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Use of Miltefosine in a Patient with Mucosal Leishmaniasis and HIV-Coinfection: a Challenge in Long-Term Management

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Use of Miltefosine in a Patient with Mucosal Leishmaniasis and HIV-Coinfection: a Challenge in Long-Term Management Le Infezioni in Medicina, n. 4, 452-455, 2019 452 CASE REPORTS Use of miltefosine in a patient with mucosal leishmaniasis and HIV-coinfection: a challenge in long-term management Giacomo Zanelli1,2, Barbara Rossetti1, Roberta Gagliardini1,3, Lorenzo Paglicci1,2, Giacinta Tordini1,2, Clelia Miracco4, Sara Aversa4, Lorenzo Zammarchi5, Trentina Di Muccio6, Marina Gramiccia6, Francesca Montagnani1,2 1Hospital Department of Specialized and Internal Medicine, Infectious Diseases Unit, University Hospital of Siena, Siena, Italy; 2Department of Medical Biotechnologies, University of Siena, Italy; 3INMI L. Spallanzani IRCCS, Rome, Italy; 4Pathological Anatomy Division, Department of Medicine, Surgery and Neuroscience, University of Siena, Siena, Italy; 5Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy; Infectious and Tropical Diseases Unit, Careggi University and Hospital, Florence, Italy; Referral Center for Tropical Diseases of Tuscany, Infectious and Tropical Diseases Unit, Careggi University Hospital, Florence, Italy; 6Department of Infectious Diseases, Unit of Vector-borne Diseases, Italian National Institute of Health, Rome, Italy SUMMARY The management of mucosal leishmaniasis in immu- tient treated with miltefosine due to a severe allergic nocompromised patients is not standardized and lim- reaction to liposomal amphotericin B. ited data are available on the use of miltefosine for treatment and secondary prophylaxis. We describe a Keywords: mucosal leishmaniasis, HIV, miltefosine, li- case of mucosal leishmaniasis in an HIV-coinfected pa- posomal B amphotericin, adverse reaction. n INTRODUCTION sometimes associated to adverse events, making alternative therapy necessary [2]. Data on the use n people infected with HIV, the clinical mani- of miltefosine for treatment and secondary proph- festations of leishmaniasis may be heterogene- I ylaxis in patients with ML and HIV-coinfection ous and not strictly species-specific [1]. The par- are extremely limited [2-4]. asites can lose their typical tropism and mucosal Here we describe a case of ML in a patient with involvement (mucosal leishmaniasis, ML) is not HIV infection, treated with miltefosine after a se- a rare event in the Old World, particularly in the vere allergic reaction to L-AmB. immunocompromised patients [1]. Treatment of this co-infection is not standardized and may be complicated by a high risk of recurrence [2]. n CASE REPORT The use of liposomal amphotericin B (L-AmB) is A 59-year-old male Nigerian patient with mucosal leishmaniasis was referred to our hospital in June 2018. He reported uncontrolled arterial hyperten- Corresponding author sion, recent thoracic herpes zoster and no other Giacomo Zanelli known major comorbidity. He had lived in Italy E-mail: [email protected] for more than 40 years and returned periodically Use of miltefosine in a patient with mucosal leishmaniasis 453 to Nigeria (the last time had been two years earli- were negative. No other co-infections were detect- er). Due to a months-long history of nasal obstruc- ed. Chest X-ray was normal; liver steatosis was tion, he underwent ENT (ear, nose and throat) as- detected by abdominal ultrasound. Left ventricu- sessment that revealed hyperplastic hemorrhagic lar hypertrophy was documented by echocardi- vestibular mucosa with external swelling of the ography. Magnetic resonance of the brain showed left nostril. The subsequent biopsy showed gran- leukoaraiosis. The patient started antiretroviral ulomatosis compatible with leishmaniasis (Figure therapy (ART) (tenofovir alafenamide/emtricit- 1, A and B), confirmed by the positivity to SSUrD- abine + dolutegravir) responding with a rapid de- NA nested-PCR [5]. The parasite was identified as crease in HIV-1 RNA; cotrimoxazole was given for belonging to the Leishmania donovani complex by prophylaxis of opportunistic infections. To treat ITS1-PCR-RFLP analysis performed at the Italian ML, L-AmB was administered with a scheduled National Institute of Health (U.O. Vector-borne dose of 4mg/Kg/day on days 1-5, 10, 17, 24, 31 diseases, Rome, Italy) [6]. On admission the pa- and 38, associated with steroid treatment (intra- tient was in good clinical condition and physi- venous methylprednisolone at dosage of 20 mg/ cal examination only revealed an exudative and day). On day 10, during the administration of the stenosing lesion in the left nasal vestibule with- sixth dose of L-Amb (and 48 hours after starting out fibrolaringoscopic evidence of pharyngeal or the antiviral drugs), the patient developed ana- glottic lesions. Laboratory tests showed a white phylactic shock with severe