• View in gallery

    Hand lesion on initial evaluation.

  • View in gallery

    Chest lesion on initial evaluation.

  • View in gallery

    H&E images of cutaneous leishmaniasis at 100× (A/C) and 600× (B/D) magnification. (A/C) Prominent lymphoplasmacytic dermal inflammation with occasional granulomas. (B/D) Histiocytes with intracellular amastigotes [arrows].

  • View in gallery

    Hand lesion after therapy at 3-month follow-up.

  • View in gallery

    Chest lesion after therapy at 3-month follow-up.

  • 1.

    Espinosa OA, Serrano MG, Camargo EP, Teixeira MMG, Shaw JJ, 2018. An appraisal of the taxonomy and nomenclature of trypanosomatids presently classified as Leishmania and Endotrypanum. Parasitology 145: 430442.

    • Search Google Scholar
    • Export Citation
  • 2.

    Aronson NE, Joya CA, 2019. Cutaneous leishmaniasis: updates in diagnosis and management. Infect Dis Clin North Am 33: 101117.

  • 3.

    Herwaldt BL, 1999. Leishmaniasis. Lancet 354: 11911199.

  • 4.

    Berman JD, 1997. Human leishmaniasis: clinical, diagnostic, and chemotherapeutic developments in the last 10 years. Clin Infect Dis 24: 684703.

    • Search Google Scholar
    • Export Citation
  • 5.

    Walton BC, Chinel LV, Eguia y Eguia O, 1973. Onset of espundia after many years of occult infection with Leishmania braziliensis. Am J Trop Med Hyg 22: 696698.

    • Search Google Scholar
    • Export Citation
  • 6.

    Organización Panamericana de la Salud, 2019. Manual Para Vigilancia y Control de las Leishmaniasis en las Américas. Available at: http://iris.paho.org/xmlui/bitstream/handle/123456789/50524/9789275320631_spa.pdf?sequence=1&isAllowed=y. Accessed December 20, 2019.

    • Search Google Scholar
    • Export Citation
  • 7.

    Hartley MA, Ronet C, Zangger H, Beverley SM, Fasel N, 2012. Leishmania RNA virus: when the host pays the toll. Front Cell Infect Microbiol 2: 99.

  • 8.

    Weiss F, Vogenthaler N, Franco-Paredes C, Parker SR, 2009. Leishmania tropica-induced cutaneous and presumptive concomitant viscerotropic leishmaniasis with prolonged incubation. Arch Dermatol 145: 10231026.

    • Search Google Scholar
    • Export Citation
  • 9.

    Olivo Freites C, Gundacker ND, Pascale JM, Saldaña A, Diaz-Suarez R, Jimenez G, Sosa N, García E, Jimenez A, Suarez JA, 2018. First case of diffuse leishmaniasis associated with Leishmania panamensis. Open Forum Infect Dis 5: ofy281.

    • Search Google Scholar
    • Export Citation
  • 10.

    Aronson N, Herwaldt BL, Libman M, Pearson R, Lopez-Velez R, Weina P, Carvalho EM, Ephros M, Jeronimo S, Magill A, 2016. Diagnosis and treatment of leishmaniasis: clinical practice guidelines by the infectious diseases society of America (IDSA) and the American society of tropical medicine and hygiene (ASTMH). Clin Infect Dis 63: e202e264.

    • Search Google Scholar
    • Export Citation
  • 11.

    Barkati S, Ndao M, Libman M, 2019. Cutaneous leishmaniasis in the 21st century: from the laboratory to the bedside. Curr Opin Infect Dis 32: 419425.

    • Search Google Scholar
    • Export Citation
  • 12.

    Guery R et al. 2017. Liposomal amphotericin B in travelers with cutaneous and muco-cutaneous leishmaniasis: not a panacea. PLoS Negl Trop Dis 11: e0006094.

    • Search Google Scholar
    • Export Citation
  • 13.

    Soto J et al. 2004. Miltefosine for new world cutaneous leishmaniasis. Clin Infect Dis 38: 12661272.

