cutaneous leishmaniasis ( cl ) is an infectious disease caused by the leishmania parasite that is transmitted through the bites of phlebotominae sand flies .
cl is characterized by broad clinical polymorphism varying from localized to diffuse and disseminated lesions .
localized cl ( lcl ) is the most prevalent clinical manifestation worldwide , characterized by the appearance of a skin lesion at the vector sting site .
the lesion occurs after reproduction of the parasites into the dermis , which generates a granuloma .
the granuloma is initially manifested as small papule that progressively increases in size to form a rounded nodule . as a consequence of the parasite virulence and host immune response , the nodules show necrosis in the center and become ulcers characterized by a round form , with high and clear borders , an indurated base and granular background , painless and with a scab firmly attached to the base .
overinfection with bacteria or fungi , often caused by empirical treatments , produces purulent and painful ulcers .
characteristic scars with hyper- or hypochromic edges , commonly called  onion bulb scars , appear after treatment .
nodular lesions sometimes become scaly epidermal plaques or warty lesions . in some patients , the parasite may spread via lymph and blood to the skin of different anatomical regions , particularly the face , chest and upper limbs , where the parasite reproduces widely and causes disseminated leishmaniasis ( dl ) or diffuse cutaneous leishmaniasis ( dcl ) . although these two clinical forms can be clearly differentiated ( see table 1 ) , some authors consider them as synonymous , which makes a meta - analysis of the literature review difficult . here , we report a series of dl patients attended at the pecet , university of antioquia ( medelln , colombia ) . a literature review focusing the attention on the available information to differentiate dl and dcl
twenty - two patients ( 85% ) were men ; 20 patients ( 77% ) were of mixed race , 4 patients ( 15% ) were black , and 2 patients were indigenous ; their age ranged from 4 to 61 years ( mean 32 years ) .
twenty - five patients ( 96% ) were from the northwest of colombia ( antioquia , choco and cordoba states ) , but only 2 patients came from the southeast of the country . only 1 patient evidenced hiv coinfection .
parasite cultures were positive in 16 patients , while the remaining 11 cultures were negative .
leishmania ( viannia ) panamensis was identified as the causative agent in 15 isolates ; the last isolate was identified as viannia subgenus , but no species was determined .
this leishmania species distribution is similar to that observed for patients with lcl from the northwestern colombian region , where 70% of the strains circulating are l. ( v. ) panamensis and 30% correspond to l. ( v. ) braziliensis , whereas in the southeastern region , 80% of the circulating species are l. ( v. ) braziliensis as identified by monoclonal antibody techniques and pcr - rflp ( unpublished data ) .
all patients met the diagnostic criteria of having 10 or more polymorphic lesions in at least 2 parts of the body surface .
the number of lesions for each patient varied between 12 and 294 ( 21 patients with 100 lesions or less , 3 patients had more than 100 lesions and less than 200 , and 4 patients had more than 200 lesions ; table 3 ) .
the evolution time since the appearance of the first lesion to the spreading was more than 2 weeks .
in most patients , the primary lesion was plaque , and the secondary lesions ( disseminated ) were nodules , papules and plaques , with different sizes but smaller than 2.0 cm in diameter . only 1 patient had frank ulcers ( fig . 1 , fig . 2 , fig . 3 , fig .
seven patients ( 25% ) had nasal mucosal involvement consisting of ulcers , scabs or septal perforation indicating an important frequency of mucosal involvement .
the montenegro skin test was positive in 18 of 21 patients ( 84% ) with an induration size that varied between 5 and 12 mm ( average 6.8 mm ; table 2 ) , suggesting no complete anergy of cellular immune response .
cell proliferation and t cell subpopulation in peripheral blood samples were evaluated only in 4 patients who had absolute values of t cell and lymphoproliferative response within the reference values .
however , the percentages of t cell cd3 + , cd4 + and cd3+cd4 + subpopulations were below the reference values , whereas the percentage of naturally occurring regulatory t cells ( cd4+cd25+foxp3 + ) were increased .
