Open Access is an initiative that aims to make scientific research freely available to all. To date our community has made over 100 million downloads. It’s based on principles of collaboration, unobstructed discovery, and, most importantly, scientific progression. As PhD students, we found it difficult to access the research we needed, so we decided to create a new Open Access publisher that levels the playing field for scientists across the world. How? By making research easy to access, and puts the academic needs of the researchers before the business interests of publishers.
We are a community of more than 103,000 authors and editors from 3,291 institutions spanning 160 countries, including Nobel Prize winners and some of the world’s most-cited researchers. Publishing on IntechOpen allows authors to earn citations and find new collaborators, meaning more people see your work not only from your own field of study, but from other related fields too.
Leishmaniasis, a neglected disease caused by protozoans of the Leishmania genus, is still present in 98 countries with about two million new cases yearly worldwide. It is transmitted by female phlebotomine sandflies and presents itself as cutaneous, mucocutaneous and visceral clinical forms, depending on the Leishmania species and the parasite‐host relationship. Visceral leishmaniasis (VL) is caused by Leishmania (Leishmania) infantum chagasi, endemic in 12 countries of Latin America, with 90% of the cases reported in Brazil. VL is characterized by irregular bouts of fever, weight loss, hepatosplenomegaly and pancytopenia, being highly fatal with no treatment. The main strategy in limiting the expansion of VL, besides the treatment of human cases, is the control of the vector Lutzomyia longipalpis and its reservoirs. There are only few studies on the natural infection of Leishmania species, especially in relation to its endemic distribution. Epidemiological studies of leishmaniasis may indicate the infection rate of parasites in sandflies in order to assess the populations at risk and to direct public health control strategies. In this context, we aimed to review the main features of VL with regard the distribution of disease cases and natural infection rates of Leishmania in Lu. longipalpis in Latin America.
Laboratory of Molecular Immunopathology, Federal University of Paraná, Curitiba, Paraná, Brazil
Fabiana A. Andrade
Laboratory of Molecular Immunopathology, Federal University of Paraná, Curitiba, Paraná, Brazil
Maria R.P.A. Tizzot
Laboratory of Molecular Immunopathology, Federal University of Paraná, Curitiba, Paraná, Brazil
Health School, UniBrasil University, Curitiba, Paraná, Brazil
Magda C.V. Costa-Ribeiro
Laboratory of Molecular Parasitology, Federal University of Paraná, Curitiba, Paraná, Brazil
Marcia H. Beltrame
Laboratory of Molecular Immunopathology, Federal University of Paraná, Curitiba, Paraná, Brazil
Department of Genetics, University of Pennsylvania, Philadelphia, USA
Iara J. Messias-Reason
Laboratory of Molecular Immunopathology, Federal University of Paraná, Curitiba, Paraná, Brazil
*Address all correspondence to: kari.lidani@gmail.com
1. Introduction
Leishmaniasis is a protozoan disease caused by the Leishmania genus, transmitted by female phlebotomine sandflies. Foxes and didelphid marsupials are the main rural reservoirs, and domestic dogs the principal reservoir in urban areas [1]. The introduction in urban settings is due to multiple conditions such as migrations, inadequate living conditions, high population density and environment changes [2].
The disease presents itself in different clinical forms including cutaneous (CL), mucocutaneous (MCL) and visceral leishmaniasis (VL), depending on the species of Leishmania and the parasite‐host relationship. In Latin America, VL is caused by the protozoan Leishmania (Leishmania) infantum chagasi and is the most severe form, characterized by intermittent fever, weight loss, hepatosplenomegaly and pancytopenia [3].
Since VL is no longer being characterized as a rural disease (1980s), [3] the main strategy to limit the expansion of the disease, besides the treatment of human cases, is the control of the vector Lutzomyia longipalpis and the parasite's reservoirs. In addition, molecular epidemiological studies of natural infection with species of Leishmania, especially in relation to its endemic distribution, may indicate the infection rate of parasites in sandflies in order to assess the populations at risk and to direct public health control strategies. In this context, we aimed in this chapter to review the main features of VL with regard the distribution of disease cases and natural infection rates of Leishmania in phlebotomine females in Latin America.