  • 14.

    Soto J, Toledo J, Gutierrez P, Nicholls RS, Padilla J, Engel J, Fischer C, Voss A, Berman J, 2001. Treatment of American cutaneous leishmaniasis with miltefosine, an oral agent. Clin Infect Dis 33: E57E61.

    • Search Google Scholar
    • Export Citation
  • 15.

    Machado PR, Ampuero J, Guimaraes LH, Villasboas L, Rocha AT, Schriefer A, Sousa RS, Talhari A, Penna G, Carvalho EM, 2010. Miltefosine in the treatment of cutaneous leishmaniasis caused by Leishmania braziliensis in Brazil: a randomized and controlled trial. PLoS Negl Trop Dis 4: e912.

    • Search Google Scholar
    • Export Citation
  • 16.

    Rubiano LC et al. 2012. Noninferiority of miltefosine versus meglumine antimoniate for cutaneous leishmaniasis in children. J Infect Dis 205: 684692.

    • Search Google Scholar
    • Export Citation
  • 17.

    Velez I, Lopez L, Sanchez X, Mestra L, Rojas C, Rodriguez E, 2010. Efficacy of miltefosine for the treatment of American cutaneous leishmaniasis. Am J Trop Med Hyg 83: 351356.

    • Search Google Scholar
    • Export Citation
  • 18.

    Sanchez-Canete MP, Carvalho L, Perez-Victoria FJ, Gamarro F, Castanys S, 2009. Low plasma membrane expression of the miltefosine transport complex renders Leishmania braziliensis refractory to the drug. Antimicrob Agents Chemother 53: 13051313.

    • Search Google Scholar
    • Export Citation
  • 19.

    Franco-Paredes C, 2014. The growing challenge of leishmaniasis in travelers. Travel Med Infect Dis 12: 559560.

 
 
 
 

 

 
 
 

 

 

 

 

 

 

Case Report: Cutaneous Leishmaniasis due to Leishmania (Viannia) panamensis in Two Travelers Successfully Treated with Miltefosine

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  • 1 Division of Infectious Diseases, University of Colorado School of Medicine, Aurora, Colorado;
  • | 2 Division of Pathology, University of Colorado School of Medicine, Aurora, Colorado;
  • | 3 Division of Dermatology, University of Colorado School of Medicine, Aurora, Colorado;
  • | 4 Gorgas Memorial Institute of Tropical Medicine, Panamá City, Panamá;
  • | 5 Hospital Infantil de México, Federico Gómez, México City, México

We present two cases of Leishmania (V) panamensis in returning travelers from Central America successfully treated with miltefosine. The couple presented with ulcerative skin lesions nonresponsive to antibiotics. Skin biopsy with polymerase chain reaction (PCR) revealed L. (V) panamensis. To prevent the development of mucosal disease and avoid the inconvenience of parental therapy, we treated both patients with oral miltefosine. We suggest that miltefosine represents an important therapeutic alternative in the treatment of cutaneous lesions caused by L. panamensis and in preventing mucosal involvement.

A 31-old-man and a 30-year-old woman traveled to Costa Rica for their honeymoon. They visited many regions of this country and participated in hiking, rafting, and camping. They both reported insect bites.

The husband had a history of Hodgkin lymphoma treated 10 years ago and was in remission. Approximately 3 weeks after returning home, the husband noticed a dime-sized papule proximal to his first, right thumb. He also reported “enlarged nodes” on his right arm. He denied any other symptoms. The lesion continued to grow in size, despite a 7-day empiric course of cephalexin.

On examination, the husband had a 6-cm ulcer (1 cm deep) on the dorsal aspect of his right thenar eminence with surrounding erythema (Figure 1) along with three erythematous slightly tender sporotrichoid nodules along the volar forearm. In addition, he had right epitrochlear and axillary lymph nodes.

Figure 1.
Figure 1.

Hand lesion on initial evaluation.

