revealed no signs of a bony destruction. The patient's travel history included trips to Italy [more than 15 journeys (approximately 14 d each time) at different seasons and to various places in the last 10 y], Greece (every year 1 wk to Crete for the last 15 y), Spain (2003), Morocco (2001), and Egypt (2000). Microscopical investigation of a mucosal biopsy confirmed the presumptive diagnosis of “mucosal leishmaniasis (ML)” (Figure 1). Polymerase chain reaction (PCR) identified Leishmania infantum as the species.1,2 As the patient lives in Switzerland outside Leishmania endemic regions, she must have acquired the infection while traveling in an L infantum endemic region (in her case: Italy, Greece, Spain, or Morocco).3
The patient was put on intramuscularly administered pentavalent antimonial treatment (meglumine antimoniate 20 mg/kg body weight/d). After 7 days of treatment, the patient developed a pronounced pruritic, partly erythematous, partly papulo-urticarial rash on the trunk and the inner thighs, which responded to oral antihistamine and topical corticosteroid treatment. On follow-up on day 12 of treatment the laboratory check-up showed severe hypokalemia (2.3 mmol/L) and an elevated serum amylase level (300 U/L). Additionally, we found a newly developed prolonged QTc interval (600 ms) on electrocardiogram (ECG). Due to the severe hypokalemia, treatment with meglumine antimoniate was immediately suspended. After aborting treatment and starting potassium substitution, the potassium level and the QTc interval showed rapid normalization (as did the serum amylase level and skin rash).
With the consent of the patient, we decided to change the antileishmanial treatment to oral miltefosine [2.5 mg/kg body weight/d = 50 mg three times a day (TID)] for 30 days. After starting miltefosine treatment, the patient complained about pronounced nausea with repeated vomiting and presented with clinical signs of dehydration. Laboratory tests showed impaired kidney function (creatinine 160 µmol/L, uric acid 839 µmol/L) and hypokalemia (2.5 mmol/L). After suspending miltefosine treatment and administering oral rehydration, the symptoms subsided and the serum potassium and kidney function tests showed rapid normalization. Finally, it was possible to complete the 30-day miltefosine treatment in conjunction with supportive antiemetic treatment with domperidone. After completion of treatment, the oral mucosal lesions healed completely without signs of recurrence on follow-up visits over the next year (Figure 1).
ML—the least common clinical form of leishmaniasis—is mostly caused by the New World species, Leishmania braziliensis and Leishmania panamensis in the Americas and the Old World species, L infantum, which is endemic in the Mediterranean region, the Middle East, Central Asia, and China. Most cases of ML arise from lymphatic or hematogenous spread of cutaneous leishmaniasis (CL) and are found in the Americas. ML can appear concurrently with or even years after cutaneous manifestations. In contrast to ML in the Americas, cases of Old World ML may not typically be preceded or accompanied by a cutaneous lesion and show a higher intralesional parasite burden. Cases of primary ML are rare, but may occur in both immunocompetent and immunosuppressed patients. While the nasal cavity is affected in more than 90% of New World ML cases, the larynx and oral mucosa are more frequently involved in Mediterranean ML. Concerning clinical outcome, cases of primary ML in the Mediterranean region show a better prognosis than South American cases.
Cases of primary ML due to L infantum are, even though rare, regularly reported from Southern Europe and should therefore be included in the differential diagnosis of any patient—immunocompetent or not—who presents with chronic mucosal lesions and has traveled to or resides in endemic areas.
Pentavalent antimonials (meglumine antimoniate and sodium stibogluconate) have been used for decades and are still the gold standard for treatment of New World Leishmania species and for patients with severe Old World leishmaniasis.4 Common side effects of antimonial treatment include nausea, abdominal complaints (pancreatitis), myalgia, arthralgia, skin rash, and laboratory abnormalities such as abnormal liver function tests and elevated serum amylase levels.5 In rare cases, meglumine antimoniate may induce a “drug reaction with eosinophilia and systemic symptoms” (DRESS), representing a drug hypersensitivity reaction.6 Concerning the skin manifestations of our patient, there were no accompanying clinical signs or laboratory finding [especially no hypereosinophilia (Eosinophiles ≤4%)] pointing to a meglumine-induced DRESS syndrome. Reversible ECG alterations are seen in 30% to 60% of cases and may occur without evidence of myocardial damage.7,8 Severe cardiotoxic side effects, including prolongation of the QTc interval9 and torsade de pointes tachycardia,10 have been observed with use of pentavalent antimonials. Our case presentation highlights the potential risk of developing severe hypokalemia during pentavalent antimonial treatment, which has so far only been reported in two cases.11,12 This rare but potentially fatal event is particularly important since most ML patients are treated as out-patients and therefore subject to limited clinical and laboratory check-ups.
Miltefosine features the advantage of oral administration and has proven efficacy in the treatment of visceral leishmaniasis and New World CL and ML. Concerning the treatment of Old World CL13–15 and ML16,17 with miltefosine, data are still scarce and do not—despite promising reports—allow for general judgement. Common side effects of miltefosine treatment include nausea, vertigo, vomiting, and diarrhea. Abnormal liver and kidney function tests are observed in 10% of the cases. In addition to the direct effects of miltefosine on kidney function, the fluid imbalance related to adverse gastrointestinal side effects may contribute to augmentation of creatinine levels.
Declaration of Interests
The authors state that they have no conflicts of interest to declare.