Leishmaniasis is one of the most neglected diseases, present in at least 88 countries across the tropical and subtropical regions of Africa, Asia, Mediterranean, South Europe as well as South and Central Americas, with a global distribution of about two million new cases yearly worldwide [4]. The disease poses a great impact in public health contributing to 3.3 million disability adjusted life years [5]. It is a parasitic disease caused by the biphasic protozoan of the family Trypanosomatidae, order Kinetoplastida and genus Leishmania, which includes 35 species, being at least 13 of them considered human pathogens [6] (Figure 1).
Figure 1.
Main species of the Leishmania genus. Those causing visceral leishmaniasis (VL): Leishmania (L.) donovani in Asia, Leishmania (L.) chagasi in the Americas and Leishmania (L.) infantum in Asia, Europe and Africa. Note: Leishmania (L.) infantum chagasi nomenclature was proposed by Marcili et al. [7] using phylogenetic analysis of Leishmania species occurring in Latin America.
Leishmania is transmitted by the bite of infected female sandflies of the Phlebotominea subfamily of the genus Phebotomus in the Old World and the genus Lutzomyia in the New World [8]. Sandflies become infected during blood meals by ingesting leishmanial amastigotes of infected cells. Amastigotes differentiated into dividing promastigotes (flagellate forms) to establish the parasite life cycle and multiplying in the gut of sandfly vector (in the hindgut and in the midgut for Viannia and Leishmania subgenus, respectively) [9, 10]. After digestion of the blood meal, successful infection in a sandfly vector results in the development of several promastigotes forms, named according to their morphology as procyclic, haptomonad, nectomonad, paramastigote and metacyclic forms. Only metacyclic forms transmitted through sandfly bites are able to begin an infection in vertebrate hosts, and thereby the transmission cycle completes [11, 12]. Thus, during blood meals, the vector injects the infective promastigotes in the host, which induce chemotaxis of neutrophils and macrophages. The parasites are then engulfed by macrophages and other types of mononuclear and polymorphonuclear phagocytic cells, becoming amastigotes, which is the tissue stage. Inside the cell, the amastigotes reproduce by binary fission, breakup the cell and are released to extracellular environment, being again engulfed by phagocytic cells and repeating the cycle [13–16] (Figure 2).
Figure 2.
Life cycle of Leishmania spp. Leishmania parasites are transmitted by the bites of infected female sandflies during their blood meals. The vector injects the metacyclic promastigote forms, which are engulfed by phagocytic cells at the bite site. Inside the cells, promastigotes transform into amastigotes, the tissue stage of the parasite, which will then reproduce by binary fission and progress to infect other mononuclear phagocytic cells. Interactions between parasite, host and other factors will determine whether the infection progress to cutaneous or visceral leishmaniasis. Sandflies become infected by ingesting infected cells during blood meals. In the digestive tract of the vector, amastigotes differentiate into promastigotes and migrate to the proboscis, from where they are injected into the hosts during the bite.
Leishmaniasis in humans presents a wide diversity of clinical manifestations depending on the complex interactions between the parasite and the host immune responses, ranging from asymptomatic to severe and potentially lethal disease. The disease is classified into three main forms: cutaneous (CL), mucocutaneous (MCL), and visceral leishmaniasis (VL) [17].
CL is the most frequent clinical form, representing 75% of leishmaniasis total cases, and has an estimated yearly incidence of 0.7–1.2 million cases, being distributed in Afghanistan, Colombia, Brazil, Algeria, Peru, Costa Rica, Iran, Syria, Ethiopia and Sudan [4, 5]. CL is characterized by localized cutaneous nodules or lesions at the site of the sandfly bite (localized form). It has an incubation time of weeks to months, and initially has the appearance of an erythematous papule, which can evolve into a plaque or ulcer or can spontaneously heal in 2–10 months. These lesions are usually painless and without evident systemic symptoms or pruritus. Parasites can disseminate through the skin and form multiple non‐ulcerative nodules (diffuse form), which is associated to an ineffective immune response, especially in patients infected with human immunodeficiency virus (HIV) [18, 19].