five of the 27 patients ( 19.3% ) had diabetes mellitus , obesity , vitiligo , hiv / aids and leukemia as baseline comorbidities , which could favor the spread of the parasite . in 92% , their immunosuppressive condition was not identified , which could facilitate the spread of the parasite since most of patients were farmers from rural areas .
only 2 patients had a clinical condition - based immunosuppression ( hiv and leukopenia ) .
twenty - two patients were treated with intramuscular meglumine antimoniate at a dose of 20 mg / kg / day for 20 days ( table 3 ) .
nineteen of these 22 patients ( 86.3% ) were cured with a single treatment cycle of meglumine antimoniate , while 3 patients did fail .
one of these 3 patients was cured with a second cycle with topical amphotericin b ( anfoleish ) applied twice daily for 28 days , and the other 2 patients were cured with a second cycle with oral miltefosine at doses of 22.5 mg / kg / day for 28 days .
one of these 2 patients had been treated before with amphotericin b deoxycholate 1 mg / kg daily only for 9 days because of renal toxicity . among the remaining 7 patients , 2 of them
were cured with 4 applications of intramuscular pentamidine at a dose of 3 mg / kg / day ( table 3 ) ; another patient , who had 103 lesions , was cured after treatment with pentamidine combined with topical amphotericin b applied as before .
another patient was cured with miltefosine alone , and the last patient , who had hiv / aids coinfection , drug abuse , kaposi 's sarcoma , extrapulmonary tuberculosis , cryptococcal meningitis and poor adherence to antiretroviral therapy , was treated with liposomal amphotericin b combined with miltefosine ; this patient showed partial clinical improvement but subsequent appearance of new skin lesions and extensive mucosal involvement .
dl is characterized by an initial injury into the dermis followed by a high number of skin lesions ( > 10 polymorphic lesions ) in at least two parts of the body surface , with or without mucosal involvement [ 2 , 3 ] .
dl has been described in brazil , venezuela , guyana and colombia , with a significant increase in the number of cases in highly endemic places as the brazilian north , colombo - brazilian amazon and colombian northwest .
this clinical manifestation is caused by leishmania species of the subgenus viannia , mainly l. ( v. ) panamensis , l. ( v. ) braziliensis and l. ( v. ) guayanensis .
patients suffering dl describe the initial appearance of a single lesion ( nodule or ulcerative plaque ) , presumably located in the vector bite site .
weeks or months later , as a consequence of parasite dissemination , polymorphic lesions ( isolated or confluent ) , different in size and growth rate , appear in remote anatomic areas from the initial lesion that may cover the entire body surface , except armpits and inguinocrural region ; lesions in the face may become disfiguring .
associated to the skin lesions , mucosal involvement or symptoms such as fever , chills and lymphadenopathy may occur [ 2 , 4 ] . dissemination may occur after therapy with immunosuppressive drugs .
the pathogenesis of dl is not well established . however , partial inhibition of specific cellular immunity against the parasite has been demonstrated . a decrease in cd4 + t cells in peripheral blood with partial absence of t cell response to leishmania antigen , evidenced by a mildly reactive ( 3 or 4 mm induration ) or positive ( > 5 mm ) montenegro skin test , is observed .
a low production of the type th1 cytokines ifn- , tnf- , il-10 and il-5 , which favor the spread of the parasite , is also registered .
histological examination of the lesions can reveal the presence of a granuloma composed of lymphocytic infiltrates with very few or no parasites [ 4 , 7 , 8 ] .
a decrease in the percentage of cd3+cd4 + t cells and an increase in the percentage of regulatory t cells could affect the immune response mediated by t cells because it has been shown that the regulatory t cells cd4+cd25+foxp3 + ( known as natural regulatory t cells ) are potent suppressors of acquired immune response , as is the immune response mediated by t cells [ 9 , 10 ] .
a decrease in the percentage of activated cd4 + t cells in the blood of patients may affect the cellular immune response associated with a decrease of the specific local cellular response against some leishmania species .
the diagnosis of dl as well as other clinical forms of cl is based on the observation of the parasite in smears or aspirates from the lesion . in most cases ,
the treatment of dl is based on systemic administration of pentavalent antimonials ( 20 mg / kg / day for 20 days ) , miltefosine ( 22.5 mg / kg / day for 28 days ) and amphotericin b both deoxycholate ( 0.71 mg / kg / day for 30 days ) or liposomal ( 3 mg / kg / day for 1014 days ) , although the liposomal form is preferred for the lower toxicity .
