Current Diag Treat of Cut and Mucocut Leish-2010

8132019 Current Diag Treat of Cut and Mucocut Leish-2010

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419

Review

wwwexpert-reviewscom ISSN 1478-7210101586ERI1019 copy 2010 Hiro Goto amp Joseacute Angelo Lauletta Lindoso

Leishmaniasis is a disease caused by different

species of protozoa of the genus Leishmania that are transmitted by Phlebotomine sandfliesLeishmania are injected into the vertebrate host asa promastigote (the elongated form with an exter-nal flagellum) which is phagocytosed by differ-ent phagocytic cells in the host Within cells ofthe mononuclear phagocyte system (its habitat)promastigotes differentiate into amastigotes (theround form without an external flagellum) andthen proliferate establishing the infection

Leishmaniasis is considered as an emergentand re-emergent disease and there has been

a worrisome increase in its incidence mostlyin the last two decades in certain parts of the world due to the migration of people fromrural to urban areas seeking work opportuni-ties migration as a consequence of war distur-bances in microenvironments due to climatechange and human intervention deteriorationof socioeconomic conditions the presence ofHIVLeishmania coinfection and so on [1]Leishmaniasis is prevalent in tropical and sub-tropical areas but due to the increase in inter-national travel it also appears to be an important

disease in people living in nonendemic areas [2]

Leishmaniasis encompasses visceral and tegu-

mentary forms including cutaneous and muco-cutaneous forms Tegumentary leishmaniasis isprevalent in 82 countries and its incidence isestimated to be 15 million cases per year Most(90) of the cases are reported in Africa (mainlyin Morocco Ethiopia and Tunisia) the MiddleEast (mainly in Afghanistan Pakistan IranIraq Syria and Saudi Arabia) and Latin America(mainly in Brazil Bolivia Colombia EcuadorPeru and Venezuela) [13]

Dermotropic strains of Leishmania belong to theorder Kinetoplastida family Trypanosomatidae

genus Leishmania and subgenus Leishmania orViannia which include approximately 20 speciesthat differ in their geographical distribution In Asia Africa and Europe tegumentary leishmani-asis is caused by Leishmania (Leishmania ) majorLeishmania (Leishmania ) tropica Leishmania(Leishmania ) aethiopica and some zimodemesfrom Leishmania infantum In the New Worldmainly Latin America the species involved arenumerous and are of the subgenus Leishmania andViannia Leishmania (Viannia ) braziliensis is themost prevalent species followed by Leishmania

(Leishmania ) amazonensis Leishmania (Viannia )

Hiro Gotodagger andJoseacute AngeloLauletta Lindosodagger Author for correspondence

Laboratoacuterio deSoroepidemiologia do Institutode Medicina Tropical daUniversidade de Satildeo Paulo Avenida Dr Eneacuteas de Carvalho Aguiar nordm 470 Preacutedio II4ordm andar CEP 05403-000Satildeo Paulo SP BrazilTel +55 113 061 7023Fax +55 113 061 8270hgotouspbrhgotopqcnpqbr

Tegumentary leishmaniasis comprising the cutaneous and mucocutaneous forms is caused byat least 13 dermotropic species of protozoa of the genus Leishmania most of which are prevalentin the New World Although diseases in the Old and New Worlds share similar characteristicsthe ultimate manifestations and severity are quite different with more severe forms associatedwith mucosal lesions observed in the New World For the diagnosis and treatment of leishmaniasisdifferences based on clinical features usefulnesssensitivity of diagnostic methods andtherapeutic responses are mainly emphasized We present a critical review of the diagnosticmethods their contribution and the necessity for their improvementdevelopment particularlyin molecular diagnosis aimed at detection and species identification as well as serodiagnosisIn addition to a review of the drugs currently utilized we describe differences in their effectivenessin Old and New World leishmaniasis HIV Leishmania coinfection is also presented in the contextof diagnosis and treatment

KEYWORDS amphotericin B bull coinfection bull ELISA bull HIV bull human bull Leishmania bull PCR bull pentamidine bull pentavalent

antimonials bull serodiagnosis

Current diagnosis and

treatment of cutaneous andmucocutaneous leishmaniasisExpert Rev Anti Infect Ther 8 (4) 419ndash433 (2010)



Expert Rev Anti Infect Ther 8(4) (2010)420

Review

guyanensis and Leishmania (Viannia ) panamensis although otherspecies such as Leishmania (Leishmania ) mexicana Leishmania(Leishmania ) pifanoi Leishmania (Leishmania ) venezuelen-sis Leishmania (Viannia ) peruviana Leishmania (Leishmania ) shawi and Leishmania (Viannia ) lainsoni are present mostly in

the Amazon region and in Central America In the Old WorldLeishmania (Leishmania ) donovani a viscerotropic species maydetermine a cutaneous disease during or after visceral leishmaniasisand is known as post-kala-azar dermal leishmaniasis (PKDL) [3ndash5]

Diagnosis of leishmaniasis

Diagnosis of leishmaniasis is based on criteria that considerepidemiological data clinical features and laboratory test results

Epidemiological criteria

The epidemiological link among individuals in an endemic area isevident but it constitutes important information for the diagnosis

of travelers living in nonendemic areas who have spent some timein areas endemic for leishmaniasis Tegumentary leishmaniasisis one of the dermatological syndromes diagnosed in travelersIn a retrospective study employing data from the GeoSentinelSurveillance Network comprising a 10-year period from 1997to 2006 skin-related diagnoses were reported for 4594 patientsand tegumentary leishmaniasis was diagnosed in 33 The traveldestination of these patients was Latin America and in 15 thetravel duration had been less than 2 weeks [6] In another twostudies carried out in Europe some patients with cutaneous leish-maniasis had traveled to endemic countries in the Old World andothers to the New World [78]

Clinical criteria

The clinical features of tegumentary leishmaniasis are diversedepending on the Leishmania species involved and host factorsincluding immune status However the initial evolution of the lesionis similar at the site of the insect bite After an incubation period of2 weeks to 3 months a small itchy erythematous papule or noduleappears sometimes preceded or accompanied by draining lymphnode enlargement This initial lesion may cure spontaneously orevolve usually after some months to patent disease with differentclinical features [910] The correlation of clinical features and spe-cies of Leishmania is currently not straightforward because in someareas many different species coexist and furthermore species iden-

tification is not usually performed for clinical specimens due to thecomplexity of the laboratory procedures as well as their accessibility

In general terms species prevalent in the Old World determinelimited clinical manifestations compared with New World speciesL (L) major L (L) tropica and L (L) aethiopica species that areprevalent in the Old World determine the characteristic ulcerativelesion of localized cutaneous leishmaniasis (LCL) in 86ndash98 ofcases that usually cure spontaneously after a period ranging from3 months to 2 years [11] In some cases L (L) tropica infectionevolves to a relapsing lesion known as leishmaniasis recidiva cutisor leishmaniasis recidivans [11] or mucosal leishmaniasis (ML)[12] and L (L) aethiopica infection to diffuse cutaneous leish-

maniasis (DCL) [11] In addition L (L) donovani may determine

PKDL [13] The species present in the New World determinemore varied clinical manifestations including the aggressive anddestructive ML In the following sections the features of the dif-ferent forms are described with an emphasis on manifestationscaused by the New World species We also highlight manifesta-

tions observed in HIVLeishmania coinfection which can presentunusual forms A detailed description of the clinical manifesta-tions of Old World cutaneous leishmaniasis can be found in arecently published comprehensive review by Akilov et al [11]

Localized cutaneous leishmaniasis

Localized cutaneous leishmaniasis (FIGURE 1A) is the most prevalentform of the disease and is most commonly caused by dermotropicLeishmania species [7] The lesions appear on an exposed area ofthe body surface varying in number from one to ten The estab-lished lesion is a round painless ulcer that is well delimited witha central crust that is sometimes hemorrhagic It may cure sponta-

neously leaving a hypopigmented smooth thin scar Dependingon the hostndashparasite balance and other undefined factors somecases evolve to other forms of the disease

Leishmaniasis recidiva cutis

Leishmaniasis recidiva cutis (F IGURE 1B) is known in the Old World to be associated with L (L) tropica infection the occur-rence of which is rare in the New World Characteristic papularand vesicular lesions appear after clinical cure in or aroundthe scar of the healed sore after a variable period of time frommonths to years Most of the identified parasites in the New World were of the subgenus Viannia [14] but L (L) amazon-ensis in Brazil [15] and L (V) panamensis in Ecuador [16] were

also observed

Disseminated leishmaniasis

Disseminated leishmaniasis (DL) (FIGURE 1C) is characterized bythe presence of multiple (10ndash300) pleomorphic lesions mainlyacneiform and papular in two or more noncontiguous areas ofthe body [17] In 29 of cases a mucosal lesion is found In anarea in the northeast of Brazil the frequency of this conditionhas increased from 02 to 19 among tegumentary leishmaniasiscases in two decades In these cases L (V) braziliensis was theonly species encountered [1819]

Diffuse cutaneous leishmaniasisDiffuse cutaneous leishmaniasis is a true anergic form of tegu-mentary leishmaniasis and is characterized by the presence ofnodular lesions that do not ulcerate (F IGURE 1D amp 1E) [20] It is arare condition It has been reported in South America Central America and Ethiopia The lesions are rich in parasites and thespecies involved are L (L) mexicana and L (L) amazonensis inthe New World and L (L) aethiopica in the Old World

Mucocutaneous leishmaniasis

Also known as lsquoespundiarsquo mucocutaneous leishmaniasis occursyears after the onset of cutaneous leishmaniasis and is character-

ized by the destruction of oralndashnasal and pharyngeal cavities

Goto amp Lindoso



wwwexpert-reviewscom 421

Review

potentially evolving to disfiguring lesions (FIGURE 1F) The initialsymptoms are mild with nasal inflammation and stuffiness butulceration and perforation of the septum may slowly ensue The

lesion may extend to the face soft palate pharynx or larynx

The mucosal lesion may be accompanied by a cutaneous lesionL (V) braziliensis is present in the majority of cases but otherspecies are also found L (V) panamensis L (V) guyanensis

