F1000Research 2017, 6(F1000 Faculty Rev):750 Last updated: 23 JUN 2019

REVIEW
Leishmaniasis: a review [version 1; peer review: 2 approved]
Edoardo Torres-Guerrero 1, Marco Romano Quintanilla-Cedillo2, 

Julieta Ruiz-Esmenjaud1, Roberto Arenas 1

1Sección de Micología, Hospital “Manuel Gea González” Secretaría de Salud, Calz. de Tlalpan 4800, Ciudad de México 14080, Mexico
2Dermatólogo, Clínica Carranza, Chetumal, Quintana Roo, Mexico

First published: 26 May 2017, 6(F1000 Faculty Rev):750 ( Open Peer Review

v1 https://doi.org/10.12688/f1000research.11120.1)
Latest published: 26 May 2017, 6(F1000 Faculty Rev):750 (
https://doi.org/10.12688/f1000research.11120.1)
Reviewer Status    

Abstract   Invited Reviewers
Leishmaniasis is caused by an intracellular parasite transmitted to humans 1   2
by the bite of a sand fly. It is endemic in Asia, Africa, the Americas, and the
Mediterranean region. Worldwide, 1.5 to 2 million new cases occur each version 1
year, 350 million are at risk of acquiring the disease, and leishmaniasis  
published
causes 70,000 deaths per year. Clinical features depend on the species of  26 May 2017
Leishmania involved and the immune response of the host. Manifestations
range from the localized cutaneous to the visceral form with potentially fatal
outcomes. Many drugs are used in its treatment, but the only effective F1000 Faculty Reviews are written by members of
treatment is achieved with current pentavalent antimonials. the prestigious F1000 Faculty. They are

Keywords commissioned and peer reviewed before publication
Leishmaniasis, Leishmania, cutaneous-chondral, chicleros ulcer to ensure that the final, published version is
comprehensive and accessible. The reviewers who
approved the final version are listed with their names
and affiliations.

1 Francisco Bravo-Puccio, Departments of
Pathology and Dermatology, Universidad
Peruana Cayetano Heredia, Lima, Lima, Peru

2 Roderick J Hay, International Foundation for
Dermatology, London, London, UK
Department of Dermatology, Kings College NHS
Trust, London, London, UK

Any comments on the article can be found at the
end of the article.

 
Page 1 of 15
 F1000Research 2017, 6(F1000 Faculty Rev):750 Last updated: 23 JUN 2019

Corresponding author: Roberto Arenas (rarenas98@hotmail.com)
Competing interests: The authors declare that they have no competing interests.
Grant information: The author(s) declared that no grants were involved in supporting this work.
Copyright: © 2017 Torres-Guerrero E et al. This is an open access article distributed under the terms of the Creative Commons Attribution
Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
How to cite this article: Torres-Guerrero E, Quintanilla-Cedillo MR, Ruiz-Esmenjaud J and Arenas R. Leishmaniasis: a review [version 1; peer
review: 2 approved] F1000Research 2017, 6(F1000 Faculty Rev):750 (https://doi.org/10.12688/f1000research.11120.1)
First published: 26 May 2017, 6(F1000 Faculty Rev):750 (https://doi.org/10.12688/f1000research.11120.1) 

 
Page 2 of 15
 F1000Research 2017, 6(F1000 Faculty Rev):750 Last updated: 23 JUN 2019

Introduction conducted in Turkey from 2009 to 2015 with 263 patients positive
Leishmaniasis is a tropical and subtropical disease caused by an for leishmaniasis using real-time and semi-nested polymerase chain
intracellular parasite transmitted to humans by the bite of a sand reactions (PCRs) revealed that 66.15% were Turkish, 33.46% were
fly, mainly Phlebotomus and Lutzomyia (Europe, Northern Africa, Syrian, and 0.38% were Afghani; the species detected were Leish-
the Middle East, Asia, and part of South America); exceptionally, mania tropica and Leishmania infantum (from Turkish and Syrian
transmission has also been reported as a laboratory accident1. patients), demonstrating the effects of the war in that territory11.
According to the World Health Organization (WHO), leishmaniasis
is one of the seven most important tropical diseases and it repre- Khezzani and Bouchemal, in Algeria, reported 4,813 confirmed
sents a serious world health problem that presents a broad spec- cases of CL in a period of 13 years: the disease affected all munici-
trum of clinical manifestations with a potentially fatal outcome2,3. palities and all age groups12. The most affected individuals were
It is found in all continents except Oceania2,4 and is endemic in 10 to 19 years old (31.41%) and children less than 9 years old
circumscribed geographic areas in Northeastern Africa, Southern (25.70%). Most of the patients were males (65%).
Europe, the Middle East, Southeastern Mexico, and Central and
South America. In Iran, Holakouie-Naieni et al. identified the geographic and sea-
sonal distribution of CL: there were 589,913 cutaneous cases, the
The clinical features include a broad range of manifestations annual incidence was approximately 30.9 per 100,000 and most
with different degrees of severity that depend on the species of cases occurred in the central regions of the country13, and the high-
Leishmania involved and the immune response of the host3. In est prevalence rate (35.14%) of lesions occurred in autumn14.
Mexico, the most characteristic form is the cutaneous-chondral
form1,4, also called “chiclero’s ulcer”. VL, also known as kala-azar, is a clinical form endemic in
Bangladesh, India, and Nepal. More than 60% of all VL cases
Epidemiology worldwide correspond to South Asia, with a predominance in rural
Leishmaniasis is a disease with a worldwide distribution; it is areas. In this respect, in Nepal, approximately 5.7 million people are
found in about 89 countries4,5. It is endemic in Asia, Africa, considered to be at risk and are confined mainly to the Terai region,
the Americas, and the Mediterranean region. In the American which borders the VL-endemic districts of the Bihar state in India.
continent, it is mainly a jungle zoonosis (but it can be acquired in Moreover, from 1980 to 2007, a total of 23,368 cases, including
semi-desert or cold regions) transmitted by sand flies mainly of 311 deaths, were reported. According to the annual health report
the genera Phlebotomus and Lutzomyia. It is found in many coun- of the Department of Health Services in Nepal, the incidence of
tries, from the southern United States to the northern provinces of VL was 2.67 per 10,000 people at risk in 2006–200715.
Argentina (seroprevalence of 0.17% for cutaneous leishmaniasis
[CL])6 with the exceptions of Chile, Uruguay, and El Salvador4,7,8. In Latin America, it is estimated that around 60,000 new cases
(including all types) occur each year. The disease is typical of envi-
Between 12 and 15 million people in the world are infected, and ronments with an altitude of 0 to 1,500 m above sea level, tem-
350 million are at risk of acquiring the disease. An estimated peratures higher than 20°C, and an annual rainfall of 1,500 to 3,000
1.5 to 2 million new cases occur each year, and it causes 70,000 mm. However, some cases known locally as “Uta” have been docu-
deaths per year4,9. mented in the highlands of Peru, which are cold and humid places
where the disease is transmitted by a small insect16,17.
In 2012, the WHO led an effort to report on the burden and dis-
tribution of leishmaniasis in 102 countries, areas, or territories More commonly, it affects men, and in Mexico the main risks are
worldwide—to identify cases of CL and visceral leishmaniasis seen among farmers (gum tree harvesters, cocoa and banana farm-
(VL)—and the data until 2010 indicate that 90% of global cases ers, among others), loggers, hunters, precious timber exploiters,
of VL occurred in Bangladesh, Brazil, Ethiopia, India, South military personnel, biologists, ornithologists, and those who prac-
Sudan, and Sudan and that about 70% of CL cases occurred in tice ecological tourism; it affects the collectors of yerba mate (tea),
Afghanistan, Algeria, Brazil, Colombia, Costa Rica, Ethiopia, Iran, rubber, banana, coffee, and coca in Peru and Brazil1,17,18.
Sudan, and the Syrian Arab Republic.
Women, the elderly, and children are also at risk of exposure in
On the other hand, of 25 countries selected to study the burden endemic zones. In Mexico, the disease has been known since the
of this disease, 13 have a high burden of VL (Bangladesh, China, pre-Hispanic era18, and all of the clinical forms of leishmaniasis
Ethiopia, Georgia, India, Kenya, Nepal, Paraguay, Somalia, South have been reported19. The most common presentations are the pure
Sudan, Spain, Sudan, and Uganda), 11 have a high burden of CL cutaneous and the cutaneous-chondral forms, which when affect-
(Afghanistan, Algeria, Colombia, Iran, Morocco, Pakistan, Peru, ing the ear cause the classic chiclero’s ulcer (gum tree harvester’s
Saudi Arabia, Syrian Arab Republic, Tunisia, and Turkey), and ulcer). The main endemic area in this country is found in the Neo-
one (Brazil) has a high burden of both clinical forms10. In Turkey, tropical zone from the southeast (southern Veracruz, Tabasco, Oax-
around 2,000 autochthonous cases of CL are reported each year. aca, Chiapas, Campeche, Quintana Roo, and part of Yucatán)1,2,7,18,20
(Figure 1). In this country, an annual incidence of 5.08 cases per
Owing to the civil war in Syria, Turkey received around 3 million 100,000 population has been observed in the Yucatán Peninsula21,22.
refugees, and they are located mainly at either camps or homes in Serological studies carried out in Becanchén (southern state of
the south or southeastern part of Turkey. An epidemiological study Yucatán) have documented specific antibodies in 17% of the

Page 3 of 15
 F1000Research 2017, 6(F1000 Faculty Rev):750 Last updated: 23 JUN 2019

In an epidemiological and historic study in Palestine, Al-Jawabreh

et al. identified Leishmania species by using amplification products
from a PCR-internal transcribed spacer 1 (PCR-ITS1) followed by
restriction fragment length polymorphism (RFLP) analysis using
Hae III and showed that the case numbers peaked in 1995, 2001,
2004, and 201228. Statistically significant clusters of cases caused
by Leishmania major were restricted to the Jericho District, and
those caused by L. tropica were located in the districts of Jericho,
Bethlehem, Nablus, and Tubas.