Citation: The American Journal of Tropical Medicine and Hygiene 103, 3; 10.4269/ajtmh.20-0086

His wife denied any past medical history. Two weeks after returning from Costa Rica, she described a well-circumscribed asymptomatic erythematous plaque on her right chest that became scaly. She denied any fevers, abdominal pain, epistaxis, mouth lesions, or enlarged lymph nodes.

On examination, the wife had a 2-cm zosteriform-like plaque on her right chest (Figure 2). No lymphadenopathy was noted. Similar to her husband, she had no evidence of abdominal tenderness, hepatosplenomegaly, or lesions in the mouth or nose.

Figure 2.
Figure 2.

Chest lesion on initial evaluation.

Citation: The American Journal of Tropical Medicine and Hygiene 103, 3; 10.4269/ajtmh.20-0086

Skin biopsies in both cases demonstrated acute, chronic, and granulomatous dermatitis with intracellular amastigotes (Figure 3). Molecular testing of the skin biopsy specimen by PCR revealed the presence of Leishmania panamensis (Division of Parasitic Diseases and malaria, CDC, Atlanta GA). Systemic therapy with oral miltefosine (Impavido®) 50 mg three times daily was instituted for both patients, as it is more convenient and less toxic than parental therapy. Given that the husband had concern for lymphangitic spread to his right axilla, we recommended a 56-day course of miltefosine therapy. At follow-up, he had significant improvement of the lesion. Because of the presence of a thick fibrous scar at the ulcerative lesion border, we recommended a short course of collagenase ointment (Santyl®), which promoted complete healing of the ulcer (Figure 4). After the wife had a negative pregnancy test and we provided contraceptive counseling, we treated her with a single course of 28-day miltefosine with substantial improvement of the cutaneous lesion (Figure 5). Both husband and wife reported nausea and mild abdominal pain with miltefosine which improved when ingested with food. No other side effects were reported.

Figure 3.
Figure 3.

H&E images of cutaneous leishmaniasis at 100× (A/C) and 600× (B/D) magnification. (A/C) Prominent lymphoplasmacytic dermal inflammation with occasional granulomas. (B/D) Histiocytes with intracellular amastigotes [arrows].

Citation: The American Journal of Tropical Medicine and Hygiene 103, 3; 10.4269/ajtmh.20-0086

Figure 4.
Figure 4.

Hand lesion after therapy at 3-month follow-up.

Citation: The American Journal of Tropical Medicine and Hygiene 103, 3; 10.4269/ajtmh.20-0086

Figure 5.
Figure 5.

Chest lesion after therapy at 3-month follow-up.

Citation: The American Journal of Tropical Medicine and Hygiene 103, 3; 10.4269/ajtmh.20-0086

DISCUSSION

Leishmaniasis refers collectively to a spectrum of clinical syndromes (cutaneous, mucocutaneous, and visceral) caused by infection with intracellular protozoa of the subgenera Leishmania (Leishmania), Leishmania (Viannia), or Leishmania (Mundinia) acquired by the bite of sand flies.1 Cutaneous leishmaniasis (CL) is the most frequently reported form of the disease, and it is associated with more than 20 Leishmania (L.) species with different degrees of pathogenicity.2 In addition to producing CL, some species may also produce nasopharyngeal and laryngeal mucosal involvement, causing additional morbidity and disfigurement. Mucosal leishmaniasis (ML) may occur concomitantly with the cutaneous lesion, or it may manifest a few months, or even years, after the cutaneous lesions have healed.35 In the New World (Americas), species of the subgenus L. Viannia (V) are associated with the mucosal forms of the disease, particularly Leishmania (V) braziliensis, Leishmania (V) guyanensis, and L. (V) panamensis.6 New evidence suggests that some of these Leishmania species are coinfected with Leishmania RNA virus and that the immune response to this virus elicits an hyperinflammatory response through toll-like receptors, leading to mucosal damage.7 In addition, some Leishmania species, which are traditional causes of CL, may produce a mixed syndrome of cutaneous and visceral disease denominated viscerotropic disease caused predominantly by Leishmania tropica in the Old World and Leishmania amazonensis in the New World.8