L (L) amazonensis and L (L) major [17] The frequency of ML

I

Figure 1 Clinical forms of tegumentary leishmaniasis (A) Localized cutaneous leishmaniasis presenting single ulcer on the leg(reprinted with permission from Luiza K Oyafuso Instituto de Infectologia Emilio Ribas de Satildeo Paulo Brazil) (B) Leishmaniasis recidiva cutispresenting papules and vesicles around the healed lesion of cutaneous leishmaniasis on the leg (reprinted with permission from JacksonML Costa Universidade Federal do Maranhatildeo Brazil) (C) Disseminated cutaneous leishmaniasis presenting numerous ulcers on the face(reprinted with permission from Jackson ML Costa) (D) Diffuse cutaneous leishmaniasis presenting infiltrated nodules on the arms andthorax (reprinted with permission from Fernando T Silveira Universidade Federal do Paraacute-Brazil Brazil) (E) Diffuse cutaneous leishmaniasispresenting inltrated nodules on the ear (reprinted with permission from Fernando T Silveira) (F) Mucosal leishmaniasis with destructivelesion in the nose (reprinted with permission from Luiza K Oyafuso) (G) Atypical cutaneous leishmaniasis in a HIV-infected patientpresenting multiple ulcers on the legs and feet (H) Atypical cutaneous leishmaniasis in HIV-infected patient presenting erythematousplaques on the back and (I) atypical cutaneous leishmaniasis in a HIV-infected patient presenting ulcers on the scrotum and penisImages G H and I reproduced from [28] with permission from Wiley-Blackwell

Current diagnosis amp treatment of cutaneous amp mucocutaneous leishmaniasis




Review

varies according to the geographical location In Brazil it variesfrom 04 in the south [21] to 14 in the central region [22] andto 27 in the northeast [23] In Andean countries ML reachesan average of 71 [24] Bolivia exhibits a high frequency of20 [25] Ecuador a medium frequency of 77 [26] Colombia

a low frequency of 23 and Venezuela a very low frequencyof 04 [24]

Tegumentary leishmaniasis in HIV-infected patients

HIVLeishmania coinfection has been reported in 34 countriesIn the Old World there are reports of PKDL in HIV-infectedpatients [27] In the New World the manifestations can be simi-lar to those found in nonimmunosuppressed patients with nosigns of aggravation but they can be quite unusual We recentlyreported a series of cases of tegumentary leishmaniasis in HIV-positive patients from Brazil [28] where we found a wide vari-ety of lesions including papules nodules plaques (FIGURE 1H) and

diverse ulcerations(FIGURE 1G)

Furthermore we observed differentforms of mucosal lesions such as widespread diffuse infiltra-tion of the mucosal surface of the palate Interestingly genitallesions (FIGURE 1I) were present in 27 of patients Of note inHIV-infected patients tegumentary leishmaniasis may presentas immune reconstitution inflammatory syndrome with theappearance of new disseminated lesions or worsening of pre-existing ones associated with a recovery of CD4+ T-cell countsand decreased virus loads upon antiretroviral treatment [29]

Differential diagnosis

Differential diagnosis should be made for sporotrichosis cutane-ous Mycobacterium infection venous stasis or traumatic ulcers

sickle-cell anemia-related ulcers blastomycosis sarcoidosissyphilis Kaposirsquos sarcoma leprosy chromoblastomycosis squa-mous cell carcinoma basal cell carcinoma B-cell cutaneouslymphoma seborrheic keratosis pyoderma gangrenosum pyo-genic skin infections including ecthyma and idiopathic midlinegranuloma [1730]

Laboratory tests for diagnosis

In all cases it is desirable to have the diagnosis of leishmaniasisconfirmed by the finding of the etiological agent or its antigenor molecule in the sample obtained from the lesion When theseapproaches fail immunological tests are used to provide indirect

parameters for the diagnosis

Parasitological diagnosis

A search for amastigotes can be performed using light microscopyto directly examine the biopsy specimen scraping or impressionsmears subjected to Giemsa staining Biopsy and aspirate samplescan be further cultured in blood agar base formerly known asNovy McNeal and Nicolle medium overlaid by liver infusiontriptose or Schneiderrsquos liquid medium or injected into a suscepti-ble animal such as a hamster for parasite recovery The sensitivityof the direct examination is low at approximately 50ndash70 in theOld World [3132] and even lower at approximately 15ndash30 in

the New World where chronic cases and ML are frequent [33ndash34]

The detection level is higher reaching 44ndash58 by culturing thesamples and 38ndash52 by injection into hamsters [3435] Whenbiopsy specimens were submitted for immunohistochemistryLeishmania amastigotes or antigen were detected at higher propor-tions 414 [34] and 885 [33] using an immunofluorescence tech-

nique and 586 [34] and 645 [33] using an immunoperoxidasetechnique Excluding direct microscopic examination other meth-ods require a complex laboratory structure and technical skills as well as longer periods of time to obtain the results

These approaches to etiological agent detection have relativelylow sensitivity and different methods do not identify the speciesof Leishmania Therefore recent efforts are aimed at developingassays to detect the parasite DNA

Detection of Leishmania DNA

A variety of molecular approaches have been developed for thediagnosis of leishmaniasis (for a comprehensive review see [36])

A molecular approach for the diagnosis of leishmaniasis basedon the detection of Leishmania DNA has two goals detectionof Leishmania similar to other parasitological methods andidentification of the Leishmania species which is not achievedby other methods except when cultured promastigotes are ana-lyzed using Leishmania species-specific monoclonal antibodies[37] or by isoenzyme profiling [38] Among the laboratory methodsemployed to detect the etiological agent or its material in rea-sonably equipped laboratories PCR is considered to be a goodmethod for use in the diagnosis Some of the advantages of thismethod when compared with other parasitological methods arethe possibility of detecting Leishmania DNA even with a lowparasite load specificity the fast availability of results the pos-

sibility of using dif ferent biological materials and the possibilityof detecting the DNA of amastigotes and promastigotes

Different primer sequences specific for different targets in theDNA of Leishmania have been used to improve parasite detec-tion Some are nuclear DNA such as the SSU rRNA gene [39]multilocus microsatellite DNA [40] some repetitive sequences [41]the tubulin gene [42] the gp63 gene locus [43] and internal tran-scribed spacer regions [4445] Others are extrachromosomal DNAsuch as the repetitive kinetoplast DNA (kDNA) [46] The latter isconsidered as an attractive target for PCR due to the abundanceof minicircles in the parasite

In laboratories where molecular diagnosis is a routine proce-

dure for diagnosis the most commonly addressed targets arekDNA and SSU rRNA In studies using kDNA as the targetto assess the sensitivity of the PCR the results for the detectionrate both in the Old World and New World were found to behigh with values of 100 in cutaneous leishmaniasis [47] and971 in ML [48]

An important approach in the diagnosis of tegumentary leish-maniasis is the characterization of the Leishmania species whichis not performed in other methods used to detect the etiologicalagent A considerable future challenge is to discriminate thevarious species present in the New World and to obtain andtest samples preferably without the need for parasite growth

in culture

Goto amp Lindoso




Review

For the identification of species repetitive and polymorphicsequences are either directly targeted or discriminated usingrestriction enzymes for targeted products The former approach was used to target the glucose-6-phosphate dehydrogenase genethe products of which discriminate between different species of

Leishmania from the New World distinguishing L (V) bra-ziliensis from other species of the Viannia subgenus [49] Similarly when the isomerase mannose enzyme gene ( MPI ) is targeted it ispossible to differentiate L (V) braziliensis from L (V) peruviana [50] The latter approach was applied for certain targets such askDNA internal transcribed spacer heat-shock protein (Hsp)70gene [51] and glycoprotein of molecular mass 63 gene (GP63)using restriction enzymes to disclose polymorphisms the result-ing restriction fragment length polymorphism (RFLP) distin-guishes various Leishmania species [52] PCR-RFLP with Hsp70 isparticularly interesting since various New World species can bedistinguished and the parasite samples can be obtained directly

from the lesion[51]

Real time-PCR (RT-PCR) using primers specific to theLeishmania genus or species has been evaluated more recently forthe diagnosis of leishmaniasis It mainly aims to approach its poly-morphism to identify Leishmania species but also to measure para-site load in the lesion [53ndash55] It is a very promising method andalthough it requires the appropriate laboratory structure (expen-sive equipment and technical skill) the results are obtained muchmore quickly with less likelihood of contamination compared with conventional PCR

There are several targets and different methodologies used todetect Leishmania and to distinguish the different species how-ever PCR-based protocols must be standardized and optimized

for use in different centers in order to achieve comparable andreliable results To achieve this goal some recommendations includethe use of standardized extraction protocols internal controls astandard Leishmania strain control replicate assays and participationin an external quality control program

Immunological test-based diagnosis

Anti-Leishmania delayed-type hypersensitivity known asthe Montenegro test or the Leishmanin skin test and anti-Leishmania antibody assays are used as indirect parameters ofLeishmania infection

Montenegro or Leishmanin skin test The Montenegro skin test reveals Leishmania infection andtherefore it is used in epidemiological studies to determine infec-tion prevalence However the test does not distinguish betweenpresent and past infection and thus its importance as a diagnostictool is questionable for people living in endemic areas The testhas demonstrated positive results in patients more than 19 monthsafter treatment [56ndash58] and positive results were also observed in75 of noninfected individuals with no disease manifestationin the past and living in an area endemic for leishmaniasis [56]This test may be useful however for the diagnosis of travel-ers living in nonendemic areas For the Montenegro skin test

01 ml of Leishmania antigen (the Leishmania species utilized

and the preparation vary in different countries and laboratories)is injected into the forearm When the local induration is 5 mmor more after 48ndash72 h the result is considered positive Positivityis detected after 4 months of the appearance of lesions Patients with LCL ML and DL present with positive results Positivity

in LCL patients varies and is approximately 82ndash89 [56ndash60] InML [58] and DL [19] patientsrsquo positivity is usually 100 DCLpatients provide a negative test [61] In 11 of patients with PKDLand concomitant visceral leishmaniasis the Montenegro test ispositive and in those without concomitant visceral leishmaniasis37 are positive [13]

Serological diagnosis

More commonly used assays for serodiagnosis in leishmaniasisare the indirect immunofluorescence assay (IIFA) and ELISASerodiagnosis is not a routine procedure for the diagnosis ofcutaneous leishmaniasis in the Old World due to the variable

or low sensitivity of the tests and cross-reactivity with otherinfections [6263] Some studies have shown a sensitivity of 60using ELISA [64] However in a recent study in Turkey morepromising results were obtained with sensitivity reaching 88by ELISA [65] demonstrating its potential as a complementaryapproach for diagnosis