In an epidemiological study in Afghanistan, Fakhar et al. con-

firmed 3,861 cases of CL in a period of 1 year, and the predominant
species of all molecularly identified samples using ITS1 PCR-
RFLP analysis was L. tropica (98%)29.

CL is found in Southern Europe, Asia (the Middle East,

Afghanistan, and Pakistan), Africa, and Latin America. On the
Figure 1. Rainforests where chewing gum workers and farmers other hand, the cases of cutaneous disseminated leishmaniasis
extract sap from Manilkara zapota trees (chewing gum tree). have been described in the northeast of Mexico and in states neigh-
boring the southern United States and in the state of Texas7,20.

Muco-cutaneous leishmaniasis is found in Latin America and less

general population. Also, in Tabasco, an incidence and prevalence frequently in Africa (Ethiopia and Sudan). VL, or kala-azar, is
rate of 2.35 and 9.41 per 100,000 population, respectively, have found in Northern and Eastern Africa and in Northern Asia (India,
been observed; therefore, it is considered a high-endemic zone18. Pakistan, Bangladesh, Nepal, and China), in Southern Europe, and
These rates are explained because farmers work only 10 km from in Latin America8. Bangladesh, Bhutan, India, and Nepal repre-
the site in which the greatest quantity of rodents’ reservoirs and sented more than 73% of the global burden of VL in 2012, and
transmission vectors are found23. Positive serology is observed the prevalence of confirmed post–kala-azar dermal leishmaniasis
in 20.42% of military personnel working in this zone24. The ranged between 4.4 and 4.8 per 10,000 population in Bangladesh
two main vectors of this disease in the Yucatán Peninsula are and India30.
Lutzomyia olmeca and Lutzomyia cruciate23,25. In Campeche and
Yucatán (Mexico), Leishmania mexicana is the main causa- Transmission of this disease is low in deforested areas, and the
tive agent; Leishmania braziliensis predominates in Belize and only isolated species in those habitats has been Lutzomyia deleoni,
Guatemala, where cases of L. mexicana have also been reported. which is not an anthropophilic species25. Nevertheless, since 1960,
Forattini has emphasized the potential capability of vectors to adapt
In an epidemiological study in Matto Grosso (Brazil), Thies et al. to suburban and urban environments7. Important contributors for
showed that the frequency and diversity of sand flies were higher the spread of leishmaniasis include environmental factors such as
in rural areas with no deforestation (areas of permanent preserva- alterations in temperature and water storage, irrigation patterns,
tion [96.85%]) than in urban areas26. Lutzomyia dasypodogeton deforestation, climate changes, immunosuppression by HIV, organ
was the most frequent species in areas of preservation, Lutzomyia transplant or immunotherapy, development of drug resistance,
antunesi was more frequent in neighborhoods with forest frag- increased traveling to endemic regions, dog importation, wars, nat-
ments and semi-urban areas, and Lutzomyia aragaoi was the ural disasters, and communities with poor socioeconomic status31.
most frequent species in completely urbanized neighborhoods;
87.92% of frequency and diversity of sand flies was observed in Despite its great epidemiological importance, leishmaniasis is
the rainy season versus 12.08% in the dry season. considered by the WHO to be a disease that has been neglected
by different public and private organizations financing health
In a descriptive study conducted by Vita et al., supported by improvement and research1,4.
data from the Brazilian Information System of Notifiable Diseases
(SINAN) and the Brazilian Institute of Geography and Statistics As part of the adaptation phenomenon of vectors to semi-urban
(IBGE), 1,470 cases of CL were analyzed; 87.89% were of the and urban environments, domestic animals play a role as new
cutaneous clinical form, and there were higher incidences in the opportunistic hosts4. A hypothesis that would explain the new epi-
white ethnic group (49.72%) and in the 20- to 39-year-old age demiological dynamics is the progressive destruction of the vector’s
group (32.44%)27. These researchers concluded that there was a natural habitat by humans, natural disasters, and global warming.
decrease in the number of cases based on a coefficient of detection The populations at risk are defined by patterns of human travel
from 1.44 per 100,000 inhabitants in 2004 to 0.20 per 100,000 in related to tourism and by populations displaced by wars, economic
2013. crises, and natural disasters4. In this regard, the case of Afghanistan

Page 4 of 15
 F1000Research 2017, 6(F1000 Faculty Rev):750 Last updated: 23 JUN 2019

is particularly telling. In its capital, Kabul, there were practically mandatory development of the parasite in the hindgut but migrates
no reported cases of leishmaniasis before 1990; however, by 2003, to the midgut and foregut. The reservoir hosts are reptiles in the
25,000 cases were documented and treated. Newer data have indi- Old World (Leishmania adleri and Leishmania tarentolae) and
cated 67,500 new cases per year4,8. mammals in the New World (L. braziliensis complex). In the
suprapillary group, development does not occur in the hindgut,
Etiopathogenesis and the parasites are restricted to the midgut and foregut. The host
The putative vectors of the different species and subspecies of reservoirs are mammals in the Old as well as in the New World
protozoa of the Leishmania genus are dipterans of the genus (species: tropica, major, donovani, mexicana, and hertigi). There-
Lutzomyia in the New World and Phlebotomus in the old conti- fore, those parasites are grouped into two subgenera: Leishmania,
nent belonging to the subfamily Phlebotominae. The taxonomy of which includes parasites that develop in the midgut and foregut,
these vectors is as follows: and Viannia, which develops in the Phlebotomus foregut, midgut,
and hindgut.
Kingdom      Animal
Phylum         Arthropoda The subgenus Viannia (Laison and Shaw, 1987) includes the fol-
lowing: L. braziliensis, which is the most frequent causative agent
Subphylum   Euarthropoda of cutaneous and muco-cutaneous clinical forms; Leishmania
Superclass    Antenata guyanensis, whose geographical localization corresponds to the
north of the Amazon River, the Guianas, Venezuela, and Peru
Class            Insecta/Hexapoda and which is usually the cause of multiple cutaneous lesions;
Order           Diptera Leishmania lainsoni, which is limited almost exclusively to the
Brazilian Amazon; Leishmania shawi, which is found in the
Suborder      Nematocera (considered the most ancient members, Brazilian state of Pará; Leishmania naiffi, which is distributed
                     dating to the Jurassic period) in Pará and Amazonas (Brazil) and in the French Guiana and is
Family          Psychodidae responsible for the cutaneous form of the disease; Leishmania
peruviana, which is found mostly in the Peruvian Andes and
Subfamily    Phlebotominae causes the CL form known locally as “Uta”; Leishmania
panamensis, which is the responsible causative agent of the disease
Genus          Old World: Phlebotomus/Sergentomyia
in Panama, Costa Rica, Colombia, Ecuador, and Honduras; and
                    N
 ew World: Lutzomyia (with six subgenera: Lutzomyia, Leishmania colombiensis, which is found in Colombia, Panama,
Dampomyia, Pintomyia, Nyssomyia, Psychodopygus, and Venezuela and has been seen in sporadic human cases.
and Peruensis/Brumptomyia/Warileya/Psychodopygus)
The species of subgenus Leishmania (Saf Janova, 1982) includes
Species         Olmeca the following: Leishmania amazonensis, which is responsible for
                     Flaviscutellata the anergic diffuse cutaneous form and the cutaneous forms with
disseminated lesions; Leishmania chagasi, which causes vis-
                    Trapidoi ceral American leishmaniasis and has a wide distribution in Latin
                    Diabolica America, extending from Mexico to Argentina; L. mexicana,
which is observed in Mexico, Colombia, the Caribbean Sea
                     Longipalpis region, and Ecuador and produces muco-cutaneous leishmaniasis
(“Espundia”) and the classic cutaneous form known as chiclero’s
The genus Lutzomyia includes 90% of the pathogenic species, ulcer (gum tree harvester’s ulcer); Leishmania pifanoi, which is
most of which infect humans. Lutzomyia is present in the tropics the causal agent of muco-cutaneous leishmaniasis in Venezuela;
of the New World. They display a dorsal hump and wings with a Leishmania venezuelensis, which is observed in the Venezue-
lanceolate oval shape. Only females nourish from blood, usually lan Andes; Leishmania donovani, which is responsible for VL in
from mammals but sometimes also from inferior terrestrial ver- the Old World; L. infantum, which causes VL and CL in infants;
tebrates. Usually they nourish at night; during the day, they hide L. tropica, which is the causal agent of CL; and Leishmania
in dark, humid places. Lutzomyia absorb sugars that may have aethiopica, which is the causal agent of CL and muco-cutaneous
an important role in the development of Leishmania in the vector leishmaniasis32.
species7.
The duration of the life cycle in the vector varies from 4 to 18 days,
Laison and Shaw proposed a classification of leishmaniasis on the depending on the species of Leishmania; it can be extended at low
basis of their pattern of development in the bowel of the sand fly, temperatures or shortened at high temperatures7.
which not only assumes evolution of the parasites but also allows
their classification into groups such as suprapillary, peripillary, In Mexico, some rodent species have been identified as reservoirs
and hypopillary. In the hypopillary group, infection is limited to for the parasites. For a species to be considered a reservoir, it must
the hindgut (that is, pylorus ileum and rectum). The reservoir’s fulfill two criteria: (1) it must carry enough parasites to make it an
hosts are limited to reptiles from the Old World: Leishmania aga- effective vector at the moment of feeding and (2) in these species
mae and Leishmania ceramodactyli. The peripillary group requires the infection must be relatively non-pathogenic or asymptomatic so