oedema of the glottis blood cells count (WBC) of 4,410 cells/mm3 (1,330 requiring intubation and admission to the inten- neutrophils), alanine aminotransferase (ALT) 80 sive care unit. In the following days, tracheosto- IU/mL, and monoclonal hypergammaglobuline- my was performed due to persistent inflamma- mia (31%). Serology was positive for HIV and tion of the glottis and the difficulty in extubation. HIV-1 RNA was 252,000 copies/mL (subtype G); PCR for Leishmania was negative in the arytenoid the CD4 count was 140 cells/mm3. No major drug mucosa. Two weeks later, the tracheostomy tube resistance mutation was detected. Leishmania real was removed, and the patient was transferred to time PCR on peripheral whole blood (Stat Nat the Infectious Disease Unit. Oral miltefosine (50 Leishmania spp, Sentinel Diagnostic, Italy) and mg x 3/day) was introduced and well tolerated. serology (IFAT, Euroimmun, Lübeck, Germany) The patient was discharged on day 49 with a mac- Figure 1 - (A) Granulomatous inflammation is observed with- in chorion in Hematoxylin/ Eosin (magnification 400x); (B) Numerous Leishmania amas- tigotes highlighted by Giemsa stain (magnification 1000x). 454 G. Zanelli, B. Rossetti, R. Gagliardini, et al. roscopic regression of the nasal lesion. After com- for ML patients treated with miltefosine [15,16]. pleting 4 weeks of therapy, miltefosine was ad- Miltefosine is therefore only FDA-approved for ministered as secondary prophylaxis at a dosage ML caused only by L. braziliensis and is consid- of 50 mg x 2/day. At subsequent follow-up there ered less effective for leishmaniasis caused by L. were no signs of recurrence or macroscopic nasal infantum-chagasi, the etiological agent of our case mucosa lesions; after 10 months HIV-1 RNA was [2]. A recent study seems to confirm the natural re- no longer detectable, CD4 count was 215 cells/ sistance of Leishmania infantum to miltefosine con- mm3, and there was no significant alteration of tributing to the treatment failure of visceral leish- liver or kidney function. The patient is continuing maniasis in Brazil [17]. Even less data is available miltefosine until sustained immunological recov- for ML in immunocompromised patients, an un- ery and tolerates it well. explored context in which systemic therapy, like for VL, is suggested [2]. The FDA-approved total dose of L-AmB for VL in immunocompromised n DISCUSSION hosts is 40 mg/kg but there is little evidence to Leishmaniasis was a relatively frequent oppor- suggest that miltefosine is effective [2]. An inter- tunistic disease during the HIV-related epidem- esting recent randomized trial showed that the ic, especially in the Mediterranean area; for this sequential use of L-AmB (30 mg/kg) followed reason the visceral form (visceral leishmaniasis, by miltefosine (100 mg/28 days) is more effective VL) was included as a stage 4, AIDS-defining con- in patients with VL and HIV in Ethiopia [18]. A dition in the World Health Organization (WHO) similar result was previously documented in In- clinical staging system for HIV [1,2,7]. Although dia with a combined treatment [3]. These findings our patient probably contracted the parasite in- could modify or direct the current recommenda- fection in Italy, where L. infantum is the only tions if confirmed in other areas and with other known endemic species, genotyping suggests Leishmania species. In line with available evidence that it is not possible to exclude reactivation of a we treated the patient with L-AmB but soon had prior latent infection due to immunosuppression to suspend it due to life-threatening anaphylaxis, [2]. In fact, very few autochthonous cases of VL despite prophylactic administration of steroids, are reported in Nigeria [8]. L. infantum is usual- expected in the treatment of ML [2]. L-AmB is not ly associated with VL, however atypical features only a high-cost drug but can also have serious including cutaneous and mucosal involvement, side effects. Acute infusion reaction and comple- isolated or in combination with VL, have been de- ment-activation-related-pseudoallergy (CARPA) scribed in immunocompromised patients [9,10]. have been described and could bring to select In severely immunocompromised HIV-positive an alternative treatment as in our case [2]. It is subjects (CD4 <50 mm3), atypical amastigotes difficult to determine whether the simultaneous localizations (digestive tract, lung, skin, tonsils) administration of antiretroviral therapy and the have been reported in up to 41% of HIV-positive risk of a Jarisch-Herxheimer reaction during ML subjects with VL in Southern France [11]. treatment have contributed to the adverse event In our case, isolated ML was also the first unmask- [2]. The subsequent tolerability of antiretroviral ing HIV condition in a late-presenter patient [12]. therapy and the negativity of Leishmania DNA in In most cases, histological examination
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