In the New World initial studies with a large sample sizefrom the North and Northeast of Brazil also reported a lowsensitivity of 277 using the IIFA and 669 by ELISA[66] for cutaneous leishmaniasis samples Higher sensitivitiesof 567 for IIFA and 933 for ELISA were obtained formucocutaneous leishmaniasis patients [67] More recent resultsdemonstrate the better performance of assays even though the

sensitivity remains low depending on the antigen preparationused Using the L major total antigen that is widely available inBrazil for IIFA and is provided by Bio-ManguinhosFIOCRUZ(Rio de Janeiro Brazil) the sensitivity reaches 754 whereasthe use of lsquoin housersquo antigen preparations with L brazilien-sis and L major -like species provides a sensitivity of 815 and954 respectively The performance of ELISA using antigenpreparations with the lat ter species showed a sensitivity of 957and 787 respectively [68] Although the antibody responsehas overall been considered to be gender-specific the resultsmay suggest species-related variation in the results This issue was addressed in a study that utilized samples from cutane-

ous leishmaniasis patients infected with L (V) guyanensis andL(V) braziliensis careful ly paired according to age gender andtime of disease evolution and using L (L) amazonensis prepa-rations as antigen Although the sensitivity was only slightlylower for L (V) guyanensis -infected patient samples than forthe L (V) braziliensis samples showing a sensitivity by IIFAof 796 and 717 respectively and by ELISA of 982 and850 respectively their titers were quite different For bothassays the titers of L (V) guyanensis samples were significantlylower than those of the L (V) braziliensis samples [69] Usinganother type of assay the direct agglutination test (DAT) usinglyophilized promastigotes a test that can be performed in less-

equipped laboratories the species specificity of the reaction was





Review

more striking In patients infected with L aethiopica using thesame species of the parasite the sensitivity reached 905 andthe specificity 918 with non-homologous antigen a sensi-tivity lower than 20 was observed [70] This certain speciesspecificity of the results of the serological tests may explain the

low sensitivity observed in some studies using samples fromareas in which many different species are prevalent for examplethe Amazon region in northern Brazil On the other hand thissuggests that serodiagnosis can be improved

In order to develop assays using specific species one impedimentis the culture of some species of Leishmania such as L (V) bra-ziliensis which is difficult to grow and maintain in culture Analternative may be the use of recombinant antigens which besidesparasite growth-independent production have advantages suchas a more standardized and uniform production Some of theseantigens L major Hsp60 [71] and L braziliensis Hsp70 [72] werecloned and the products tested using cutaneous leishmaniasis and

mucocutaneous samples from Colombia with promising resultsL (L) infantum Hsp83 [73] was also tested using a limited numberof cutaneous and mucocutaneous samples and showed 100reactivity interestingly without any cross-reactivity with Chagasrsquodisease samples Considering those data showing a certain speciesspecificity of the antibody reactivity the development of assaysusing combined recombinant antigens should be contemplated

In tegumentary leishmaniasis the anti-Leishmania antibody leveldoes not remain high after treatment [69] and therefore positiveresults generally indicate current infection Hence there is roomfor the use of immunological tests for the diagnosis of ongoinginfection and such tests deserve research and development

Considering that HIVLeishmania is becoming an important

medical problem the performance of immunological tests mustbe evaluated Data from HIVLeishmania -infected individu-als based on observations in the Mediterranean area showeda relatively low sensitivity [74] However in coinfected patientsin Brazil the sensitivity was not low showing 77 positivity inserology [28] This proportion of positivity may be related to theendemicity of leishmaniasis in Brazil and the fact that anti-Leish-mania antibody-producing memory cells may be preserved evenin the presence of immunosuppression due to HIV infection

Considering the high prevalence of leishmaniasis in poor areasand in developing countries tests characterized by easy applica-tion in the field and in modestly equipped laboratories must be

developed Immunochromatography-based rapid tests and DATare in this category They have been used for the diagnosis ofvisceral leishmaniasis with variable performance [75] but it maynot be possible to use the rapid tests in particular due to thelower antibody titer in tegumentary leishmaniasis DAT revealedspecies specificity-related performance [70] and therefore it maybe impractical in areas where different species prevail unlessreactivity to different species were to be tested at the same t ime

Treatment

Drug treatment for leishmaniasis has been available since thebeginning of the 20th Century but only a few drugs have been

developed for use Although we observed differences between

various Leishmania species susceptibility to drugs and diseasemanifestations between Old World and New World leishmania-sis the same drugs are used for treatment Although the WHOhas provided a recommendation for the treatment of leishma-niasis different therapeutic guidelines exist in different coun-

tries and regions of the world that suggest the complexity of thetherapeutic approach in leishmaniasis Since in addition we facean increase in the resistance to available drugs in some regions aglobal discussion is needed to improve the use of available drugsand to further novel drug development

Antimonia ls are the most commonly prescribed treatmentalthough other drugs have been used with varying success andother therapeutic modalities have been used as a topical treat-ment Leishmania species clinical presentation extensivenessand the existence of nodular lymphangitis or comorbiditiessuch as HIV infection influence the choice of therapy [76] Otherfactors that influence the choice of therapy may be earlier thera-

peutic failures local availability of the drug and localizationof the lesions Although nonfatal cutaneous leishmaniasis istreated to accelerate cure to reduce scar formation especially atcosmetic sites and to prevent parasite dissemination (ie ML)or relapse The aim of chemotherapy is clinical healing of lesionsand elimination of the parasite by destroying them or improv-ing the hostrsquos ability to heal the lesion [77] Below we discussthe major drugs available to treat tegumentary leishmaniasisthe problems related to resistance and the responses of dif ferentLeishmania species to treatment

First-line drugs

Pentavalent antimonials (Sbv ) are the first-line drugs used to

treat tegumentary leishmaniasis caused by different species(T ABLE 1) Unfortunately an increase in treatment failure has beendocumented in several regions of the world This drug is avail-able as one of two formulations meglumine antimoniate andsodium stibogluconate The mechanism of action is not knownbut the drug inhibits the activity of the glycolytic and fatty acidoxidative pathways in amastigotes [77] The major side effectsare arthralgy and myalgy however severe side effects relatedto cardiotoxocity or renal failure can occur mainly in olderpatients Use of this drug is not indicated during pregnancyThe efficacy of Sbv varies according to the geographic regionspecies of Leishmania and clinical presentation In the New

World the efficacy of antimonials for the treatment of cutane-ous leishmaniasis has been variable In Bolivia treatment failure was observed in 7 of patients [78] in 16 in Brazil [79] andin 39 of patients in Colombia [80] In the Old World failureof this drug is approximately 13 and this drug i s consideredas satisfactory for the treatment of cutaneous leishmaniasis InML the cure rate ranges from 30 to 90 with antimonialsdepending on the country in which the study was carried outand the dosage used [81ndash83]

Amphotericin B has been used to treat leishmaniasis and insome parts of the world it is the drug of choice This drug actson ergosterol present in the Leishmania membrane By increas-

ing the permeability of the cell membrane it promotes an ion

Goto amp Lindoso




Review

influx into the parasite both promastigotes and amastigotesleading to their death [84] Four drug formulations are availableamphotericin B deoxycholate liposomal amphotericin choles-terol dispersion amphotericin and lipid complex amphotericin All formulations share a similar efficacy however differenceshave been observed regarding the side effects of the formulations with more intense side effects associated with amphotericin Bdeoxycolate which can induce renal injury

Pentamidine has been used with success to treat cutaneous leish-maniasis or ML in some regions of the New World This druginterferes with Leishmania DNA synthesis modifying the morphol-ogy of the kinetoplast and promotes fragmentation of the mito-

chondrial membrane killing the parasite This drug was shown topresent the same efficacy as antimonials [85] Hypoglycemia andhyperglycemia are the main adverse effects of pentamidine

Alternative drugs

Miltefosine was originally used to treat cancer It is a phosphoryl-choline ester of hexadecanol a membrane-active alkylphospholipidIt is contraindicated in women with child-bearing potential becauseof its teratogenic effects in animal studies [77] Miltefosine was effec-tive in curing patients with visceral leishmaniasis in India howeverfew studies on the treatment of tegumentary leishmaniasis have beenreported In Colombia a cure rate of 89ndash100 was observed for

cutaneous leishmaniasis and was dependent on the dose used [86]however in general the results in the New World are poor [87]

Azoles which were initially designed to treat fungal infectionhave been used to treat tegumentary leishmaniasis [88] Some reportsdemonstrate the efficacy of fluconazole ketoconazole and itracona-zole to treat leishmaniasis These drugs inhibit 14-a-demethylationof lanosterol to ergosterol in cell wall synthesis and promote mem-brane permeability of Leishmania A cure rate of between 55 and79 was observed in the Old World using these drugs

Paromomycin acts on Leishmania both in vitro and in vivo Thisdrug has been used for parentheral and local application in thetreatment of tegumentary leishmaniasis in both the New and Old

Worlds [89] A meta-analysis involving 14 randomized controlled

trials including 1221 patients revealed that topical paramomycinassociated with methylbenzethonium chloride was similar to intra-lesional pentavalent antimony in its efficacy in treating the Old World cutaneous leishmaniasis However the response to topicalparamomycin associated with methylbenzethonium chloride was worse than parenteral pentavalent antimony in treating cutaneousleishmaniasis in the New World Similar efficacy to SbV in thetreatment of leishmaniasis in the New World was observed whenparenteral paramomycin was used to treat New World LCL [90]

Azithromycin presents activity against L major in vitro andin vivo but its mechanism of action is not yet known Reportsfrom the New and Old World show divergent results with cure

rates of 85 [91] and 276 [92] respectively Allopurinol alone or in association with antimonials has been

used to treat leishmaniasis both in the New and Old World andhas presented discordant results The drug was not effective whenused alone [93] however in association with a low dose of antimo-nials treatment achieved similar results to those obtained usingfull-dose antimonials [94]

Dapsone and rifampicin are also used to treat leishmania-sis Using dapsone a cure rate of 82 was observed in the Old World [95] but a very poor response was observed in the New World[96] Rifampicin alone or in combination with other drugs hasbeen used to treat leishmaniasis with divergent results from a cure

rate of 70ndash80 [9798] to almost no response The poor responseis seemingly related to the parasite species L (L) aethiopica andL (V) braziliensis [99100]

Some drugs such as paramomycin ketoconazole antimoni-als azithromycin and imiquimod have been used topically totreat cutaneous leishmaniasis mainly in the Old World Thispractice is not a routine procedure in the New World probablybecause of the risk of progression to mucosal involvement Morepromising results were obtained when paramomycin was used inassociation with methylbenzethonium chloride

Some physical modalities have been used to treat cutaneousleishmaniasis mainly in the Old World Leishmania promastig-

otes are thermosensitive and heat and cold treatments have been

Table 1 Recommended doses of first-line drugs to treat tegumentary leishmaniasis according to the WHOand the Ministry of Health of Brazil

Clinical form Pentavalent antimonial Amphothericin B Pentamidine

WHO Brazil WHO Brazil WHO Brazil

Localized cutaneousleishmaniasis

20 mgkgday for20 days

10ndash20 mgkgday(15 mgkgday)

for 20 days

NA 1 mgkgdayTotal dose 1ndash15 g

4 mgkgday 4mgkgdayMaximum total

dose 20 g

Disseminated cutaneous

leishmaniasis

20 mgkgday for

20 days

10ndash20 mgkgday

for 20 days

NA 1 mgkgday

Total dose 1ndash15 g

NA 4 mgkgday

Maximum total

dose 20 g

Diffuse cutaneous

leishmaniasis

20 mgkgday for

20 days

20 mgkgday for

20 days

NA 1 mgkgday


NA NA

Mucosal leishmaniasis NA 20 mgkgday for

30 days

NA 1 mgkgday


NA 4 mgkgday

Maximum total

dose 20 g

NA Not available





Review

applied for the treatment of cutaneous leishmaniasis Infrared heatand ultraviolet light have been used with success Cryosurgeryusing CO