Page 5 of 15
 F1000Research 2017, 6(F1000 Faculty Rev):750 Last updated: 23 JUN 2019

as not to affect the survival of the reservoir22. In these mammals, the The causal agent is an obligatory unicellular protozoan of the fam-
skin and the blood provide adequate environments for the parasite ily Trypanosomatidae, suborder Trypanosomatina, and the genus
to reproduce. Leishmania. Two stages in the life cycle have been defined: a
promastigote (flagellated) that measures 12 to 20 μm is found in
Laboratory studies from Ethiopia suggest that an L. donovani arthropods (diptera), which represent the vector that is infected
parasite load of 20,000 per mL of blood in the host is required to while nourishing from the blood of the vertebrate host. It remains
infect the sand fly species, such as Phlebotomus orientalis30. in the gut of the diptera where, within 4 to 25 days, it shows a
second stage as an amastigote (non-flagellated); this is an obliga-
Generally, more than half of reservoirs remain asymptomatic22,33. tory intracellular parasite that measures from 2.5 to 3.5 μm and is
It is possible that dogs play some role in maintaining endemic localized to the phagocytic cells of the host. The infected female
peri-urban areas; in the border strip of Mexico and Belize and Phlebotomus (which is hematophagous), when biting the infected
Guatemala, when workers’ dogs keep company with their mas- animal, absorbs the amastigote forms from the blood of the reser-
ters in the woods, sometimes they develop ulcers that clinically voir. In the insect’s gut, the parasite begins a process of transfor-
resemble the lesions of leishmaniasis17. mation and the amastigotes change to procyclic promastigotes and
then to metacyclic promastigotes; the latter have infectious capac-
Human-to-human transmission (mediated by vectors without any ity, and, upon biting a healthy animal, the vector inoculates it by
other living species) has been well documented in some endemic regurgitating such promastigotes1,4,8,32.
areas; this means that a sand fly bites the human patient and then
infects another human in an “anthropozoonotic” cycle3,4. When the parasite is deposited by regurgitation in the host
tegument, it is phagocytized by local macrophages and epidermal
Moreover, the demonstration of parasite in the blood of domes- Langerhans cells without the involvement of circulating monocytic
tic animals using molecular tools such as PCR has suggested cells, so this is a local event only in the skin, constituting localized
that domestic animals could serve as an alternate reservoir for an CL (LCL).
infection in India. Domestic animals like pets or cattle could
increase transmission pressure by virtue of being an untreated reser- The host machinery that mediates amastigote uptake is poorly
voir for the parasite, and their proximity to human owners may also understood; however, it is known that, in the human host, amas-
increase the transmission ratio because of increased availability of tigotes bind Fc receptors and enter macrophages primarily through
blood meals for the sand fly as well as organic manure for breed- immunoglobulin-mediated phagocytosis. Wetzel et al. demon-
ing of larvae and resting. In mixed dwellings where cattle sheds strated that a tyrosine kinase non-receptor known as Abl2 facilitates
are attached to the house, bovine origin represented 66% of the L. amazonensis amastigote uptake by macrophages34. Once inside
blood meals of the sand fly whereas human blood represented 19%; the phagolysosomes, promastigotes differentiate into amastigotes
however, even though domestic animals are seen to be infected, and proliferate extensively by binary fission, evading the immune
there is not enough evidence of their role in anthroponotic trans- response. The biological cycle described is performed in 53 to 100
mission in India and the Indian subcontinent30. Such a biologi- days1,8,9. Pathogen species for humans are classified according to
cal cycle has never been documented in the Yucatán Peninsula3,4. their molecular biology, and in America the predominant complexes
Factors that affect the occurrence of disease include the agent are L. mexicana and L. braziliensis. In the Old World, the disease
(species of Leishmania), the host (genetic susceptibility, degree of is caused by L. tropica, L. major, L. aethiopica, L. donovani, and
immunocompetence, poor nutrition, and other underlying diseases), L. infantum. According to the type of immune response elicited, the
and environment4. disease can be localized; it can have a tendency to be spontaneously
healing or generalized and progressive35.
Hypotheses that explain these variations include (a) differences
in the virulence of the parasites, (b) differences in the cutaneous Different factors that determine the parasite’s virulence have been
permeability, (c) individual variations of genetic susceptibility of identified experimentally and may help to understand the mecha-
the host, and (d) variations in the attraction of the Phlebotomus nisms of evasion of the immune response by the parasite. These
toward different individuals3,4. can be classified into three main categories: (1) invasive and eva-
sive determinants, such as lipophosphoglycans (not found in
Parasite transmission from the sand fly to the host depends on how L. mexicana), leishmanolysin, and proteasomes; (2) pathoantigenic
infective the host is, how infective the sand fly is with a single bite, determinants such as histone “chaperones” or proteasomes; and
the average rate of biting, and the number of sand flies present. (3) protective determinants, which are still being identified. On
The biting rate was calculated as 0.25 per day—the inverse of the the other hand, it has been recognized that different components
feeding interval (4 days)—and the latency period in the sand fly in the saliva of the Phlebotomus determine the local reaction after
was 5 days30. the bite.

When a human enters the jungle and is bitten by the infected The immunological basis of these findings is not completely
Phlebotomus, the biological cycle, which is represented by the understood; however, it is known that an adaptive change in the
equation “wild animal ‘reservoir’ → Phlebotomus-infected female immune response occurs with a shifting from Th1 to Th2 with
→ wild healthy animal”, is broken, converting it into “wild animal increments in the production of interleukin-4 (IL-4) and IL-6 or
reservoir → Phlebotomus-infected female → healthy human”32. rather through inhibition of tumor necrosis factor alpha (TNFα),

Page 6 of 15
 F1000Research 2017, 6(F1000 Faculty Rev):750 Last updated: 23 JUN 2019

interferon gamma (IFNγ), IL-12, and the production of nitric Localized cutaneous leishmaniasis
oxide36. Pure CL was first described in the Old World by Lewis and
Cunningham in 1876. It is caused by L. tropica17. In the Mexican
The immune response can vary depending on each clinical form. Southwest and at its border with Guatemala, the causal agent is
In the LCL forms, humoral immunity is not triggered; in the muco- L. mexicana2. It occurs in areas of the body exposed to insect
cutaneous form, specific IgG antibodies can be detected; and in the bites; in decreasing order of frequency, the most involved regions
diffuse cutaneous form, high levels of IgA are occasionally detected. are the ears (areas usually involved are the helix and anti-helix),
Production of IL-4 in the first few weeks after disease onset has nose, upper lip, cheeks, legs, hands and forearms, and ankles17. It is
been observed; faster resolution of the lesions is mediated by the striking that in Guatemala the most affected sites are the upper
production of IFNγ by CD8 T lymphocytes35. It was also observed limbs (up to 43% of cases)3. The incubation period is from 1 to
that the immune response of “resistance” to infections caused by 4 weeks2 but can last for up to several years1. Patients may refer
L. major is mediated mainly by a Th1 response with the to previous travel to endemic zones2.
activation of macrophages, in which the production of IFNγ
predominates and prevents recrudescence and the development of It is characterized by a local increase in temperature and swell-
chronic clinical forms. ing. An erythematous asymptomatic papule appears at the site of
the bite, although pruritus may be present. The size ranges from
On the other hand, progression of the disease has been associated 1 to 10 mm in diameter. After 2 days, it turns into a vesicle and
with a Th2 type response and greater production of IL-4, IL-5, later into a pustule, and when it breaks, either spontaneously or by
transforming growth factor beta (TGFβ), and IL-10. Similar studies trauma due to scratching, it results in a rounded ulcer with nodular
have found an increment in the production of IL-1α, IL-6, IL-10, or thick borders with sharp and peaked edges (Figure 2). Such
TGFβ, IFNγ, and TNFα during the early lesions of LCL, but in the ulcers can last from 3–5 months to 15–20 years. The bottom of
chronic lesions cytokines are decreased37–39. In cases of VL, abnor- the ulcer shows granulation tissue that bleeds when rubbing and
mal patterns of resistance, which were related to class II molecules a pink periphery and sometimes is covered by a whitish pseudo-
of the major histocompatibility complex, have been identified. In membrane (Figure 3). In some cases, abundant secretion forms
cases of leishmaniasis caused by L. major, it has been observed an adherent crust17. The lesion is not painful if it is not second-
that natural killer cells play a role in the initiation of differentiation arily infected. Ulcers may be solitary or multiple; autoinoculation
of T CD4 lymphocytes and in the control of the initial response35. has been observed with the infection at sites distant to the previ-
During VL, intracellular parasites are managed via the activation of ous mosquito bite (as in the forearms) by prolonged contact with
Th1-associated inflammation. IL-10, and eventually programmed ulcerated areas1,41. The clinical picture is usually afebrile with
death 1-mediated T-cell exhaustion, diminishes pathology caused regional adenopathy2,17.
by inflammation. It is not known which cell types are responsible
for initiating T cell–produced IL-10 during VL; however, the popu- On rare occasions, the initial lesion may not ulcerate and develop
lation of IgD (hi) B cells was found to grow threefold during the vegetating appearance12,28. LCL can heal spontaneously in
progression of VL40. 3–9 months in the case of L. mexicana, 2–6 months in the case of
L. major, and 6–15 months if the agent is L. braziliensis, L. tropica,
In both forms, there is an association between CD4+ Th1 lym-
or L. panamensis4,42,43.
phocytes with resistance and Th2 with susceptibility. Nevertheless,
it is clear that CD4 as well as CD8 lymphocytes are activated and
required to control the disease35.