therapeutic response may also vary from poor to good , depending on the leishmania species .
thus , for example , the percentage of cured patients with dl by l. ( v. ) braziliensis treated with 1 course of antimony therapy for 30 days in its highest dosage ( 20 mg / kg / day ) is 24% , while in patients with dl by l. ( v. ) panamensis , the cure rate is 86.3% , as shown here . with liposomal amphotericin use ( dose ranging from 17 to 37 mg / kg ,
as shown in this work , pentamidine at a dose of 3 mg / kg / day ( 4 applications ) is also a good option to treat dl even in cases having a high number of lesions . in endemic areas for leishmaniasis
, dl is considered as an opportunistic infection mainly in hiv positive patients in whom therapeutic failures and relapses are frequent .
differential diagnosis of dl include diseases such as psoriasis , histoplasmosis ( and other relevant deep mycoses in immunosuppressed patients ) , pemphigus , pityriasis rosea and lupus   but also other cutaneous forms of leishmaniasis such as dcl and post - kala - azar dermal leishmaniasis ( pkdl ) .
dcl was described for the first time in venezuela by convit and lapenta   in 1948 .
this clinical manifestation of dcl is associated with leishmania species of the leishmania subgenus , mainly l. ( l. ) amazonensis ( in the new world ) and l. ( l. ) aethiopica ( in the old world ) [ 17 , 18 ] .
dcl appears during the first decades of age , with periods of remission and frequent relapses .
the montenegro skin test is predominantly negative , and histologically , granulomas with few lymphocytes and abundant parasites are observed .
dcl is more severe because a complete inhibition of specific cellular immunity occurs and the therapeutic response is poor and therefore , relapses occur more frequently [ 19 , 20 ] . in dcl ,
temporary improvement has been observed in venezuela using immunotherapy with bcg and heat - dead l. ( l. ) amazonensis promastigotes , combined with other drugs such as pentavalent antimonial , amphotericin b and miltefosine .
however , relapses of lesions make it necessary to use multiple schemes of treatment [ 22 , 23 , 24 ] . in turn
, pkdl is caused by l. ( l. ) donovani in east africa and india .
this disease is characterized by the appearance of rash during weeks or months , followed by macules and plaques especially in the face , upper chest and upper limbs .
, pkdl requires specific treatment , while in african countries , the disease usually heals spontaneously .
although dl has been showing an increase in the number of cases in recent years in countries such as brazil and colombia , this is a rare entity and poorly described in the literature . in this clinical manifestation , anergy is not absolute , lesions heal easily and patients show good response to drugs recommended by the who to treat lcl such as pentavalent antimonials and miltefosine , and therefore , patients have good prognosis .
it is very important to distinguish it from other cutaneous manifestations , mainly from dcl and pkdl , because there are significant differences in etiology , treatment response and prognosis .
the authors state that the patients gave their informed consent complying with all ethical guidelines for human studies .
 disseminated leishmaniasis ( dl ) is a poorly described disease that is frequently misdiagnosed as other clinical manifestations of cutaneous leishmaniasis ( cl ) such as diffuse cl or post - kala - azar dermal leishmaniasis . 
 twenty - seven cases of dl diagnosed between 1997 and 2015 are described . 
 a higher prevalence was observed in men ( mean age 32 years ) . 
 the number of lesions per patient ranged from 12 to 294 , distributed mainly in the upper extremities , face and trunk . 
 the lesions were mostly plaques or nodules . 
 seven patients had nasal mucous damage , 74% of the patients were of mixed race , 92% lived in northwestern colombia , and leishmania ( viannia ) panamensis was identified as the causative agent in 58% of cases . 
 eighteen patients recovered with pentavalent antimonial . 
 the importance of distinguishing dl from those other clinical presentations is based on the fact that disseminated , diffuse and post - kala - azar cl are very different in etiology , clinical manifestations and response to treatment and prognosis . 
Introduction
Case Presentation
Discussion
Statement of Ethics
Disclosure Statement