2 or liquid N

2 has also demonstrated success however

the efficacy of this remains questionable In a large-scale study Al-Gindan et al [101] obtained a cure rate of 27 [76] Another

physical treatment employed is photodynamic therapy (PDT)using porphyrin precursors as sensitizers to treat cutaneous leish-maniasis [102] An advantage of PDT is the cosmetic result andthis treatment may prevent the development of drug resistanceLimitations of this method include the need for specific equip-ment application only to cutaneous lesions and impediment touse when Leishmania species that develop mucosal lesions areinvolved There are some reports on cutaneous leishmaniasistreatment in the Old World utilizing PDT but few reports inthe New World Recently we used PDT on L (L) amazonensis promastigotes in vitro and observed Leishmania death using ahigh concentration of the porphyrin precursor methylene blue

Furthermore in patients with cutaneous leishmaniasis PDT was used in associat ion with antimonial treatment and woundhealing was observed to occur in half the time of that achievedfor patients receiving only antimonial injection [L983145983150983140983151983155983151 JAL P983141983154983155

C983151983149983149] In fact it is necessary to evaluate the topical or physicaltreatment of leishmaniasis mainly in the New World

New targets for the development of drugs against Leishmania have been studied but are still in the experimental phase Someof these drugs include the sirtuin family of NAD-dependentdeacetylases [103] topoisomerase [104] protease inhibitors [105]and inhibitors of the mevalonate pathway such as terpene nero-lidol [106] In addition the antiestrogen tamoxifen has shownactivity against Leishmania amazonensis and Leishmania chagasiboth in vitro and in vivo in experimental models [107108] Usingproteomics and transcriptomic tools some other targets havebeen identified as candidate drug targets for Leishmania [109]

Immunotherapyimmunomodulation

Immunotherapy is based on the belief that the patient has adefective immune response against the parasite and thus isan attempt to increase the specific immune response For thisreason immunotherapy has been introduced as an alternativetherapy in specific clinical situations Leishmania antigen aloneor in combination with other antigens such as BCG has beenused to treat tegumentary leishmaniasis with partial success

Convit et al [110] and Mayrink et al [111] revisited immuno-therapy and reported the treatment of LCL and ML using vac-cines based on whole promastigote preparations obtaining curerates ranging from 76 to 94 Recombinant Leishmania antigenhas been identified as a candidate for immunotherapy Leish-111f formulated in monophosphoryl lipid A with a squaleneoil emulsion [112] was used to treat refractory ML with prom-ising results [113] Immunotherapy associated with antimoni-als could be an alternative for the treatment of leishmaniasisincluding HIVndashLeishmania coinfection PKDL and chronicrefractory tegumentary leishmaniasis [114] Furthermore drugtoxicity and the emergence of resistance could be dramatically

reduced if the present long-term monotherapy was supplemented

with immunotherapy Although this modality of treatment isincreasing clinical trials are necessary to demonstrate its benefitin some clinical situations However analysis of the immuno-pathogenesis of New World cutaneous leishmaniasis and MLhas revealed that lesion development is more dependent on the

immune inflammatory process Disease manifestation and sever-ity in al l forms but DCL are due to hypersensitivity rather thanimmunosuppression The observation that there is no reductionin the time for healing of the lesion with the early introductionof treatment suggests that the pathogenesis is related more to theinflammatory process rather than to the amount of the parasitein the lesion [18] Some data show an increased production ofinflammatory modulators such as TNF-a and IFN-g in ML[115] which is more evident when compared with cutaneous leish-maniasis [116] For this reason the use of immunomodulatorsassociated with some drugs seems appropriate and it has beentested in some patients with promising results Pentoxifylline an

inhibitor of TNF-a has been used in association with antimoni-als to treat mucosal and cutaneous leishmaniasis and a reduc-tion in healing time has been observed [117118] Another drugimiquimod is considered an activator of Toll-like receptor 7 anda mediator of cytokine production (IFN-a TNF-a IL-1 andIL-12) that may directly activate macrophages enhancing thelocal immune response Imiquimod has been used in combina-tion with a systemic antimonial in the treatment of cutaneousleishmaniasis and presented a cure rate of 90 in patients withcutaneous leishmaniasis refractory to pentavalent antimonialtreatment [119] It has been shown that it is also more effectivein the initial treatment of cutaneous leishmaniasis [120] In arecent clinical trial in Peru Miranda-Verastegui et al showed

that this combination was better than placebo plus pentavalentantimony [121]

The combination of antimonials and immunomodulators couldbe an alternative treatment for patients refractory to antimonialtreatment A better evaluation using new clinical trials is requiredto define the use of these drugs in clinical routine

Efficacy of treatment

The identification of the factors associated with chemotherapyfailure would allow better clinical management of patients Theefficacy of treatment depends on factors related to the host andto the parasite

Host factors

The immune status of leishmaniasis patients has long been knownto affect drug efficacy This has proven to be of particular impor-tance in relation to pentavalent antimonial treatment of DCLand HIVLeishmania coinfection in the visceral form of leishma-niasis where there is a deficiency in the specific T-cell-mediatedimmune response leading to exacerbation of the infection Usingexperimental models the anti-leishmanial activities of antimoni-als and pentamidine have been shown to be T-cell dependent whereas those of amphotericin B and miltefosine are T-cell inde-pendent [77] Furthermore we observed an increase in relapse in

HIV-infected patients after treatment with antimonials [28]

Goto amp Lindoso




Review

Parasite factors

We have observed a clear difference between the responses ofOld and New World Leishmania species The Old World speciesL tropica and L major but not L aethiopica are susceptible toboth systemic and local treatment while those from the New

World are only susceptible to systemic treatment This is due tothe variety of Leishmania species that cause tegumentary leish-maniasis in America and in the Caribbean with different clinicalpresentations The influence of Leishmania species is clear in Latin America In Peru patients infected with L (V) guyanensis werefound to be much more responsive to SbV therapy than patientsinfected with L (V) braziliensis [119] On the other hand in Brazilfailure of antimonial therapy was higher in patients infected withL (V) guyanensis (737) than in those infected with L (V) bra-ziliensis (492) [82] This difference could be explained by thedifferences between the strains of Leishmania even though thespecies were the same In addition differences in the dose or

treatment regimen cannot be disregardedThe efficacy of drugs for the treatment of leishmaniasis is oftena consequence of differences in the sensitivity of Leishmania spe-cies to the drugs as well as the immune status of the patient orthe pharmacokinetic properties of the drug

From the data available in the l iterature it is very difficult toextract conclusions regarding the best drugs or combinationsof drugs for the treatment of both Old and New World leish-maniasis owing to the differences between and the scientificaccuracy of the studies Recently a Spanish group published ameta-analysis on interventions for tegumentary leishmaniasis inthe Old [122] and New [123] Worlds based on various databases Although it is difficult to draw any clear conclusion the analysis

shows more frequent use and efficacy of oral and topical treat-ment in Old World leishmaniasis and systemic treatment mainlyantimonials alone or in combination with other drugs in theNew World confirmed by another meta-analysis performed by aBrazilian group The authors included 12 articles that met inclu-sion criteria with 1150 patients and concluded that pentavalentantimonials were the drugs most involved with a cure rate of766 When compared with pentavalent antimonials pentami-dine had a similar cure rate however other drugs such as para-momycin and imidazole had an inferior response It is possibleto conclude that pentavalent antimonials a re the drugs of choicein the treatment of cutaneous leishmaniasis and pentamidine is a

good alternative drug to treat it [85] Most important from theseanalyses is their conclusion that we reproduce here lsquoThere is adesperate need for large well-conducted studies that evaluatelong-term effects of current therapies We suggest the creation ofan international platform to improve quality and standardizationof future trials in order to inform clinical practicersquo [122123]

Expert commentary amp five-year view

Tegumentary leishmaniasis constitutes a serious public health prob-lem in different parts of the world with a significant increase in itsincidence that has mostly occurred in the last two decades It affectsareas considered endemic for leishmaniasis but it is also becoming

an important disease in travelers living in nonendemic areas who

have visited endemic areas In addition the recent finding thatHIVLeishmania coinfection is increasing is another concern ofours For this challenge healthcare systems should be preparedand research and development improved on present and upcomingdiagnostic methods treatment procedures and novel drugs

For appropriate diagnosis and treatment of tegumentary leishma-niasis knowledge on disease manifestation diagnostic approachesand their availability and treatment options should be extendedbroadly to professionals in endemic and nonendemic areas

These achievements would come from the solid and increasingknowledge of usual disease manifestations but also of unusualmanifestations that may occur in immunosuppressed individualsExamples of these are the manifestations seen in individualsinfected with HIV or in undernourished people in a war environ-ment or refugee camp Regarding disease manifestation with theavailability of conventional or new methods to identify Leishmania species from patient samples studies correlating disease mani-

festation evolution and therapeutic response to parasite speciesare needed These studies will bring considerable benefits forthe treatment of patients and will ensure the proper follow up ofpatients In the coming 5 years studies investigating these areasshould have high priority From these studies new insight con-cerning Leishmania species-related pathogenic mechanisms withconsequent improvements in the treatment approaches shouldhopefully appear

A crucial point in the laboratory diagnosis is etiological agentdetection and Leishmania species identification In this fieldmolecular diagnostic procedures are more promising but are stillcomplex and expensive procedures only feasible in places with well-structured laboratories

For the detection of Leishmania in the diagnosis of leishmania-sis without species identification approaches using material fromthe lesion using anti-Leishmania antibodies and sensitive dye forviewing with the naked eye would be ideal for use in the fieldThis is an area to focus on in coming years

Studies on Leishmania species identification and correlation withclinical parameters should be sought with available methods butalternative methods feasible in more modest laboratories would bedesirable For this purpose we may consider an indirect approachanalyzing antibody production that seems to have some speciesspecificity Therefore anti-Leishmania antibody detection shouldbe revisited for diagnostic purposes Furthermore better analysis of

a response that seems to be species specific and the development ofapproaches to test serum reactivity to different species in the samesample would improve the diagnostic potential of serological tests

An init ial approach at which to aim treatment is an accu-rate diagnosis without delay but then the selection of a betterdrug or procedure is also important For treatment first-linedrugs are pentavalent antimonials amphotericin B and penta-midine These drugs are used without considering Leishmania species differences susceptibility to drugs in some regions anddisease manifestations