Because of these observations, it can be said that the “spectral”

behavior of leishmaniasis is similar to that of leprosy in such a way
that LCL represents the hyperergic pole in which patients have an
intense cellular response and at the other end of the spectrum is
diffuse CL with a progressive course and usually a fatal outcome.

These two ends of the spectrum yield a positive and negative

response, respectively, to the leishmanin skin test (intradermal
Montenegro’s reaction). The muco-cutaneous form is a variant of
the hyperergic spectrum always produced by L. braziliensis and by
definition is not part of the spectrum of the cutaneous forms1,4.

Classification and clinical picture

The clinical features vary depending on the parasite’s character-
istics and on the genetic aspects of the host that determine the
effectiveness of the immune response. According to the clinical
manifestations, it can be divided into (1) cutaneous (localized and
disseminated), (2) muco-cutaneous, and (3) visceral or kala-azar2. Figure 2. Early ulcer on the forearm with meliceric crust.

Page 7 of 15
 F1000Research 2017, 6(F1000 Faculty Rev):750 Last updated: 23 JUN 2019

Spontaneous healing in up to 4 years, in which healing progresses

from the periphery to the center of the lesion, has been described17.
Spontaneous healing leaves a depressed plaque with uneven pig-
mentation and telangiectasia, or retractile scars with hypopigmented
center and hyperpigmented periphery, as well as local deformity
due to large tissue destruction (Figure 4). When the ear is affected
(chiclero’s or gum tree harvester’s ulcer), it results in mutilations in
the form of notches, or clefts1,17,41 (Figure 5 and Figure 6).

Around 33% of patients can relapse, or the scarring lesion may

reopen, presenting with features similar to those of the origi-
nal episode; recurring manifestations can be mild or more severe
than those observed at the initial episode1,17, called Leishmania
recidivans4. There is an abortive form in which the lesion is a
“regressive” papule44.
Figure 5. Atrophic stage of chiclero’s ulcer with deforming
Diffuse cutaneous leishmaniasis scarring of the ear.
This form is characterized by anergy (that is, lack of cellular
immune response to parasite antigens). This allows dissemination

Figure 3. Ulcer on the upper limb with crusts and raised

borders.

Figure 6. Chiclero’s ulcer with bleeding bed and periphery

covered by fibrin.

through tissue, lymph, and blood pathways, developing lesions in

most of the skin, except in the scalp, and sometimes with involve-
ment of mucous membranes. It is observed in Central America,
Amazonian Brazil, Venezuela, Ethiopia, and Kenya; is caused
by the L. mexicana complex (L. amazonensis, L. braziliensis and
L. pifanoi); and predominates in exposed areas (for example, the
ears (pinna), cheeks, and extremities). It usually starts with hard
erythematous nodules and reddish-brown infiltrative smooth or
verrucous plaques. The latter may or may not ulcerate and are
present first on the face and afterwards progressively affect the
extremities, buttocks, and mucous membranes and in some cases
can involve the entire skin surface (Figure 7). Lymphedema, lym-
Figure 4. Atrophic scar on forearm. phadenopathy, poor general condition, and fever may be observed.

Page 8 of 15
 F1000Research 2017, 6(F1000 Faculty Rev):750 Last updated: 23 JUN 2019

When the mucosae such as the oropharynx and nasopharynx are on some occasions, it causes only mild local pruritus and
involved, painful nodules may lead to airway obstruction. This clin- swelling4,9,17,42,46. In Panama, the “Bejuco’s ulcer” affecting young
ical form is very difficult to treat, there is no spontaneous resolu- individuals is caused by L. panamensis.
tion, and a long evolution of up to 20 years has been observed1,4,9.
Usually, lesions start in the nasal mucosa and spread to the oral
Muco-cutaneous leishmaniasis, cutaneous-mucosal, and pharynx mucosa, the larynx, and the skin of the nose and lips1.
American cutaneous, or “Espundia” Lesions of the oral mucosa usually produce symptoms that range
In South America and in endemic areas, it has been noted that in from simple discomfort and mild pain or odynophagia to cachexia
1 to 10% of patients the LCL form evolves into muco-cutaneous in extreme cases; the latter is observed only in cases in which the
leishmaniasis after 5 years of having healed. Cases from Bolivia, lesion involves the totality of the pharynx, larynx (with hoarse-
Brazil, and Peru represent 90% of this variant. The causal spe- ness), and esophagus (with dysphagia). Early in the disease, there is
cies of this clinical form belong to the complex L. braziliensis, infiltration of the mucosa with superficial ulcerations; later on, when
which includes L. braziliensis, L. guyanensis, and L. panamensis. the ulcers are well developed, their borders have a necrotic appear-
It causes invasion and destruction of the nasopharyngeal mucosa45 ance and are torn and detached. The uvula, pillars of the palate roof,
(Figure 8). Invasion occurs slowly, sometimes causing no initial and tonsils can be destroyed. Owing to superimposed infections,
disturbance, thus allowing the mucosal injury to go unnoticed; the regional lymph nodes can become infarcted and become pain-
ful. When the infection is in the nasal cavity, atrophy of the nasal
turbinates and destruction of the cartilaginous septum with foul
smell can occur and in extreme cases can cause death4,17,46.

Visceral leishmaniasis, or kala-azar (black fever)

The febrile infectious illness known as kala-azar (black fever)
spreads over a large part of south and east Asia (mainly in India
and China), a large part of Africa, the Mediterranean (affect-
ing children and adults), and South America (where children are
affected). It is caused by L. donovani (India and Eastern Africa),
L. infantum (Mediterranean area), and L. chagasi, L. amazonensis,
and L. tropica in South America47,48. The incubation period is from
3 to 8 months. The at-risk population includes preschool children
and immunocompromised and undernourished individuals.

Recently, this type of leishmaniasis has been seen with increas-

ing frequency in patients who have AIDS or who are intravenous
drug users or both, suggesting a potential transmission mechanism
through contaminated syringes1. Lesions in the reticuloendothelial
system may follow a subclinical course (the minority of cases),
or patients may be oligosymptomatic or frankly symptomatic. It
is manifested by lymphadenopathy, hepatomegaly, splenomegaly,
Figure 7. Diffuse cutaneous leishmaniasis (anergic clinical pallor, anemia, leukopenia, thrombocytopenia, fever, night sweats,
form).
weakness, anorexia, asthenia, cutaneous pigmentation, and weight
loss, which can progress rapidly in weeks or months. In addition,
affected children present characteristic chronic diarrhea and growth
retardation.

Typical laboratory abnormalities include pancytopenia and hyper-

gammaglobulinemia. If the disease progresses in the absence of
treatment, cachexia and multisystem failure, hemorrhage due to
thrombocytopenia, and superimposed infections can cause death.

A decrease in the number or function of CD4 cells may cause

recurrence, as in the case of patients receiving corticosteroids or
chemotherapy, in transplant recipients, or in association with infec-
tion with HIV; in this scenario, a new therapeutic regimen may be
required49–51.