Moreover, Leishmania spp. can propagate through the lymphatic system, resulting in nasobronchial and oral mucosal tissue destruction (MCL form) [18, 19]. The MCL form affects both nasal and oral mucous membranes, leading to partial or total destruction. The VL is a systemic and chronic disease, and it is highly fatal if not treated [1].
VL is recognized by the World Health Organization (WHO) as one of the most important zoonoses, due to its high incidence and mortality. Every year about 500,000 new cases of VL are reported, with 40,000–50,000 deaths worldwide [20]. The disease is endemic in 65 countries, including Bangladesh, India, Brazil, Nepal, Ethiopia and Sudan. In Latin America, VL is present in 12 countries and is caused by the protozoan Leishmania (L.) infantum chagasi, with 90% of the cases being reported in Brazil, especially in the Northeast and Southeast regions, representing a significant public health concern [3, 21]. In Brazil, the average number of cases of VL increased from 2866 in 1990–2000 to 3353 in 2001–2014 [22], with a fatality rate of about 7% in 2014 [23].
The disease has shown significant changes in the pattern of transmission, initially with a predominantly rural distribution, which fly has expanded to peri‐urban and large urban areas [20, 24]. Although the main route of transmission is associated to hematophagous sandfly vectors, there are other routes which are important to be reported, including sexual, vertical and hematogenic [16].
Although the infection can affect people of all ages, in endemic areas, most reported cases are children below 10 years old. This is probably due to their immunological immaturity aggravated by malnutrition, which is common in these areas [3, 20]. Over 60% of the affected people are males [21, 25].
3.2. Clinical features
VL is also known as kala‐azar or “black fever/disease”, which is a reference to the skin hyperpigmentation by melanocyte stimulation during infection. In addition, other terms are used to describe VL, such as Dumdum fever, Assam fever and infantile splenomegaly. It is the most severe leishmaniasis form and generally affects the spleen, liver, bone marrow or other lymphoid tissues. The syndrome is characterized by fever, weight loss, hepatosplenomegaly, pancytopenia and hypergammaglobulinemia. The fever can be continuous or remittent, and also characteristically described as periods with and without pyrexia, becoming intermittent at a later stage. Patients may also report night sudoresis, weakness, diarrhea, malaise and anorexia [26].
The onset of VL can be insidious or sudden, and the incubation period varies from 3 to 6 months, depending on the patient’s age and immune status, as well as the species of Leishmania. If untreated, it is frequently fatal within 2 years. Death may be related to hemorrhage, severe anemia, immunosuppression and/or secondary infections. Interestingly, some successfully treated VL cases may develop maculopapular or nodular rashes, named post‐kala‐azar dermal leishmaniasis [17, 19] and classified into three types: depigmented macules, erythematous patches, and yellowish pink nodules [27]. Complications of VL include amyloidosis, glomerulonephritis [28] and cirrhosis [29]. In HIV patients coinfected with VL, atypical symptoms include gastrointestinal ulcerations, pleural effusion and odynophagia [30].
3.3. Diagnosis and treatment
The diagnosis of VL is still a challenge, especially in needy regions. Even though serological and molecular tests have improved the laboratory diagnosis of VL considerably, none of the available methods present 100% sensitivity and specificity [31]. The gold standard diagnosis method is still the identification of the parasite, with visualization of amastigotes from bone marrow or visceral aspirates, which holds 100% specificity. However, the sensitivity of the parasitological test varies depending on the sample, and aspirations are invasive and can cause life‐threatening hemorrhages. Serological methods, on the other hand, are highly sensitive but with varying specificity [32], showing cross‐reactivity with trypanosomiasis, malaria, tuberculosis, brucellosis and typhoid fever [31]. In addition, antileishmanial antibodies can be found in asymptomatic individuals and are still present after treatment and recovery, making the evaluation of therapeutic response difficult [33, 34]. Molecular techniques are remarkably sensitive and specific and can differentiate asymptomatic from clinically active infection even in HIV coinfected patients, but are costly [35, 36].
The first choice of treatment for VL is the antimonial N‐methyl glucamine followed by amphotericin B (AmpB) and derivatives [37] (Table 1). The AmpB isolated in 1955 as a natural antibiotic was first reported as having antileishmanial activity in the early 1960s. Currently, its liposomal formulation is used to treat VL with a 95% cure rate for a single‐course therapy [38, 39]. Although there are no absolute contraindications against the use of AmpB, nephrotoxicity [40] and hematotoxicity [41] should be considered [42].