Old World leishmaniasis shows better therapeutic responsesexcept when caused by L aethiopica In the Old World topi-

cal treatment is an alternative and products of this type should







Review

leishmaniasis imported into Paris a reviewof 39 cases Int J Dermatol 43 120ndash125(2004)

9 Walton BC American cutaneous andmucocutaneous leishmaniasis In TheLeishmaniases in Biology and Medicine

(Volume II ) Peters W Killick-Kendrick R(Eds) Academic Press London UK637ndash664 (1987)

10 Machado P Araujo C Da Silva AT et alFailure of early treatment of cutaneousleishmaniasis in preventing thedevelopment of an ulcer Clin Infect Dis 34 E69ndashE73 (2002)

bullbull Original data show that early treatment

does not prevent the development of an

ulcer and suggests the importance of the

inammatory process rather than the

parasite load in ulcer formation

11 Akilov OE Khachemoune A Hasan TClinical manifestations andclassification of Old World cutaneousleishmaniasis Int J Dermatol 46132ndash142 (2007)

bull Comprehensive and detailed description

of clinical manifestations of Old World

cutaneous leishmaniasis

12 Kharfi M Fazaa B Chaker EKamoun MR [Mucosal localization ofleishmaniasis in Tunisia 5 cases] Ann Dermatol Venereol 130 27ndash30(2003)

13 Zijlstra EE Musa AM Khalil EAel-Hassan IM el-Hassan AM Post-kala-azar dermal leishmaniasis Lancet InfectDis 3 87ndash98 (2003)

bull Comprehensive review on post-kala-azar

dermal leishmaniasis

14 Oliveira-Neto MP Mattos M Souza CSFernandes O Pirmez C Leishmaniasisrecidiva cutis in New World cutaneousleishmaniasis Int J Dermatol 37846ndash849 (1998)

15 Bittencourt AL Costa JM Carvalho EMBarral A Leishmaniasis recidiva cutis in American cutaneous leishmaniasis Int JDermatol 32 802ndash805 (1993)

16 Calvopina M Uezato H Gomez EAKorenaga M Nonaka S Hashiguchi YLeishmaniasis recidiva cutis due toLeishmania (Viannia ) panamensis insubtropical Ecuador isoenzymaticcharacterization Int J Dermatol 45116ndash120 (2006)

17 Reithinger R Dujardin JC Louzir HPirmez C Alexander B Brooker SCutaneous leishmaniasis Lancet Infect Dis 7 581ndash596 (2007)

18 Turetz ML Machado PR Ko AI et alDisseminated leishmaniasis a new andemerging form of leishmaniasis observed innortheastern Brazil J Infect Dis 1861829ndash1834 (2002)

bull Parameters and characteristics of

disseminated leishmaniasis are presented

based on 42 cases

19 Costa JM Marsden PD Llanos-Cuentas EA et al Disseminated cutaneousleishmaniasis in a field clinic in BahiaBrazil a report of eight cases J Trop MedHyg 89 319ndash323 (1986)

20 Barral A Costa JM Bittencourt ALBarral-Netto M Carvalho EM Polar andsubpolar diffuse cutaneous leishmaniasis inBrazil clinical and immunopathologicaspects Int J Dermatol 34(7) 474ndash479(1995)

bull Initial description of disseminated

leishmaniasis from Brazil with Leishmania

species identication

21 de Castro EA Luz E Telles FQ et alEco-epidemiological survey ofLeishmania (Viannia ) braziliensis Americancutaneous and mucocutaneousleishmaniasis in Ribeira Valley RiverParana State Brazil Acta Trop 93 141ndash149(2005)

22 Gontijo CM da Silva ES de Fuccio MBet al Epidemiological studies of anoutbreak of cutaneous leishmaniasis in the

Rio Jequitinhonha Valley Minas GeraisBrazil Acta Trop 81 143ndash150 (2002)

23 Jones TC Johnson WD Jr Barretto ACet al Epidemiology of American cutaneousleishmaniasis due to Leishmania braziliensisbraziliensis J Infect Dis 156 73ndash83(1987)

24 Davies CR Reithinger R Campbell-Lendrum D Feliciangeli D Borges RRodriguez N The epidemiology andcontrol of leishmaniasis in Andeancountries Cad Saude Publica 16 925ndash950(2000)

bullbull Comprehensive review on comparativeepidemiological parasitological and

clinical data on leishmaniasis in

Venezuela Colombia Ecuador Peru

and Bolivia

25 Garcia AL Parrado R Rojas E Delgado RDujardin JC Reithinger R Leishmaniasesin Bolivia comprehensive review andcurrent status Am J Trop Med Hyg 80704ndash711 (2009)

26 Hashiguchi Y Gomez Landires EA Areview of leishmaniasis in Ecuador BullPan Am Health Organ 25 64ndash76 (1991)

27 Puig L Pradinaud R Leishmania and HIVco-infection dermatologicalmanifestations Ann Trop Med Parasitol 97(Suppl 1) 107ndash114 (2003)

28 Lindoso JA Barbosa RN Posada-Vergara MP et al Unusual manifestations

of tegumentary leishmaniasis in AIDSpatients from the New World Br JDermatol 160 311ndash318 (2009)

bull Describes unusual manifestations of

tegumentary leishmaniasis in HIV-

infected patients that may pose

difculties for diagnosis

29 Posada-Vergara MP Lindoso JATolezano JE Pereira-Chioccola VLSilva MV Goto H Tegumentaryleishmaniasis as a manifestation of immunereconstitution inflammatory syndrome in2 patients with AIDS J Infect Dis 192

1819ndash1822 (2005)

bullbull First report showing tegumentary

leishmaniasis as a manifestation of

immune reconstitution inammatory

syndrome in HIV-infected patients

30 David CV Craft N Cutaneous andmucocutaneous leishmaniasis DermatolTher 22 491ndash502 (2009)

31 Vega-Lopez F Diagnosis of cutaneousleishmaniasis Curr Opin Infect Dis 1697ndash101 (2003)

32 Al-Hucheimi SN Sultan BA Al-Dhalimi MA A comparative study of thediagnosis of Old World cutaneousleishmaniasis in Iraq by polymerase chainreaction and microbiologic and histopathologicmethods Int J Dermatol 48 404ndash408(2009)

33 Sotto MN Yamashiro-Kanashiro EHda Matta VL de Brito T Cutaneousleishmaniasis of the New World diagnosticimmunopathology and antigen pathways inskin and mucosa Acta Trop 46 121ndash130(1989)

34 Schubach A Cuzzi-Maya T Oliveira AVet al Leishmanial antigens in the

diagnosis of active lesions and ancientscars of American tegumentaryleishmaniasis patients Mem Inst OswaldoCruz 96 987ndash996 (2001)

35 Weigle KA de Davalos M Heredia PMolineros R Saravia NG DrsquoAlessandro ADiagnosis of cutaneous andmucocutaneous leishmaniasis in Colombiaa comparison of seven methods Am JTrop Med Hyg 36 489ndash496 (1987)

36 Reithinger R Dujardin JC Moleculardiagnosis of leishmaniasis current statusand future applications J Clin Microbiol45 21ndash25 (2007)





Review

bull Comprehensive review and perspectives

on molecular techniques for diagnosis and

identication of Leishmania

37 Grimaldi G McMahon-Pratt DMonoclonal antibodies for the identificationof New World Leishmania species MemInst Oswaldo Cruz 91 37ndash42 (1996)

bull Review on the use of monoclonal

antibodies for the identication of New

World Leishmania species

38 Cupolillo E Grimaldi G Jr Momen HDiscrimination of Leishmania isolatesusing a limited set of enzymatic loci AnnTrop Med Para sitol 89 17ndash23 (1995)

bull Initial study that dened the isoenzyme

analysis for identication of New World

Leishmania species

39 van Eys GJ Schoone GJ Kroon NC

Ebeling SB Sequence analysis of smallsubunit ribosomal RNA genes and its usefor detection and identification ofLeishmania parasites Mol BiochemParasitol 51 133ndash142 (1992)

40 Russell R Iribar MP Lambson B et al Intra and inter-specific microsatellitevariation in the Leishmania subgenusViannia Mol Biochem Parasitol 10371ndash77 (1999)

41 Piarroux R Azaiez R Lossi AM et al Isolation and characterization of a repetitiveDNA sequence from Leishmania infantumdevelopment of a visceral leishmaniasispolymerase chain reaction Am J Trop Med Hyg 49 364ndash369 (1993)

42 Luis L Ramirez A Aguilar CM Eresh SBarker DC Mendoza-Leon A Thegenomic fingerprinting of the codingregion of the b-tubulin gene in Leishmaniaidentification Acta Trop 69 193ndash204(1998)

43 Victoir K Banuls AL Arevalo J et alThe gp63 gene locus a target for geneticcharacterization of Leishmania belonging tosubgenus Viannia Parasitology 117(Pt 1)1ndash13 (1998)

44 Cupolillo E Grimaldi Juacutenior GMomen H Beverley SM Intergenic regiontyping (IRT) a rapid molecular approachto the characterization and evolution ofLeishmania Mol Biochem Parasitol 73145ndash155 (1995)

45 Eisenberger CL Jaffe CL Leishmania identification of Old World species using apermissively primed intergenicpolymorphic-polymerase chain reactionExp Parasitol 91 70ndash77 (1999)

46 de Bruijn MH Barker DC Diagnosis ofNew World leishmaniasis specific

detection of species of the Leishmania

braziliensis complex by amplification ofkinetoplast DNA Acta Trop 52 45ndash58(1992)

bullbull Sequencing of widely used kinetoplast

DNA of Leishmania as a target for

Leishmania detection

47 Nasereddin A Bensoussan-Hermano ESchonian G Baneth G Jaffe CLMolecular diagnosis of old world cutaneousleishmaniasis and species identification byuse of a reverse line blot hybridizationassay J Clin Microbiol 46 2848ndash2855(2008)

48 Oliveira JG Novais FO de Oliveira CIet al Polymerase chain reaction (PCR) ishighly sensitive for diagnosis of mucosalleishmaniasis Acta Trop 94 55ndash59(2005)

49 Castilho TM Shaw JJ Floeter-Winter LM

New PCR assay using glucose-6-phosphatedehydrogenase for identification ofLeishmania species J Clin Microbiol 41540ndash546 (2003)

bull One-step PCR that is able to distinguish

Leishmania (Viannia) braziliensis from

other Leishmania (Viannia) species

50 Zhang WW Miranda-Verastegui C Areva lo J et al Development of a geneticassay to distinguish between Leishmaniaviannia species on the basis of isoenzymedifferences Clin Infect Dis 42 801ndash809(2006)

bull PCR that can distinguish

L (V) braziliensis from Leishmania

(Viannia) peruviana

51 Garcia L Kindt A Bermudez H et al Culture-independent species typing ofneotropical Leishmania for clinicalvalidation of a PCR-based assay targetingheat shock protein 70 genes J Clin Microbiol 42 2294ndash2297 (2004)

bullbull PCR-restriction fragment length

polymorphism able to distinguish various

Leishmania species and Trypanosoma in

the New World

52 Marfurt J Niederwieser I Makia NDBeck HP Felger I Diagnostic genotypingof Old and New World Leishmania speciesby PCR-RFLP Diagn Microbiol InfectDis 46 115ndash124 (2003)