Leishmaniasis and HIV

Initial data in this regard came from Southern Europe from intrave-
Figure 8. Muco-cutaneous leishmaniasis (“Espundia”). nous drug abusers who share syringes, leading to a decrease in the

Page 9 of 15
 F1000Research 2017, 6(F1000 Faculty Rev):750 Last updated: 23 JUN 2019

number of T CD4 lymphocytes; in 90% of these patients, the infec- Cultures

tion represents reactivation of a previously acquired subclinical or The culture is performed through the inoculation of the triturated
latent infection. This immunodeficiency, in turn, leads to a lower tissue in special media. Leishmania is cultured in Novy–McNeal–
response to treatment and frequent recurrence. No guidelines have Nicolle medium (currently called “N-N-N medium”) or in a variant
been established to discontinue anti-parasite medications after the of the Evans biphasic medium. In the first culture, forms devoid of
T CD4 cell counts increase post-treatment with the highly effec- flagella are almost always obtained, but from the first re-seeding
tive anti-retroviral treatment49,52. Similar to HIV-infected patients, onwards flagellated forms appear which reach up to 50 μm long17.
pregnant women can be considered a particular population with a Both techniques (microscopic exam and culture) have a sensitivity
condition predisposing to Leishmania reactivation and to changes of 85%49,55.
in immune response owing to a switch toward a Th2 response that
has been reported during pregnancy53. Laboratory data
The Montenegro skin test is sensitive and specific. It is positive for
Diagnosis the localized forms and negative in the anergic forms; a positive test
Diagnosis is based on the clinical and congruent epidemiological supports the diagnosis (especially when the patient does not live in
context17. Laboratory confirmation and identification of the spe- endemic areas), but a negative test does not exclude it1. This aller-
cies of Leishmania are important2. The protozoan is found in the gic index is useful to determine whether previous contact with the
scraping of cutaneous or mucosal ulcerations (especially scraping parasite has occurred, even in the absence of lesions19. A positive
the borders) as well as in non-ulcerated lesions17. Biopsy is another skin test is when the reaction is greater than 5 mm after 72 hours18.
diagnostic tool; it should be obtained from the active border of the However, intradermal injection of Leishmania antigen is not
lesion. A smear may reveal the parasites in free form or inside mac- approved by the US Food and Drug Administration56.
rophages or less frequently in polymorphonuclear leukocytes, rang-
ing in number from 2 to 20 in a single cell. The parasite shape is The parasites are observed in the smear or in the imprint stained
oval or piriform (with an oval or rounded nucleus) and ranges in with Giemsa or Wright; this is the most common and useful diag-
size from 2 to 5 μm long and 1 to 2 μm wide. Exceptionally flagel- nostic method4,18. In the case of the visceral forms, the diagnosis
lated forms have been observed. Inoculation is also used for the is performed by observing protozoans through the microscope in
culture1,17,41. a tissue sample obtained by aspiration from the spleen, bone mar-
row, or lymph node with a sensitivity of 95%, 55–97%, or 60%,
Histopathological data respectively.
In cases of LCL, sections stained with hematoxylin and eosin show
epidermal atrophy or hyperplasia with an inflammatory infiltrate Determination of serum anti-Leishmania IgG and the determination
consisting of macrophages, lymphocytes, and plasma cells with of anti-K39 antibodies are also used, with a sensitivity of 90 to 100%
focal necrotic areas. In the early stages of the infection, parasites and variable specificity according to geographic area. Detection of
can be recognized within cytoplasmic vacuoles in histiocytes Leishmania antigens in urine is a new diagnostic approach49,57.
(Leishman bodies)2, and in late stages, infected macrophages are
less numerous, with few amastigotes predominating, and with The complement fixation test is used to detect antibodies;
some lympho-histiocytic infiltrates confirming a tuberculoid granu- titers equal to or above 1:8 are consistent with infection, as are tit-
loma. The granuloma evolves in three phases: (1) development of ers equal to or above 1:16 in immunofluorescence tests. However,
a mononuclear phagocytic infiltrate, (2) maturation and cellular lower titers do not exclude the infection9. In addition, antibodies
aggregation into a disorganized granuloma, and (3) maturation of can be detected by direct agglutination, direct immunofluorescence,
these cells into an epithelioid granuloma54. Patients with diffuse CL and enzyme-linked immunosorbent assay1,2; however, these sero-
have lesions with highly parasitized macrophages and few dermal logical tests are infrequently recommended in CL because of their
lymphocytes1,2. scarce availability18.

Based on the Magalhaes histopathological classification, the find- PCR has a reported specificity in LCL of 100% with an improved
ings are categorized into five groups: type I, which exhibits an sensitivity of 20 to 30% when compared with conventional parasi-
exudative cellular reaction due to lymphocyte, histiocyte, and tology diagnosis; it can also be used in cases of mucosal leishma-
plasma cell infiltration without granuloma; type II, which exhib- niasis. Unfortunately, this method is available only in specialized
its exudative necrotic reaction characterized by cellular infiltration laboratories or in travelers’ clinics4.
and necrosis without granulomas; type III, which has disorganized
granulomatous necrotic and exudative granuloma corresponding to Recently, in a study in Jordan conducted by Hijjawi et al. using
the pattern of a chronic and necrotic inflammatory reaction; type IV, ITS1-PCR applied to 41 skin scraps on glass slides, 30 were
which shows an exudative granulomatous reaction without necrosis successfully identified58. Furthermore, in 28 samples, PCR-RFLP
and with disorganized granulomas; and type V, which exhibits an analysis allowed species identification corresponding to L. major
exudative tuberculoid reaction with typical organized tuberculoid and two more corresponding to L. tropica. However, it is still not
granuloma. Of these types, the most frequently encountered and available in medical laboratories in Jordan. For the most part,
documented in patients with chiclero’s ulcer has been type IV54. molecular amplification of the hsp70 gene fragment (PCR-hsp70)
When special stains such as Wright-Giemsa are used, the protozoan followed by RFLP analysis is a valid tool for the identification of
cytoplasm stains blue and the nucleus stains red17. Leishmania species isolated from clinical samples of patients, as

Page 10 of 15
 F1000Research 2017, 6(F1000 Faculty Rev):750 Last updated: 23 JUN 2019

was demonstrated in Colombia by Montalvo et al., and could be In the diffuse form, pentamidine is useful and is the second choice.
applicable to epidemiological studies59. Each flask has 300 mg of the drug, a dose that should be diluted in
5 mL of distilled water to be applied intramuscularly in the gluteus.
Prophylaxis The dose is 4 mg/kg with a maximum dose of 240 mg per day on
The eradication of the vector through insecticides, elimination of alternate days. The total dose is dependent on the clinical response
stagnant water, use of insect repellents, and prophylaxis can be and the adverse effects, including nephrotoxicity, hepatotoxicity,
achieved through the use of thick clothes with long sleeves that can hypertension, hypoglycemia, hyperglycemia (rarely), electrocar-
be impregnated with insecticides4 and long pants and by avoiding diographic alterations, gluteal abscess, central facial paresthesia,
night walks in jungle areas17. The WHO is planning a vaccine that cephalea, epigastralgia, and vertigo.
would protect against all types of leishmaniasis44.
For treatment of the muco-cutaneous forms, the duration of a
Treatment parenteral therapeutic regimen with antimonials is 28 days, achiev-
The only effective treatment with satisfactory clinical and micro- ing a cure rate of about 75% in patients with mild or moderate
biological results for all clinical forms of leishmaniasis is achieved forms; it is lower in patients with more severe clinical forms, in
with current intravenous pentavalent antimonials (Sb5+) in the whom amphotericin B is used as a rescue treatment, and in patients
form of sodium stibogluconate (SSG; Pentostam, UK) or meg- with anergic forms49,63.
lumine antimoniate (Glucantime, France), except in the state of
Bihar in India49. In Bihar, parasite resistance to antimonials caused Treatment failure for VL with pentavalent antimonial (SSG)
a dramatic rise in treatment failure of up to 65% between 1980 has been reported in recent years in Nepal; as a result, liposomal
and 1997; in addition, there is the potential for resistance to amphotericin B is currently recommended by the National Program
miltefosine and liposomal amphotericin B to develop30. of Nepal for kala-azar treatment15.