Cutaneous leishmaniasis typically occurs at the site of the sand fly bite, starting as small papules which enlarge slowly over months eventually ulcerating with heaped up borders.4 The spectrum of cutaneous manifestations associated with CL in the New World includes ulcerative, diffuse, disseminated, and atypical forms (psoriasiform, verrucous, zosteriform, or nodular).6,9

The Pan American Health Organization recommends assessing the annual CL transmission index to identify the locations within the Americas with the highest risk of transmission. Used to prioritize and control interventions, this index is constituted by the annual incidence of CL and the density of transmission which is defined as the total annual number of CL cases in a defined geographic area by municipalities, regions, and subregions of countries with existing leishmaniasis transmission. Travel medicine practitioners can use this index to counsel travelers about high transmission areas and prevent phlebotomine sand fly bites.6

Cutaneous leishmaniasis occurring in an immune-competent individual with no evidence of mucosal involvement does not usually require treatment because it spontaneously resolves. However, local or systemic treatment is recommended for individuals with complex CL defined as the presence of subcutaneous nodules; area greater than 5 cm; regional adenopathy; lesions on the face, fingers, toes, or genitalia; location or size not amenable to localized treatment; immunocompromised host; previous clinical failure; infection due to a Leishmania species potentially associated with mucosal disease; or diffuse CL.9,10 In these clinical scenarios, treatment accelerates the healing process and reduces the chances of relapse and dissemination (mucosal or visceral).

Treatment options for CL acquired in the New World include either systemic or local therapy. Systemic therapies include parenteral or oral options. In the armamentarium of parenteral infusions, the most frequently used is pentavalent antimonial compounds (SbV), followed by amphotericin B (deoxycholate or liposomal formulations), and pentamidine. Oral options include azoles and the more recently approved antiparasitic drug miltefosine. Local treatment includes topical paromomycin, intralesional injections of antimonials, thermotherapy, and photo or laser treatment for clinically simple lesions not associated with ML.

There is no ideal treatment regimen for leishmaniasis. Experts recommend individualizing therapy based on a patient’s immune status, comorbid conditions, childbearing plans, risk of mucocutaneous disease, extent of involvement, and published agent response rates of the therapy in the relevant geographic region.11 A retrospective study of CL involving 43 European travelers demonstrated that the use of amphotericin B formulations was mostly effective against some of the Old World leishmaniasis: Leishmania infantum and Leishmania tropica.12 However, for species of the subgenus L. Viannia, the use of amphotericin B was associated with high rates of treatment failure.12

Because our patients had confirmed L. (V) panamensis, we decided to institute systemic therapy. We chose miltefosine over pentavalent antimonials based on existing efficacy against L. (V) panamensis13,14 and for logistic reasons to avoid the need for parenteral administration. We also recommended wound care and applying emollients, such as petroleum jelly, to the wound.

Miltefosine, approved by the FDA in 2014 for CL caused by L. panamensis, L. braziliensis, and L. guyanensis, is a phosphocholine analogue that interferes with cell-signaling pathways and membrane synthesis.14 The major benefits of this treatment regimen are oral administration and a minimal side effect profile. Adverse effects include nausea and diarrhea, which can be ameliorated by ingesting the medication with food. Patients should also receive safe sex counseling, as the medication has teratogenic potential. Other rare side effects include hepatotoxicity and renal insufficiency. Additional disadvantages are the cost of the medication and the potential risk of relapse.

Although there are a limited number of clinical trials evaluating miltefosine, most of the studies have revealed that miltefosine is efficacious. A randomized open-label trial of 90 patients with L. braziliensis revealed a statistically significant cure rate of 75% in the miltefosine group compared with 53.3% in the pentavalent antimony group.15 Furthermore, a trial of miltefosine in pediatric children in Colombia with L. panamensis and L. guyanensis revealed that miltefosine was not inferior to meglumine antimoniate and had a lower toxicity profile.16 The use of miltefosine in CL from Columbia revealed cure rates > 80% for patients infected with L. panamensis.13,14 Other trials demonstrated a cure rate of < 70% that was attributed to higher proportions of L. braziliensis cases.17 This may be secondary to L. braziliensis’ reduced capacity to internalize milefosine.18