53 de Monbrison F Mihoubi I Picot SReal-time PCR assay for the identificationof cutaneous Leishmania parasite species inConstantine region of Algeria Acta Trop 102 79ndash83 (2007)

54 Antinori S Ca lattini S Piolini R et al Is real-time polymerase chain reaction(PCR) more useful than a conventional

PCR for the clinical management ofleishmaniasis Am J Trop Med Hyg 8146ndash51 (2009)

55 Castilho TM Camargo LM McMahon-Pratt D Shaw JJ Floeter-Winter LM A real-time polymerase chain reaction assay

for the identification and quantification of American Leishmania species on the basisof glucose-6-phosphate dehydrogenase Am J Trop Med Hyg 78 122ndash132(2008)

56 Sassi A Louzir H Ben Salah A Mokni MBen Osman A Dellagi K Leishmanin skintest lymphoproliferative responses andcytokine production after symptomatic orasymptomatic Leishmania major infectionin Tunisia Clin Exp Immunol 116127ndash132 (1999)

bull Strong data showing long-lived positive

Leishmanin skin test after cure and alsopositivity in noninfected individuals in

endemic areas

57 Reed SG Diagnosis of leishmaniasis ClinDermatol 24 471ndash478 (1996)

58 Shaw JJ Lainson R Leishmaniasis inBrazil X Some observations of intradermalreactions to different trypanosomatidantigens of patients suffering fromcutaneous and mucocutaneousleishmaniasis Trans R Soc Trop MedHyg 69 323ndash335 (1975)

59 Luz ZM Silva AR Silva Fde O Caligiorne

RB Oliveira E Rabello A Lesion aspirateculture for the diagnosis and isolation ofLeishmania spp from patients withcutaneous leishmaniasis Mem Inst Oswaldo Cruz 104 62ndash66 (2009)

60 Reis Lde C Brito ME Almeida EL et alClinical epidemiological and laboratoryaspects of patients with Americancutaneous leishmaniasis in the State ofPernambuco Rev Soc Bras Med Trop 41439ndash443 (2008)

61 Bryceson AD Diffuse cutaneousleishmaniasis in Ethiopia 3Immunological studies IV Pathogenesisof diffuse cutaneous leishmaniasis TransR Soc Trop Med Hyg 64 380ndash393(1970)

62 Kar K Serodiagnosis of leishmaniasis CritRev Microbiol 21 123ndash152 (1995)

bull Review on serodiagnosis in the Old World

63 Edrissian GH Darabian P A comparisonof enzyme-linked immunosorbent assayand indirect fluorescent antibody test inthe sero-diagnosis of cutaneous andvisceral leishmaniasis in Iran TransR Soc Trop Med Hyg 73 289ndash292(1979)

Goto amp Lindoso




Review

64 el Safi SH Evans DA A comparison of thedirect agglutination test and enzyme-linked immunosorbent assay in thesero-diagnosis of leishmaniasis in theSudan Trans R Soc Trop Med Hyg 83334ndash337 (1989)

65 Zeyrek FY Korkmaz M Ozbel YSerodiagnosis of anthroponotic cutaneousleishmaniasis (ACL) caused by Leishmaniatropica in Sanliurfa Province Turkey where ACL is highly endemic Clin VaccineImmunol 14 1409ndash1415 (2007)

66 Guimaraes MC Celeste BJ Franco ELDiagnostic performance indices forimmunofluorescent tests and enzymeimmunoassays of leishmaniasis sera fromnorthern and north-eastern Brazil BullWorld Health Organ 68 39ndash43 (1990)

67 Guimaraes MC Celeste BJ Franco EL

Cuce LC Belda W Jr Evaluation ofserological diagnostic indices formucocutaneous leishmaniasisimmunofluorescence tests and enzyme-linked immunoassays for IgG IgM and IgAantibodies Bull World Health Organ 67643ndash648 (1989)

68 Barroso-Freitas AP Passos SRMouta-Confort E et al Accuracy of anELISA and indirect immunofluorescencefor the laboratory diagnosis of Americantegumentary leishmaniasis Trans R SocTrop Med Hyg 103 383ndash389 (2009)

69 Romero GA de la Gloria Orge Orge Mde Farias Guerra MV Paes MG de OliveiraMacedo V de Carvalho EM Antibodyresponse in patients with cutaneousleishmaniasis infected by Leishmania (Viannia ) braziliensis or Leishmania (Viannia ) guyanensis in Brazil Acta Trop93 49ndash56 (2005)

bullbull Data clearly demonstrating that antibody

reactivity varies considerably in

individuals infected with different

Leishmania species

70 Hailu A The use of direct agglutinationtest (DAT) in serological diagnosis of

Ethiopian cutaneous leishmaniasis Diagn Microbiol Infect Dis 42 251ndash256 (2002)


reactivity varies considerably with the use

of homologous or heterologous Leishmania

species as antigen for direct agglutination

test assay

71 Rey-Ladino JA Joshi PB Singh B Gupta RReiner NE Leishmania major molecularcloning sequencing and expression of theheat shock protein 60 gene reveals uniquecarboxy terminal peptide sequences ExpParasitol 85 249ndash263 (1997)

72 Amorim AG Carrington M Miles MABarker DC de Almeida ML Identificationof the C-terminal region of 70 kDa heatshock protein from Leishmania (Viannia )braziliensis as a target for the humoralimmune response Cell Stress Chaperones 1

177ndash187 (1996)73 Celeste BJ Angel SO Castro LG

Gidlund M Goto H Leishmania infantum heat shock protein 83 for the serodiagnosisof tegumentary leishmaniasis Braz J Med Biol Res 37 1591ndash1593 (2004)

74 Alvar J Aparicio P Aseffa A et alThe relationship between leishmaniasis and AIDS the second 10 years Clin MicrobiolRev 21 334ndash359 (2008)

bull Comprehensive review on HIV

Leishmania coinfection in the

Mediterranean area including

performance of diagnostic tests75 Boelaert M El-Safi S Hailu A et al

Diagnostic tests for kala-azar a multi-centre study of the freeze-dried DAT rK39strip test and KAtex in East Africa and theIndian subcontinent Trans R Soc Trop Med Hyg 102 32ndash40 (2008)

bull Data showing the importance of a

comparative study on performance of

serological tests in different

geographical regions

76 Mahajan VK Sharma NL Therapeuticoptions for cutaneous leishmaniasis

J Dermatolog Treat 18 97ndash104 (2007)

77 Croft SL Sundar S Fairlamb AH Drugresistance in leishmaniasis Clin MicrobiolRev 19 111ndash126 (2006)

78 Bermudez H Rojas E Garcia L et al Genericsodium stibogluconate is as safe and effectiveas branded meglumine antimoniate for thetreatment of tegumentary leishmaniasis inIsiboro Secure Park Bolivia Ann Trop MedParasitol 100 591ndash600 (2006)

79 Oliveira-Neto MP Schubach A Mattos MGoncalves-Costa SC Pirmez C A low-doseantimony treatment in 159 patients with

American cutaneous leishmaniasisextensive follow-up studies (up to 10 years) Am J Trop Med Hyg 57 651ndash655 (1997)

80 Palacios R Osorio LE Grajalew LFOchoa MT Treatment failure in childrenin a randomized clinical trial with 10 and20 days of meglumine antimonate forcutaneous leishmaniasis due to Leishmaniaviannia species Am J Trop Med Hyg 64187ndash193 (2001)

81 Franke ED Wignall FS Cruz ME et alEfficacy and toxicity of sodiumstibogluconate for mucosal leishmaniasis Ann Intern Med 113 934ndash940 (1990)

82 Romero GA Lessa HA Orge MGMacedo VO Marsden PD [Treatment ofmucosal leishmaniasis with aminosidinesulfate results of two year follow-up]Rev Soc Bras Med Trop 31 511ndash516(1998)

83 Amato VS Tuon FF Imamura R Abegao de Camargo R Duarte MINeto VA Mucosal leishmania sisdescription of case managementapproaches and analysis of risk factors fortreatment failure in a cohort of 140patients in Brazil J Eur Acad DermatolVenereol 23 1026ndash1034 (2009)

84 Ellis M Bernsen R Ali-Zadeh H et al A safety and feasibility study comparingintermittent high dose with daily standarddose liposomal amphotericin B forpersistent neutropenic fever amphotericin

B spectrum and resistance J Med Microbiol 49(Suppl 1) 7ndash10 (2009)

85 Tuon FF Amato VS Graf ME et alTreatment of New World cutaneousleishmaniasis ndash a systematic review with ameta-analysis Int J Dermatol 47 109ndash124(2008)

bull Meta-analysis allowing an evaluation of

the efcacy of drugs used in American

tegumentary leishmaniasis

86 Soto J Toledo J Gutierrez P et alTreatment of American cutaneousleishmaniasis with miltefosine an oral

agent Clin Infect Dis 33 E57ndashE61(2001)

87 Soto J Arana BA Toledo J et alMiltefosine for new world cutaneousleishmaniasis Clin Infect Dis 381266ndash1272 (2004)

88 Khatami A Firooz A Gorouhi FDowlati Y Treatment of acute Old Worldcutaneous leishmaniasis a systematicreview of the randomized controlled trials J Am Acad Dermatol 57 335 e331ndashe329(2007)

89 Llanos-Cuentas A Echevarria J Seas Cet al Parenteral aminosidine is not effectivefor Peruvian mucocutaneous leishmaniasis Am J Trop Med Hyg 76 1128ndash1131(2007)

90 Kim DH Chung HJ Bleys JGhohestani RF Is paromomycin aneffective and safe treatment againstcutaneous leishmaniasis A meta-analysisof 14 randomized controlled trials PLoSNegl Trop Dis 3 e381 (2009)

91 Prata A Silva-Vergara ML Costa L et alEfficacy of azithromycin in the treatmentof cutaneous leishmaniasis Rev Soc Bras Med Trop 36 65ndash69 (2003)





Review

92 Layegh P Yazdanpanah MJ Vosugh EMPezeshkpoor F Shakeri MTMoghiman T Efficacy of azithromycinversus systemic meglumine antimoniate(Glucantime) in the t reatment ofcutaneous leishmaniasis Am J Trop

Med Hyg 77 99ndash101 (2007)93 Velez I Agudelo S Hendrickx E et al

Inefficacy of allopurinol asmonotherapy for Colombian cutaneousleishmaniasis A randomized controlledtrial Ann Intern Med 126 232ndash236(1997)