It has been generally accepted that American CL, especially that The drug also results in a good response in immunocompromised
caused by L. braziliensis, should be treated with a dose of 20 mg patients, but the percentage of recurrences in these patients is high.
of Sb5+/kg per day for 20 days, especially to prevent disfiguring Amphotericin B is an extremely effective but toxic alternative;
sequelae in mucosal lesions17,60,61. it is effective even in forms resistant to antimonials. The dose is
l mg/kg per day with a maximum of 50 mg per dose. It is prepared
Trivalent antimonials are prescribed parenterally (repodral and by diluting it in 500 mL of 5% dextrose and delivered on alternate
anthiomaline) in a dose of 2–3 mL (0.02 to 0.03 g) on alternate days up to a total dose of 1 to 1.5 g, while liposomal amphotericin
days for 12 to 20 days, pentavalents such as meglumine (glucan- is used at 2 to 3 mg/kg as a total dose over the course of 20 days.
time) in a dose of 10–60 mg/kg for 12 days to 3 weeks (or until
clinical and parasitological evidence of cure), and SSG (Pentostam) Clinical improvement is observed from 7 to 10 days after therapy
in a dose of 20 mg/kg per day for 30 days, not necessarily consecu- is initiated; after 2 weeks of treatment, the clinical cure is almost
tive; this periodicity can be determined by the onset of side effects. complete with cessation of fever, decrease in size of the spleen, and
The drug should be diluted in 200 mL of 5% dextrose and absence of amastigotes in the aspirate.
delivered in 1 hour32. Intravenous administration is used only in
hospitalized patients, as intramuscular injection is very painful, but An alternative is the transfer factor and more recently paromomy-
it is the only feasible alternative for treatment on a large scale. cin, which has finished phase III experimental studies in India and
Africa and has been approved in some cases49,64. In some cases of
Intralesional treatment has been documented recently as the CL, diaminodiphenyl sulfone (Dapsone®) has been useful at a dose
first therapeutic line in LCL caused by L. major, L. tropica, and of 3 mg/kg per day for 3 weeks1,2,32.
L. panamensis. It causes damage to the cellular membranes and
fragmentation of microtubules, preventing division of the organ- In cases caused by L. mexicana, there is a good response to
ism. On the other hand, previous experimental studies have shown ketoconazole 200 to 400 mg per day for 4 to 6 weeks with or
that the combination with lidocaine, besides decreasing local without cryotherapy2,65 or itraconazole 200 to 400 mg per day for
discomfort, favors the fragmentation and loss of morphologic 1 to 2 months32. Fluconazole has not been demonstrated to be
definition of the plasma membrane (due to its amphophylic proper- effective as a therapeutic option66.
ties) and other organelles in the protozoa of L. braziliensis4,62.
Other alternatives include rifampicin 600 to 1,200 mg per day for
The most frequently described adverse effects of antimonials are more than 2 months, either alone or with isoniazid, IFNγ at a dose
local irritation, anorexia, nausea, vomiting, myalgia, arthralgia, of 50 to 100 μm/m2 per day (subcutaneously for 10 to 15 days,
increases in hepatic enzymes, urea, and creatinine, and electro- although it is not curative if used alone), recombinant human
cardiographic alterations, such as inversion of the T wave, prolon- granulocyte-macrophage colony-stimulating factor (rHGM-CSF) at
gation of Q-T segment, depression of the S-T segment, and sinus subcutaneous doses of 5 μg/kg per day for 10 days or intralesional
bradycardia. In case these effects occur, it will be necessary to stop 200 μg per dose, metronidazole 250 mg three times a day in cycles
the drug until normalization of the clinical and laboratory abnor- of 10 to 15 days, trimethoprim-sulfamethoxazole 160/800 mg
malities, re-introducing the drug on alternate days2,32. twice a day for 4 weeks, azithromycin at a dose of 500 mg per day

Page 11 of 15
 F1000Research 2017, 6(F1000 Faculty Rev):750 Last updated: 23 JUN 2019

for 3, 5, and 10 days or 1 g per day for 2 days, and pentoxifylline in 10 days to 3 weeks. Another alternative in the local treatment of
doses of 1,200 mg per day for 30 days32. LCL is the injection of intralesional amphotericin, which has
demonstrated its effectiveness using 2.5 mg/mL weekly without
Clinical studies with paromomycin and miltefosine have shown recurrences after a 6-month period of follow-up in a study per-
them to be useful; currently, the combination of thermotherapy and formed by Mushtaq et al. in India71. Thermotherapy, cryosurgery,
miltefosine has been considered as an effective alternative in the curettage, and laser and radiotherapy have been tried with relative
treatment of CL4,67,68. efficacy1,4,72,73. Sometimes, in spite of successful treatment, recur-
rent lesions have been reported74. Immunotherapy that combines
A randomized phase II–III clinical trial conducted in Brazil with topical imiquimod with systemic antimonials and vaccines against
90 patients with confirmed CL due to L. guyanensis to compare the sand fly will be fundamental for the future treatment and pre-
miltefosine versus parenteral antimonials revealed cure rates of vention of leishmaniasis75.
71.4% and 53.6%, respectively, with no statistically significant
differences between age groups within the same treatment arms69.
However, in a phase II open-label, non-comparative randomized Competing interests
trial conducted in Sudan and Kenya to evaluate the efficacy and The authors declare that they have no competing interests.
safety of three treatment regimens for VL caused by L. donovani
based on the combination of liposomal amphotericin, SSG, and Grant information
miltefosine divided into three arms of 50 patients each, the results The author(s) declared that no grants were involved in supporting
demonstrated cure ratios of 87% for liposomal amphotericin plus this work.
SSG, 77% for liposomal amphotericin plus miltefosine, and 72%
for miltefosine alone, and efficacy was lower in younger patients; Acknowledgments
therefore, none of these regimes achieves cure ratios of 90%, so The authors acknowledge the assistance of Juan Carlos Manivel,
they should not be used as monotherapy70. of the Department of Pathology, Veterans Administration Medical
Center, Minneapolis, MN, USA, and Francisco G. Bravo, Associate
Locally, one can use antiseptics such as 15% paromomycin Professor, Department of Pathology, Universidad Peruana Cayetano
sulfate and 12% methylbenzethonium ointment twice daily for Heredia, Lima, Peru.

References F1000 recommended

1. Vera-Izaguirre D, Vega-Memije E, Quintanilla Cedillo M, et al.: Leishmaniasis

revisión. DCMQ. 2006; 4(4): 252–260. 11. Ozkeklikci A, Karakus M, Ozbel Y, et al.: The new situation of cutaneous
Reference Source leishmaniasis after Syrian civil war in Gaziantep city, Southeastern region of
Turkey. Acta Trop. 2017; 166: 35–8.
2. Vargas-Martínez F, Torres-Guerrero E, Quintanilla-Cedillo MR, et al.: PubMed Abstract | Publisher Full Text | F1000 Recommendation
Leishmaniasis en México. Academia Mexicana de Dermatología, Colegio de
Dermatólogos de Yucatán A. C., Fundación Mexicana para la Dermatología, 12. Khezzani B, Bouchemal S: Demographic and spatio-temporal distribution of
Universidad Autónoma de Campeche y Secretaría de Salud, México. 2013. cutaneous leishmaniasis in the Souf oasis (Eastern South of Algeria): Results
3. Andrade-Narváez FJ, Vargas-González A, Canto-Lara SB, et al.: Clinical picture of 13 years. Acta Trop. 2017; 166: 74–80.
of cutaneous leishmaniases due to Leishmania (Leishmania) mexicana in the PubMed Abstract | Publisher Full Text | F1000 Recommendation
Yucatan peninsula, Mexico. Mem Inst Oswaldo Cruz. 2001; 96(2): 163–7. 13. Holakouie-Naieni K, Mostafavi E, Boloorani AD, et al.: Spatial modeling of
PubMed Abstract | Publisher Full Text cutaneous leishmaniasis in Iran from 1983 to 2013. Acta Trop. 2017; 166: 67–73.
4. Reithinger R, Dujardin J, Louzir H, et al.: Cutaneous leishmaniasis. Lancet PubMed Abstract | Publisher Full Text | F1000 Recommendation
Infect Dis. 2007; 7(9): 581–96. 14. Khosravani M, Moemenbellah-Fard MD, Sharafi M, et al.: Epidemiologic
PubMed Abstract | Publisher Full Text | F1000 Recommendation profile of oriental sore caused by Leishmania parasites in a new endemic
5. Kashif M, Manna PP, Akhter Y, et al.: The Screening of novel inhibitors against focus of cutaneous leishmaniasis, southern Iran. J Parasit Dis. 2016; 40(3):
Leishmania donovani Calcium ion channel to fight Leishmaniasis. Infect Disord 1077–81.
Drug Targets. 2016; 16. PubMed Abstract | Publisher Full Text | Free Full Text | F1000 Recommendation
PubMed Abstract | Publisher Full Text 15. Pandey BD, Pun SB, Kaneko O, et al.: Case report: Expansion of visceral
6. Hoyos CL, Cajal SP, Juarez M, et al.: Epidemiology of American Tegumentary leishmaniasis to the western hilly part of Nepal. Am J Trop Med Hyg. 2011;
Leishmaniasis and Trypanosoma cruzi Infection in the Northwestern 84(1): 107–8.
Argentina. Biomed Res Int. 2016; 2016: 6456031. PubMed Abstract | Publisher Full Text | Free Full Text
PubMed Abstract | Publisher Full Text | Free Full Text 16. Cruz Ruiz AL, García-Miss MR: Incriminación del “Sand Fly” como vector de
7. Albertos-Alpuche N: Vectores de la leishmaniasis cutánea en México. Rev leishmania. Rev Biomed. 1990; 1(2): 103–108.
Biomed. 1990; 1(2): 92–102. Reference Source
Reference Source 17. Incháustegui A: De la leishmaniosis americana y de la úlcera de los chicleros
8. Miranda O, González I: Leishmaniasis cutánea. Presentación de casos. Rev Cub en México. Tesis, Universidad Nacional de México. 1918.
Med Mil. 2007: 36(4); 51–54. 18. Cordova-Uscanga C, Albertos-Alpuche NE, Andrade-Narvaez FJ, et al.:
Reference Source Leishmaniasis: estudio epidemiologico preliminar en una localidad de la
9. Bravo F, Sanchez MR: New and re-emerging cutaneous infectious diseases in zona endemica del estado de Tabasco. Salud Publica Mex. 1993; 35(4): 345–50.
Latin America and other geographic areas. Dermatol Clin. 2003; 21(4): 655–68, viii. Reference Source
PubMed Abstract | Publisher Full Text 19. Albertos Alpuche N, Andrade Narváez A, Burgos Patrón J, et al.: Leishmaniasis
10. World Health Organization: Weekly Epidemiological Record (WER). 2016; 91(22): cutanea localizada: indice alergico en la comunidad de becanchen, tekax,
285–296. yucatan, México. Rev Biomed. 1996; 7(1): 11–18.
Reference Source Reference Source