For treatment, a course of 28 days of miltefosine is preferred, but one may recommend extended courses for lymphangitic spread such as in our patient. Because leishmaniasis may recur, there is a need for intermittently monitoring patients after completing therapy. If treatment is successful, the lesion size should decrease by greater than 50%, with no evidence of new lesions. In addition, ulcerative lesions should re-epithelialize and heal by 3 months.10 The wife had resolution of ulcerations with no new lesions (Figure 4), and the husband had re-epithelialization of his ulcer at of our first 3-month follow-up (Figure 5). We also identified the potential benefit of collagenase ointment in patients with CL to improve residual scar accumulation at the prior ulcer border.

In summary, our cases contribute to the growing threat of CL in travelers.19 Travel health practitioners should advice travelers to avoid phlebotomine sand fly bites in regions with high leishmaniasis cutaneous indexes. Cutaneous leishmaniasis should always be on the differential diagnosis for a returning traveler with cutaneous lesions. Because of the risk of mucosal involvement with particular Leishmania species in returning travelers from the New World, it is highly recommended to identify the species involved to guide the preferred treatment regimen. Miltefosine is a convenient and well-tolerated oral alternative for the treatment of CL caused by L. (V) panamensis.

REFERENCES

  • 1.

    Espinosa OA, Serrano MG, Camargo EP, Teixeira MMG, Shaw JJ, 2018. An appraisal of the taxonomy and nomenclature of trypanosomatids presently classified as Leishmania and Endotrypanum. Parasitology 145: 430442.

    • Search Google Scholar
    • Export Citation
  • 2.

    Aronson NE, Joya CA, 2019. Cutaneous leishmaniasis: updates in diagnosis and management. Infect Dis Clin North Am 33: 101117.

  • 3.

    Herwaldt BL, 1999. Leishmaniasis. Lancet 354: 11911199.

  • 4.

    Berman JD, 1997. Human leishmaniasis: clinical, diagnostic, and chemotherapeutic developments in the last 10 years. Clin Infect Dis 24: 684703.

    • Search Google Scholar
    • Export Citation
  • 5.

    Walton BC, Chinel LV, Eguia y Eguia O, 1973. Onset of espundia after many years of occult infection with Leishmania braziliensis. Am J Trop Med Hyg 22: 696698.

    • Search Google Scholar
    • Export Citation
  • 6.

    Organización Panamericana de la Salud, 2019. Manual Para Vigilancia y Control de las Leishmaniasis en las Américas. Available at: http://iris.paho.org/xmlui/bitstream/handle/123456789/50524/9789275320631_spa.pdf?sequence=1&isAllowed=y. Accessed December 20, 2019.

    • Search Google Scholar
    • Export Citation
  • 7.

    Hartley MA, Ronet C, Zangger H, Beverley SM, Fasel N, 2012. Leishmania RNA virus: when the host pays the toll. Front Cell Infect Microbiol 2: 99.

  • 8.

    Weiss F, Vogenthaler N, Franco-Paredes C, Parker SR, 2009. Leishmania tropica-induced cutaneous and presumptive concomitant viscerotropic leishmaniasis with prolonged incubation. Arch Dermatol 145: 10231026.

    • Search Google Scholar
    • Export Citation
  • 9.

    Olivo Freites C, Gundacker ND, Pascale JM, Saldaña A, Diaz-Suarez R, Jimenez G, Sosa N, García E, Jimenez A, Suarez JA, 2018. First case of diffuse leishmaniasis associated with Leishmania panamensis. Open Forum Infect Dis 5: ofy281.

    • Search Google Scholar
    • Export Citation
  • 10.

    Aronson N, Herwaldt BL, Libman M, Pearson R, Lopez-Velez R, Weina P, Carvalho EM, Ephros M, Jeronimo S, Magill A, 2016. Diagnosis and treatment of leishmaniasis: clinical practice guidelines by the infectious diseases society of America (IDSA) and the American society of tropical medicine and hygiene (ASTMH). Clin Infect Dis 63: e202e264.