94 Llanos-Cuentas A Echevarria J Cruz Met al Efficacy of sodium stibogluconatealone and in combination with a llopurinolfor treatment of mucocutaneousleishmaniasis Clin Infect Dis 25 677ndash684(1997)

95 Dogra J A double-blind study on theefficacy of oral dapsone in cutaneousleishmaniasis Trans R Soc Trop MedHyg 85 212ndash213 (1991)

96 Osorio LE Palacios R Chica MEOchoa MT Treatment of cutaneousleishmaniasis in Colombia with dapsoneLancet 351 498ndash499 (1998)

97 Joshi RK Nambiar PM Dermalleishmaniasis and rifampicin Int JDermatol 28 612ndash614 (1989)

98 Kochar DK Saini G Kochar SK et al A double blind randomised placebo

controlled trial of rifampicin withomeprazole in the treatment of humancutaneous leishmaniasis J Vector BorneDis 43 161ndash167 (2006)

99 Bygbjerg IC Knudsen L Kieffer MFailure of rifampin therapy to curecutaneous leishmaniais Arch Dermatol 116 988 (1980)

100 Do Valle TZ Ol iveira Neto MPSchubach A Lagrange PH Da Costa SCNew World tegumentar leishmaniasischemotherapeutic activity of rifampicinin humans and experimental murinemodel Pathol Biol (Paris ) 43 618ndash621

(1995)

101 al-Gindan Y Kubba R el-Hassan AMOmer AH Kutty MK Saeed MBDissemination in cutaneousleishmaniasis 3 Lymph nodeinvolvement Int J Dermatol 28248ndash254 (1989)

102 van der Snoek EM Robinson DJvan Hellemond JJ Neumann HA A review of photodynamic therapy incutaneous leishmaniasis J Eur AcadDermatol Venereol 22 918ndash922(2008)

103 Kaur S Shivange AV Roy N Structuralanalysis of trypanosomal sirtuin an insightfor selective drug design Mol Divers 14(1) 169ndash178 (2010)

104 Das BB Sen N Dasgupta SB Ganguly ADas R Majumder HK Topoisomerase

research of kinetoplastid parasiteLeishmania with special reference todevelopment of therapeutics Indian J Med Res 123 221ndash232 (2006)

105 Desai PV Patny A Gut J et al Identificationof novel parasitic cysteine protease inhibitorsby use of virtual screening 2 The availablechemical directory J Med Chem 491576ndash1584 (2006)

106 Arruda DC DrsquoAlexandri FL Katzin AMUliana SR Antileishmanial activity of theterpene nerolidol Antimicrob AgentsChemother 49 1679ndash1687 (2005)

107 Miguel DC Yokoyama-Yasunaka JK UlianaSR Tamoxifen is effective in the treatmentof Leishmania amazonensis infections inmice PLoS Negl Trop Dis 2 e249 (2008)

108 Miguel DC Zauli-Nascimento RC Yokoyama-Yasunaka JK Katz SBarbieri CL Uliana SR Tamoxifen as apotential antileishmanial agent efficacy inthe treatment of Leishmania braziliensis andLeishmania chagasi infections J AntimicrobChemother 63 365ndash368 (2009)

109 Kumari S Kumar A Samant M Singh NDube A Discovery of novel vaccine

candidates and drug targets against visceralleishmaniasis using proteomics andtranscriptomics Curr Drug Targets 9938ndash947 (2008)

110 Convit J Ulrich M Zerpa O et alImmunotherapy of american cutaneousleishmaniasis in Venezuela during theperiod 1990ndash99 Trans R Soc Trop MedHyg 97 469ndash472 (2003)

bull Data on immunotherapy (combination of

Leishmania antigen and bacillus

CalmettendashGueacuterin) given to more than

10000 Venezuelan patients

111 Mayrink W Magalhaes PA MichalickMS et al Immunotherapy as a treatmentof American cutaneous leishmaniasispreliminary studies in BrazilParassitologia 34 159ndash165 (1992)

bull Outcomes of immunotherapy with

Leishmania antigen was worse than that

with antimonial treatment

112 Coler RN Goto Y Bogatzki L Raman VReed SG Leish-111f a recombinantpolyprotein vaccine that protects againstvisceral Leishmaniasis by elicitation ofCD4+ T cells Infect Immun 754648ndash4654 (2007)

113 Badaro R Lobo I Munos A et alImmunotherapy for drug-refractorymucosal leishmaniasis J Infect Dis 1941151ndash1159 (2006)

114 Musa AM Noazin S Khalil EAModabber F Immunological stimulation

for the treatment of leishmaniasis amodality worthy of serious considerationTrans R Soc Trop Med Hyg 104(1) 1ndash2(2009)

115 Bacellar O Lessa H Schriefer A et al Up-regulation of Th1-type responses inmucosal leishmaniasis patients InfectImmun 70 6734ndash6740 (2002)

116 Carvalho LP Passos S Bacellar O et al Differential immune regulation ofactivated T cells between cutaneous andmucosal leishmaniasis as a model forpathogenesis Parasite Immunol 29

251ndash258 (2007)bull Data strongly suggest the role of

hypersensitivity in the pathogenesis and

the more intense reactivity in mucosal

leishmaniasis than in localized cutaneous

leishmaniasis (LCL)

117 Machado PR Lessa H Lessa M et al Oralpentoxifylline combined with pentavalentantimony a randomized trial for mucosalleishmaniasis Clin Infect Dis 44788ndash793 (2007)

bull Promising results with a

immunomodulatory drug in combination

with antimonials reinforce thehypersensitivity in the pathogenesis of

New World leishmaniasis

118 Sadeghian G Nilforoushzadeh MAEffect of combination therapy withsystemic glucantime and pentoxifylline inthe treatment of cutaneous leishmaniasisInt J Dermatol 45 819ndash821 (2006)

bull Promising results with an

immunomodulatory drug in LCL patients

in Iran

119 Arevalo I Ward B Mil ler R et alSuccessful treatment of drug-resistant

cutaneous leishmaniasis in humans by useof imiquimod an immunomodulatorClin Infect Dis 33 1847ndash1851 (2001)

120 Arevalo I Tulliano G Quispe A et alRole of imiquimod and parenteralmeglumine antimoniate in the initialtreatment of cutaneous leishmaniasisClin Infect Dis 44 1549ndash1554 (2007)

121 Miranda-Verastegui C Tulliano GGyorkos TW et al First-line therapy forhuman cutaneous leishmaniasis in Peruusing the TLR7 agonist imiquimod incombination with pentavalent antimony

PLoS Negl Trop Dis 3(7) e491 (2009)

Goto amp Lindoso



433

Review

122 Gonzalez U Pinart M Reveiz L Alvar JInterventions for Old World cutaneousleishmaniasis Cochrane Database Syst Rev CD005067 (2008)

bullbull Comprehensive meta-analysis showing

some conclusions on drugs used in the

Old World but mainly highlights the

need to improve the quality and

standardization of future trials

123 Gonzalez U Pinart M Rengifo-Pardo MMacaya A Alvar J Tweed JAInterventions for American cutaneous andmucocutaneous leishmaniasis CochraneDatabase Syst Rev CD004834 (2009)



New World but mainly highlights the



Affiliations

bull Professor Hiro GotoLaboratoacuterio de Soroepidemiologia doInstituto de Medicina Tropical daUniversidade de Satildeo Paulo Avenida DrEneacuteas de Carvalho Aguiar nordm 470Preacutedio II 4ordm andar CEP 05403-000Satildeo Paulo SP BrazilTel +55 11 3061 7023Fax +55 11 3061 8270hgotouspbr hgotopqcnpqbrandDepartment of Preventive MedicineFaculdade de Medicina da Universidade deSatildeo Paulo Satildeo Paulo Brazil

bull Joseacute Angelo Lauletta LindosoHospital das Cliacutenicas Faculdade deMedicina da Universidade de Satildeo PauloLaboratory of Soroepidemiology (LIM-38)Instituto de Infectologia Emiacutelio RibasSecretaria de Estado da Sauacutede de Satildeo Paulo

Satildeo Paulo Brazil





Review

guyanensis and Leishmania (Viannia ) panamensis although otherspecies such as Leishmania (Leishmania ) mexicana Leishmania(Leishmania ) pifanoi Leishmania (Leishmania ) venezuelen-sis Leishmania (Viannia ) peruviana Leishmania (Leishmania ) shawi and Leishmania (Viannia ) lainsoni are present mostly in

the Amazon region and in Central America In the Old WorldLeishmania (Leishmania ) donovani a viscerotropic species maydetermine a cutaneous disease during or after visceral leishmaniasisand is known as post-kala-azar dermal leishmaniasis (PKDL) [3ndash5]

Diagnosis of leishmaniasis

Diagnosis of leishmaniasis is based on criteria that considerepidemiological data clinical features and laboratory test results

Epidemiological criteria

The epidemiological link among individuals in an endemic area isevident but it constitutes important information for the diagnosis

of travelers living in nonendemic areas who have spent some timein areas endemic for leishmaniasis Tegumentary leishmaniasisis one of the dermatological syndromes diagnosed in travelersIn a retrospective study employing data from the GeoSentinelSurveillance Network comprising a 10-year period from 1997to 2006 skin-related diagnoses were reported for 4594 patientsand tegumentary leishmaniasis was diagnosed in 33 The traveldestination of these patients was Latin America and in 15 thetravel duration had been less than 2 weeks [6] In another twostudies carried out in Europe some patients with cutaneous leish-maniasis had traveled to endemic countries in the Old World andothers to the New World [78]

Clinical criteria

The clinical features of tegumentary leishmaniasis are diversedepending on the Leishmania species involved and host factorsincluding immune status However the initial evolution of the lesionis similar at the site of the insect bite After an incubation period of2 weeks to 3 months a small itchy erythematous papule or noduleappears sometimes preceded or accompanied by draining lymphnode enlargement This initial lesion may cure spontaneously orevolve usually after some months to patent disease with differentclinical features [910] The correlation of clinical features and spe-cies of Leishmania is currently not straightforward because in someareas many different species coexist and furthermore species iden-

tification is not usually performed for clinical specimens due to thecomplexity of the laboratory procedures as well as their accessibility

In general terms species prevalent in the Old World determinelimited clinical manifestations compared with New World speciesL (L) major L (L) tropica and L (L) aethiopica species that areprevalent in the Old World determine the characteristic ulcerativelesion of localized cutaneous leishmaniasis (LCL) in 86ndash98 ofcases that usually cure spontaneously after a period ranging from3 months to 2 years [11] In some cases L (L) tropica infectionevolves to a relapsing lesion known as leishmaniasis recidiva cutisor leishmaniasis recidivans [11] or mucosal leishmaniasis (ML)[12] and L (L) aethiopica infection to diffuse cutaneous leish-

maniasis (DCL) [11] In addition L (L) donovani may determine

PKDL [13] The species present in the New World determinemore varied clinical manifestations including the aggressive anddestructive ML In the following sections the features of the dif-ferent forms are described with an emphasis on manifestationscaused by the New World species We also highlight manifesta-

tions observed in HIVLeishmania coinfection which can presentunusual forms A detailed description of the clinical manifesta-tions of Old World cutaneous leishmaniasis can be found in arecently published comprehensive review by Akilov et al [11]