Page 12 of 15
 F1000Research 2017, 6(F1000 Faculty Rev):750 Last updated: 23 JUN 2019

20. Canto-Lara SB, Cardenas-Maruffo MF, Vargas-Gonzalez A, et al.: Isoenzyme J Immunol. 2016; 196(10): 4100–9.
characterization of Leishmania isolated from human cases with localized PubMed Abstract | Publisher Full Text | Free Full Text | F1000 Recommendation
cutaneous leishmaniasis from the State of Campeche, Yucatan Peninsula, 41. Seidelin H: Leishmaniasis and Babesiasis in Yucatan. Ann Trop Med Parasit.
Mexico. Am J Trop Med Hyg. 1998; 58(4): 444–7. 2016; 6(2): 295–300.
PubMed Abstract | Publisher Full Text Publisher Full Text
21. Andrade-Narváez FJ, Simmonds-Díaz E, Rico-Aguilar S, et al.: Incidence of 42. Dowlati Y: Cutaneous leishmaniasis: clinical aspects. Clin Dermatol. 1996; 14(5):
localized cutaneous leishmaniasis (chiclero’s ulcer) in Mexico. Trans R Soc 425–31.
Trop Med Hyg. 1990; 84(2): 219–20. PubMed Abstract | Publisher Full Text
PubMed Abstract | Publisher Full Text
43. Soto JM, Toledo JT, Gutierrez P, et al.: Treatment of cutaneous leishmaniasis
22. van Wynsberghe NR, Canto-Lara SB, Sosa-Bibiano EI, et al.: Comparison of with a topical antileishmanial drug (WR279396): phase 2 pilot study. Am J Trop
small mammal prevalence of Leishmania (Leishmania) mexicana in five foci of Med Hyg. 2002; 66(2): 147–51.
cutaneous leishmaniasis in the State of Campeche, Mexico. Rev Inst Med Trop PubMed Abstract | Publisher Full Text
Sao Paulo. 2009; 51(2): 87–94.
44. Arenas R: Dermatología, Atlas diagnóstico y tratamiento. 6ta Ed. México,
PubMed Abstract | Publisher Full Text
McGraw Hill, 2015; 465–472.
23. Andrade-Narvaez FJ, Canto Lara SB, van Wynsberghe NR, et al.: Seasonal Reference Source
transmission of Leishmania (Leishmania) mexicana in the state of Campeche,
45. Davies CR, Reithinger R, Campbell-Lendrum D, et al.: The epidemiology and
Yucatan Peninsula, Mexico. Mem Inst Oswaldo Cruz. 2003; 98(8): 995–8.
control of leishmaniasis in Andean countries. Cad Saude Publica. 2000; 16(4):
PubMed Abstract | Publisher Full Text
925–50.
24. Andrade Narváez F, Valerio Castro E, Simmonds Díaz E, et al.: Leishmaniasis PubMed Abstract | Publisher Full Text
cutánea mexicana. Índice alérgico en una población militar ubicada en una
46. Marsden PD: Mucosal leishmaniasis (“espundia” Escomel, 1911). Trans R Soc
zona epidémica. Rev Sanid Milit Méx. 1985; 39(5): 152–154.
Trop Med Hyg. 1986; 80(6): 859–76.
25. Rebollar-Téllez EA, Ramírez-Fraire A, Andrade-Narvaez FJ: A two years study on PubMed Abstract | Publisher Full Text
vectors of cutaneous leishmaniasis. Evidence for sylvatic transmission cycle
47. Desjeux P: Leishmaniasis: current situation and new perspectives. Comp
in the State of Campeche, Mexico. Mem Inst Oswaldo Cruz. 1996; 91(5): 555–60.
Immunol Microbiol Infect Dis. 2004; 27(5): 305–18.
PubMed Abstract | Publisher Full Text
PubMed Abstract | Publisher Full Text
26. Thies SF, Bronzoni RV, Espinosa MM, et al.: Frequency and diversity of 48. Guerin PJ, Olliaro P, Sundar S, et al.: Visceral leishmaniasis: Current status of
phlebotomine sand flies (Diptera: Psychodidae) in Sinop, State of Mato control, diagnosis, and treatment, and a proposed research and development
Grosso, Brazil. Rev Soc Bras Med Trop. 2016; 49(5): 544–52. agenda. Lancet Infect Dis. 2002; 2(8): 494–501.
PubMed Abstract | Publisher Full Text | F1000 Recommendation PubMed Abstract | Publisher Full Text
27. Vita GF, Pereira MA, Ferreira I, et al.: Status of the American tegumentary 49. Murray HW, Berman JD, Davies CR, et al.: Advances in leishmaniasis. Lancet.
Leishmaniasis in the State of Rio de Janeiro , Brazil, from 2004 to 2013. Rev 2005; 366(9496): 1561–77.
Inst Med Trop Sao Paulo. 2016; 58: 71. PubMed Abstract | Publisher Full Text
PubMed Abstract | Publisher Full Text | Free Full Text | F1000 Recommendation 50. Collin S, Davidson R, Ritmeijer K, et al.: Conflict and kala-azar: determinants of
adverse outcomes of kala-azar among patients in southern Sudan. Clin Infect
28. Al-Jawabreh A, Dumaidi K, Ereqat S, et al.: Molecular epidemiology of
Dis. 2004; 38(5): 612–9.
human cutaneous leishmaniasis in Jericho and its vicinity in Palestine from
PubMed Abstract | Publisher Full Text
1994 to 2015. Infect Genet Evol. 2017; 50: 95–101.
PubMed Abstract | Publisher Full Text | F1000 Recommendation 51. Kumar Bhat N, Ahuja V, Dhar M, et al.: Changing Epidemiology: A New
Focus of Kala-azar at High-Altitude Garhwal Region of North India. J Trop
29. Fakhar M, Pazoki Ghohe H, Rasooli SA, et al.: Genetic diversity of
Pediatr. 2017; 63(2): 104–8.
Leishmania tropica strains isolated from clinical forms of cutaneous
PubMed Abstract | Publisher Full Text | F1000 Recommendation
leishmaniasis in rural districts of Herat province, Western Afghanistan, based
on ITS1-rDNA. Infect Genet Evol. 2016; 41: 120–7. 52. Berenguer J, Cosín J, Miralles P, et al.: Discontinuation of secondary anti-
PubMed Abstract | Publisher Full Text | F1000 Recommendation leishmania prophylaxis in HIV-infected patients who have responded to highly
active antiretroviral therapy. AIDS. 2000; 14(18): 2946–8.
30. Hirve S, Boelaert M, Matlashewski G, et al.: Transmission Dynamics of PubMed Abstract | Publisher Full Text
Visceral Leishmaniasis in the Indian Subcontinent - A Systematic Literature
Review. PLoS Negl Trop Dis. 2016; 10(8): e0004896. 53. Pagliano P, Ascione T, Di Flumeri G, et al.: Visceral leishmaniasis in
PubMed Abstract | Publisher Full Text | Free Full Text | F1000 Recommendation immunocompromised: diagnostic and therapeutic approach and evaluation of
the recently released IDSA guidelines. Infez Med. 2016; 24(4): 265–71.
31. Oryan A, Akbari M: Worldwide risk factors in leishmaniasis. Asian Pac J Trop PubMed Abstract | F1000 Recommendation
Med. 2016; 9(10): 925–32.
54. Andrade-Narvaez FJ, Medina-Peralta S, Vargas-Gonzalez A, et al.: The
PubMed Abstract | Publisher Full Text | F1000 Recommendation
histopathology of cutaneous leishmaniasis due to Leishmania (Leishmania)
32. Azulay D, Rubem Azulay D, Azulay A: Dermatología. 4ta Ed. Ediciones Guanabara mexicana in the Yucatan peninsula, Mexico. Rev Inst Med Trop Sao Paulo. 2005;
Koogan, Río de Janeiro. 2008; 415–425. 47(4): 191–4.
33. Van Wynsberghe NR, Canto-Lara SB, Damián-Centeno AG, et al.: Retention of PubMed Abstract | Publisher Full Text
Leishmania (Leishmania) mexicana in naturally infected rodents from the State 55. Ramírez JR, Agudelo S, Muskus C, et al.: Diagnosis of cutaneous leishmaniasis
of Campeche, Mexico. Mem Inst Oswaldo Cruz. 2000; 95(5): 595–600. in Colombia: the sampling site within lesions influences the sensitivity of
PubMed Abstract | Publisher Full Text parasitologic diagnosis. J Clin Microbiol. 2000; 38(10): 3768–73.
PubMed Abstract | Free Full Text
34. Wetzel DM, Rhodes EL, Li S, et al.: The Src kinases Hck, Fgr and Lyn
activate Arg to facilitate IgG-mediated phagocytosis and Leishmania infection. 56. Arenas R: Leishmaniasis. In: Arenas R, Estrada R: Tropical Dermatology. 1era Ed.
J Cell Sci. 2016; 129(16): 3130–43. Texas. Landes Bioscience; 2001; 228–238.
PubMed Abstract | Publisher Full Text | Free Full Text | F1000 Recommendation 57. Sundar S, Sahu M, Mehta H, et al.: Noninvasive management of Indian visceral
35. García Miss M: Cellular response to leishmaniasis. Rev Biomed. 1995; 6: leishmaniasis: clinical application of diagnosis by K39 antigen strip testing at
92–100. a kala-azar referral unit. Clin Infect Dis. 2002; 35(5): 581–6.
Reference Source PubMed Abstract | Publisher Full Text
36. Chang KP, Reed SG, McGwire BS, et al.: Leishmania model for microbial 58. Hijjawi N, Kanani KA, Rasheed M, et al.: Molecular Diagnosis and
virulence: the relevance of parasite multiplication and pathoantigenicity. Acta Identification of Leishmania Species in Jordan from Saved Dry Samples.
Trop. 2003; 85(3): 375–390. Biomed Res Int. 2016; 2016: 6871739.
PubMed Abstract | Publisher Full Text PubMed Abstract | Publisher Full Text | Free Full Text | F1000 Recommendation
37. Melby PC, Andrade-Narvaez F, Darnell BJ, et al.: In situ expression of
59. Montalvo AM, Fraga J, Montano I, et al.: Molecular identification of
interleukin-10 and interleukin-12 in active human cutaneous leishmaniasis.
Leishmania spp. clinical isolates from Colombia based on hsp70 gene.
FEMS Immunol Med Microbiol. 1996; 15(2–3): 101–7.
Biomedica. 2016; 36: 37–44.
PubMed Abstract | Publisher Full Text
PubMed Abstract | Publisher Full Text | F1000 Recommendation
38. Melby PC, Andrade-Narvaez FJ, Darnell BJ, et al.: Increased expression
60. Roberts WL, McMurray WJ, Rainey PM: Characterization of the antimonial
of proinflammatory cytokines in chronic lesions of human cutaneous
antileishmanial agent meglumine antimonate (glucantime). Antimicrob Agents
leishmaniasis. Infect Immun. 1994; 62(3): 837–42.
Chemother. 1998; 42(5): 1076–82.
PubMed Abstract | Free Full Text
PubMed Abstract | Free Full Text
39. Romero GA, Guerra MV, Paes MG, et al.: Comparison of cutaneous 61. Vargas-Gonzalez A, Canto-Lara SB, Damian-Centeno AG, et al.: Response of
leishmaniasis due to Leishmania (Viannia) braziliensis and L. (V.) guyanensis cutaneous leishmaniasis (chiclero’s ulcer) to treatment with meglumine
in Brazil: therapeutic response to meglumine antimoniate. Am J Trop Med Hyg. antimoniate in Southeast Mexico. Am J Trop Med Hyg. 1999; 61(6): 960–3.
2001; 65(5): 456–65. PubMed Abstract | Publisher Full Text
PubMed Abstract | Publisher Full Text
62. Yépez J, Cazorla D, Sánchez de Mirt A, et al.: Effect of intralesional treatment
40. Schaut RG, Lamb IM, Toepp AJ, et al.: Regulatory IgDhi B Cells Suppress with lidocaine and glucantime® in hamsters infected with Leishmania
T Cell Function via IL-10 and PD-L1 during Progressive Visceral Leishmaniasis. (Viannia) braziliensis. Boletín de la dirección de malariología y saneamiento