    • Search Google Scholar
    • Export Citation
  • 11.

    Barkati S, Ndao M, Libman M, 2019. Cutaneous leishmaniasis in the 21st century: from the laboratory to the bedside. Curr Opin Infect Dis 32: 419425.

    • Search Google Scholar
    • Export Citation
  • 12.

    Guery R et al. 2017. Liposomal amphotericin B in travelers with cutaneous and muco-cutaneous leishmaniasis: not a panacea. PLoS Negl Trop Dis 11: e0006094.

    • Search Google Scholar
    • Export Citation
  • 13.

    Soto J et al. 2004. Miltefosine for new world cutaneous leishmaniasis. Clin Infect Dis 38: 12661272.

  • 14.

    Soto J, Toledo J, Gutierrez P, Nicholls RS, Padilla J, Engel J, Fischer C, Voss A, Berman J, 2001. Treatment of American cutaneous leishmaniasis with miltefosine, an oral agent. Clin Infect Dis 33: E57E61.

    • Search Google Scholar
    • Export Citation
  • 15.

    Machado PR, Ampuero J, Guimaraes LH, Villasboas L, Rocha AT, Schriefer A, Sousa RS, Talhari A, Penna G, Carvalho EM, 2010. Miltefosine in the treatment of cutaneous leishmaniasis caused by Leishmania braziliensis in Brazil: a randomized and controlled trial. PLoS Negl Trop Dis 4: e912.

    • Search Google Scholar
    • Export Citation
  • 16.

    Rubiano LC et al. 2012. Noninferiority of miltefosine versus meglumine antimoniate for cutaneous leishmaniasis in children. J Infect Dis 205: 684692.

    • Search Google Scholar
    • Export Citation
  • 17.

    Velez I, Lopez L, Sanchez X, Mestra L, Rojas C, Rodriguez E, 2010. Efficacy of miltefosine for the treatment of American cutaneous leishmaniasis. Am J Trop Med Hyg 83: 351356.

    • Search Google Scholar
    • Export Citation
  • 18.

    Sanchez-Canete MP, Carvalho L, Perez-Victoria FJ, Gamarro F, Castanys S, 2009. Low plasma membrane expression of the miltefosine transport complex renders Leishmania braziliensis refractory to the drug. Antimicrob Agents Chemother 53: 13051313.

    • Search Google Scholar
    • Export Citation
  • 19.

    Franco-Paredes C, 2014. The growing challenge of leishmaniasis in travelers. Travel Med Infect Dis 12: 559560.

Author Notes

Address correspondence to S. Mann, Division of Infectious Diseases, University of Colorado School of Medicine, 12700 E. 19th Ave., Aurora, CO 80045. E-mail: sarah.c.mann@cuanschutz.edu

Authors’ addresses: S. Mann, T. Phupitakphol, and A. Henao-Martínez, Division of Infectious Diseases, University of Colorado School of Medicine, Aurora, CO, E-mails: sarah.c.mann@cuanschutz.edu, tanit.phupitakphol@cuanschutz.edu, and andres.henaomartinez@cuanschutz.edu. B. Davis, Division of Pathology, University of Colorado School of Medicine, Aurora, CO, E-mail: brandi.2.davis@cuanschutz.edu. S. Newman, Division of Dermatology, University of Colorado School of Medicine, Aurora, CO, E-mail: sabrina.newman@cuanschutz.edu. J. A. Suarez, Unidad Clínica de Investigación, Clínica de Medicina Tropical, Instituto Conmemorativo Gorgas de Estudios de la Salud (ICGES), Panamá City, Panamá, E-mail: jsuarez@gorgas.gob.pa. C. Franco-Paredes, Division of Infectious Diseases, University of Colorado School of Medicine, Aurora, CO and Hospital Infantil de México, Federico Gómez, México City, México, E-mail: carlos.franco-paredes@cuanschutz.edu.

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