Localized cutaneous leishmaniasis

Localized cutaneous leishmaniasis (FIGURE 1A) is the most prevalentform of the disease and is most commonly caused by dermotropicLeishmania species [7] The lesions appear on an exposed area ofthe body surface varying in number from one to ten The estab-lished lesion is a round painless ulcer that is well delimited witha central crust that is sometimes hemorrhagic It may cure sponta-

neously leaving a hypopigmented smooth thin scar Dependingon the hostndashparasite balance and other undefined factors somecases evolve to other forms of the disease

Leishmaniasis recidiva cutis

Leishmaniasis recidiva cutis (F IGURE 1B) is known in the Old World to be associated with L (L) tropica infection the occur-rence of which is rare in the New World Characteristic papularand vesicular lesions appear after clinical cure in or aroundthe scar of the healed sore after a variable period of time frommonths to years Most of the identified parasites in the New World were of the subgenus Viannia [14] but L (L) amazon-ensis in Brazil [15] and L (V) panamensis in Ecuador [16] were

also observed

Disseminated leishmaniasis

Disseminated leishmaniasis (DL) (FIGURE 1C) is characterized bythe presence of multiple (10ndash300) pleomorphic lesions mainlyacneiform and papular in two or more noncontiguous areas ofthe body [17] In 29 of cases a mucosal lesion is found In anarea in the northeast of Brazil the frequency of this conditionhas increased from 02 to 19 among tegumentary leishmaniasiscases in two decades In these cases L (V) braziliensis was theonly species encountered [1819]

Diffuse cutaneous leishmaniasisDiffuse cutaneous leishmaniasis is a true anergic form of tegu-mentary leishmaniasis and is characterized by the presence ofnodular lesions that do not ulcerate (F IGURE 1D amp 1E) [20] It is arare condition It has been reported in South America Central America and Ethiopia The lesions are rich in parasites and thespecies involved are L (L) mexicana and L (L) amazonensis inthe New World and L (L) aethiopica in the Old World

Mucocutaneous leishmaniasis

Also known as lsquoespundiarsquo mucocutaneous leishmaniasis occursyears after the onset of cutaneous leishmaniasis and is character-

ized by the destruction of oralndashnasal and pharyngeal cavities

Goto amp Lindoso




Review





I






Review



























in culture

Goto amp Lindoso




Review



from the lesion[51]





















Review










Treatment







First-line drugs






Goto amp Lindoso




Review




Alternative drugs





















for 20 days



dose 20 g


leishmaniasis

20 mgkgday for

20 days

10ndash20 mgkgday

for 20 days

NA 1 mgkgday


NA 4 mgkgday

Maximum total

dose 20 g

Diffuse cutaneous

leishmaniasis

20 mgkgday for

20 days

20 mgkgday for

20 days

NA 1 mgkgday


NA NA


30 days

NA 1 mgkgday


NA 4 mgkgday

Maximum total

dose 20 g

NA Not available





Review


2 or liquid N


















Host factors



Goto amp Lindoso




Review

Parasite factors



























Review

























based on 42 cases














and Bolivia











1819ndash1822 (2005)

















Review











Leishmania species

























(Viannia) peruviana





the New World










endemic areas










Goto amp Lindoso




Review











Leishmania species







test assay










































Review












(1995)































leishmaniasis (LCL)









in Iran






Goto amp Lindoso



433

Review













Affiliations








Review





I






Review



























in culture

Goto amp Lindoso




Review



from the lesion[51]





















Review










Treatment







First-line drugs






Goto amp Lindoso




Review




Alternative drugs





















for 20 days



dose 20 g


leishmaniasis

20 mgkgday for

20 days

10ndash20 mgkgday

for 20 days

NA 1 mgkgday


NA 4 mgkgday

Maximum total

dose 20 g

Diffuse cutaneous

leishmaniasis

20 mgkgday for

20 days

20 mgkgday for

20 days

NA 1 mgkgday


NA NA


30 days

NA 1 mgkgday


NA 4 mgkgday

Maximum total

dose 20 g

NA Not available





Review


2 or liquid N


















Host factors



Goto amp Lindoso




Review

Parasite factors



























Review

























based on 42 cases














and Bolivia











1819ndash1822 (2005)

















Review











Leishmania species

























(Viannia) peruviana





the New World










endemic areas










Goto amp Lindoso




Review











Leishmania species







test assay










































Review












(1995)































leishmaniasis (LCL)









in Iran






Goto amp Lindoso



433

Review













Affiliations








Review



























in culture

Goto amp Lindoso




Review



from the lesion[51]





















Review










Treatment







First-line drugs






Goto amp Lindoso




Review




Alternative drugs





















for 20 days



dose 20 g


leishmaniasis

20 mgkgday for

20 days

10ndash20 mgkgday

for 20 days

NA 1 mgkgday


NA 4 mgkgday

Maximum total

dose 20 g

Diffuse cutaneous

leishmaniasis

20 mgkgday for

20 days

20 mgkgday for

20 days

NA 1 mgkgday


NA NA


30 days

NA 1 mgkgday


NA 4 mgkgday

Maximum total

dose 20 g

NA Not available





Review


2 or liquid N


















Host factors



Goto amp Lindoso




Review

Parasite factors



























Review

























based on 42 cases














and Bolivia











1819ndash1822 (2005)

















Review











Leishmania species

























(Viannia) peruviana





the New World










endemic areas










Goto amp Lindoso




Review











Leishmania species







test assay










































Review












(1995)































leishmaniasis (LCL)









in Iran






Goto amp Lindoso



433

Review













Affiliations








Review



from the lesion[51]





















Review










Treatment







First-line drugs






Goto amp Lindoso




Review




Alternative drugs





















for 20 days



dose 20 g


leishmaniasis

20 mgkgday for

20 days

10ndash20 mgkgday

for 20 days

NA 1 mgkgday


NA 4 mgkgday

Maximum total

dose 20 g

Diffuse cutaneous

leishmaniasis

20 mgkgday for

20 days

20 mgkgday for

20 days

NA 1 mgkgday


NA NA


30 days

NA 1 mgkgday


NA 4 mgkgday

Maximum total

dose 20 g

NA Not available





Review


2 or liquid N


















Host factors



Goto amp Lindoso




Review

Parasite factors



























Review

























based on 42 cases














and Bolivia











1819ndash1822 (2005)

















Review











Leishmania species

























(Viannia) peruviana





the New World










endemic areas










Goto amp Lindoso




Review











Leishmania species







test assay










































Review












(1995)































leishmaniasis (LCL)









in Iran






Goto amp Lindoso



433

Review













Affiliations








Review










Treatment







First-line drugs






Goto amp Lindoso




Review




Alternative drugs





















for 20 days



dose 20 g


leishmaniasis

20 mgkgday for

20 days

10ndash20 mgkgday

for 20 days

NA 1 mgkgday


NA 4 mgkgday

Maximum total

dose 20 g

Diffuse cutaneous

leishmaniasis

20 mgkgday for

20 days

20 mgkgday for

20 days

NA 1 mgkgday


NA NA


30 days

NA 1 mgkgday


NA 4 mgkgday

Maximum total

dose 20 g

NA Not available





Review


2 or liquid N


















Host factors



Goto amp Lindoso




Review

Parasite factors



























Review

























based on 42 cases














and Bolivia











1819ndash1822 (2005)

















Review











Leishmania species

























(Viannia) peruviana





the New World










endemic areas










Goto amp Lindoso




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Leishmania species







test assay










































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(1995)































leishmaniasis (LCL)









in Iran






Goto amp Lindoso



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Review













Affiliations








Review




Alternative drugs





















for 20 days



dose 20 g


leishmaniasis

20 mgkgday for

20 days

10ndash20 mgkgday

for 20 days

NA 1 mgkgday


NA 4 mgkgday

Maximum total

dose 20 g

Diffuse cutaneous

leishmaniasis

20 mgkgday for

20 days

20 mgkgday for

20 days

NA 1 mgkgday


NA NA


30 days

NA 1 mgkgday


NA 4 mgkgday

Maximum total

dose 20 g

NA Not available





Review


2 or liquid N


















Host factors



Goto amp Lindoso




Review

Parasite factors



























Review

























based on 42 cases














and Bolivia











1819ndash1822 (2005)

















Review











Leishmania species

























(Viannia) peruviana





the New World










endemic areas










Goto amp Lindoso




Review











Leishmania species







test assay










































Review












(1995)































leishmaniasis (LCL)









in Iran






Goto amp Lindoso



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Review













Affiliations








Review


2 or liquid N


















Host factors



Goto amp Lindoso




Review

Parasite factors



























Review

























based on 42 cases














and Bolivia











1819ndash1822 (2005)

















Review











Leishmania species

























(Viannia) peruviana





the New World










endemic areas










Goto amp Lindoso




Review











Leishmania species







test assay










































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(1995)































leishmaniasis (LCL)









in Iran






Goto amp Lindoso



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Review













Affiliations








Review

Parasite factors



























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based on 42 cases














and Bolivia











1819ndash1822 (2005)

















Review











Leishmania species

























(Viannia) peruviana





the New World










endemic areas










Goto amp Lindoso




Review











Leishmania species







test assay










































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(1995)































leishmaniasis (LCL)









in Iran






Goto amp Lindoso



433

Review













Affiliations










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based on 42 cases














and Bolivia











1819ndash1822 (2005)

















Review











Leishmania species

























(Viannia) peruviana





the New World










endemic areas










Goto amp Lindoso




Review











Leishmania species







test assay










































Review












(1995)































leishmaniasis (LCL)









in Iran






Goto amp Lindoso



433

Review













Affiliations








Review











Leishmania species

























(Viannia) peruviana





the New World










endemic areas










Goto amp Lindoso




Review











Leishmania species







test assay










































Review












(1995)































leishmaniasis (LCL)









in Iran






Goto amp Lindoso



433

Review













Affiliations








Review











Leishmania species







test assay










































Review












(1995)































leishmaniasis (LCL)









in Iran






Goto amp Lindoso



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Review













Affiliations








Review












(1995)































leishmaniasis (LCL)









in Iran






Goto amp Lindoso



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Review













Affiliations







433

Review













Affiliations





Current Diag Treat of Cut and Mucocut Leish-2010

Documents

Transcript of Current Diag Treat of Cut and Mucocut Leish-2010