Page 13 of 15
 F1000Research 2017, 6(F1000 Faculty Rev):750 Last updated: 23 JUN 2019

ambiental. 1999; 39(1): 10–20. clinical trial to access efficacy and safety of miltefosine in the treatment
Reference Source of cutaneous leishmaniasis Caused by Leishmania (Viannia) guyanensis in
63. Sundar S, Jha TK, Thakur CP, et al.: Low-dose liposomal amphotericin B in Manaus, Brazil. Am J Trop Med Hyg. 2011; 84(2): 255–60.
refractory Indian visceral leishmaniasis: a multicenter study. Am J Trop Med PubMed Abstract | Publisher Full Text | Free Full Text
Hyg. 2002; 66(2): 143–6. 70. Wasunna M, Njenga S, Balasegaram M, et al.: Efficacy and Safety of
PubMed Abstract | Publisher Full Text AmBisome in Combination with Sodium Stibogluconate or Miltefosine
64. Jha TK, Olliaro P, Thakur CP, et al.: Randomised controlled trial of aminosidine and Miltefosine Monotherapy for African Visceral Leishmaniasis: Phase II
(paromomycin) v sodium stibogluconate for treating visceral leishmaniasis in Randomized Trial. PLoS Negl Trop Dis. 2016; 10(9): e0004880.
North Bihar, India. BMJ. 1998; 316(7139): 1200–1205. PubMed Abstract | Publisher Full Text | Free Full Text | F1000 Recommendation
PubMed Abstract | Publisher Full Text | Free Full Text
71. Mushtaq S, Dogra D, Dogra N: Clinical Response with intralesional
65. Saenz RE, Paz H, Berman JD: Efficacy of ketoconazole against Leishmania
Amphotericin B in the treatment of old world cutaneous leishmaniasis: a
braziliensis panamensis cutaneous leishmaniasis. Am J Med. 1990; 89(2):
preliminary report. Dermatol Ther. 2016; 29(6): 398–405.
147–55.
PubMed Abstract | Publisher Full Text | F1000 Recommendation
PubMed Abstract | Publisher Full Text
72. Croft SL, Yardley V: Chemotherapy of leishmaniasis. Curr Pharm Des. 2002; 8(4):
66. Prates FV, Dourado ME, Silva SC, et al.: Fluconazole in the Treatment of 319–42.
Cutaneous Leishmaniasis Caused by Leishmania braziliensis: A Randomized PubMed Abstract | Publisher Full Text
Controlled Trial. Clin Infect Dis. 2017; 64(1): 67–71. 73. Panagiotopoulos A, Stavropoulos PG, Hasapi V, et al.: Treatment of cutaneous
PubMed Abstract | Publisher Full Text | F1000 Recommendation leishmaniasis with cryosurgery. Int J Dermatol. 2005; 44(9): 749–52.
67. Sundar S, Jha TK, Thakur CP, et al.: Oral miltefosine for Indian visceral PubMed Abstract | Publisher Full Text
leishmaniasis. N Engl J Med. 2002; 347(22): 1739–46. 74. Weigel MM, Armijos RX: The traditional and conventional medical treatment
PubMed Abstract | Publisher Full Text of cutaneous leishmaniasis in rural Ecuador. Rev Panam Salud Publica. 2001;
68. Bhattacharya SK, Jha TK, Sundar S, et al.: Efficacy and tolerability of miltefosine 10(6): 395–404.
for childhood visceral leishmaniasis in India. Clin Infect Dis. 2004; 38(2): 217–21. PubMed Abstract | Publisher Full Text
PubMed Abstract | Publisher Full Text 75. Nelson S, Warschaw K: Chapter 83: Protozoa and Worms. In: Bolognia J, Jorizzo R,
69. Chrusciak-Talhari A, Dietze R, Chrusciak Talhari C, et al.: Randomized controlled Schaffer JV. Dermatology. 3rd Ed. Elsevier-Saunders. New York, 2012; 1391–1421.

Page 14 of 15
 F1000Research 2017, 6(F1000 Faculty Rev):750 Last updated: 23 JUN 2019

Open Peer Review

Current Peer Review Status:

Editorial Note on the Review Process

F1000 Faculty Reviews are written by members of the prestigious F1000 Faculty. They are commissioned and
peer reviewed before publication to ensure that the final, published version is comprehensive and accessible. The
reviewers who approved the final version are listed with their names and affiliations.

The reviewers who approved this article are:

Version 1
1 Roderick J Hay 
Department of Dermatology, International Foundation for Dermatology, London, W1P 5HQ, UK
Competing Interests: No competing interests were disclosed.
2 Francisco Bravo-Puccio 
-, -, -, -, -, USA
Competing Interests: No competing interests were disclosed.

The benefits of publishing with F1000Research:

Your article is published within days, with no editorial bias

You can publish traditional articles, null/negative results, case reports, data notes and more

The peer review process is transparent and collaborative

Your article is indexed in PubMed after passing peer review

Dedicated customer support at every stage

For pre-submission enquiries, contact research@f1000.com 

 
Page 15 of 15