Medication
Molecular formula
Presentation
Dose/route administration
Antimonial N‐methylglucamine
C7H20NO9Sb
Pentavalent antimony (Sb+5) Ampoules 5 mL (300 mg/mL)
20 mg/Sb+5/kg/day, once daily, endovenosa or intramuscular for 30 days. Max dose of 3 ampoules per day.
Amphotericin B
C47H73NO17
Amphotericin B deoxycholate Bottle with 50 mg (lyophilized)
The liposomal form of AmpB is ideal in the treatment of leishmaniasis, since enables the drug to concentrate specifically at the site of infection, reducing the concentration in others organs [43, 44]. More recently, other drugs such as miltefosine, paromomycin and pentamidine have been used in the treatment of VL in some countries of Africa and Asia, but the efficacy and required dosage of several of these medicines have not been demonstrated in all endemic areas and may differ between these areas [20].
Some criteria need to be observed for the choice of treatment, such as assessment and stabilization of clinical conditions and comorbidities present at the diagnosis of VL and electrocardiogram. The use of methylglucamine antimoniate has been especially critical in cases where resistance against pentavalent antimonials is widely spread [45].
Unfortunately, the majority of the population affected by VL is of low income, having no access to diagnosis and treatment options, thereby increasing the mortality rate due to the infection. In endemic areas, VL diagnosis is in most cases based only on clinical characteristics and epidemiologic aspects. Despite the urgent needs, research and development on leishmaniasis have been regrettably neglected.
4. Natural infection of phebotomine with Leishmania
4.1. Vectors of L. (Leishmania) infantum chagasi
According to Killick‐Kendrick [47], four criteria must be fulfilled before incriminating a given specie as a vector for a zoonotic disease: feeding on humans and in the animal reservoir, supporting the parasites after ingestion, displaying indistinguishable parasites from those isolated from patients and transmitting the parasite by biting.
Lutzomyia (Lutzomyia) longipalpis is the most competent vector for L. (L.) infantum chagasi in VL Latin American foci; however, other sandflies species may be acting in the cycle of VL, mainly in areas where Lu. longipalpis is absent [48, 49]. In fact, Pintomyia (Pifanomyia) evansi has been related to VL transmission in Colombia [50–53] and Venezuela [54, 55].
Other reports from Argentina and Brazil associated the presence of Migonemyia migonei with autochthonous cases of VL [49, 56, 57]. Recent studies using quantitative polymerase chain reaction (qPCR) [58] and experimental infection [59] confirmed Mg. migonei as a potential vector of VL in Latin America. In addition, Nyssomyiaantunesi [60] and Lu. (Lutzomyia) cruzi [61] were found naturally infected with L. chagasi in Brazil. Montoya‐Lerma et al. [62] observed an association between Pi. evansi and L. (L.) infantum chagasi infection, and indicated that Pi. evansi represents a potential vector for VL in Colombia and Venezuela.
Evidence of transmission of VL by Lu. cruzi in the area of Jaciara, State of Mato Grosso in Brazil was confirmed by Missawa et al. [63]. Lu. cruzi and Lu. (Lutzomyia) forattinii are potential VL vectors in the area of Corumbá (Brazil), where notifications of the disease in humans and dogs have increased over the last two decades [64].
CL vectors such as Nyssomyia neivai were found infected with L. (L.) infantum chagasi in the city of Florianópolis (in the South region of Brazil) [65] and in an urban area of Minas Gerais state (in the Central region of Brazil), with no records of human VL and no data available for canine VL [66]. Similarly, as observed in Brazil, natural infection of Mg. migonei and Nyssomyia whitmani were found in Argentina [67].
Note: The classification and abbreviation of sandflies were used here according to Galati [68] and Marcondes [69], respectively.
4.2. Methods for detecting naturally infected vectors
The report of natural infection by L. (L.) i. chagasi in female phlebotomine sandflies is an important tool for epidemiological investigation, being indispensable for appropriate VL control strategy. Distinct techniques have been applied to identify parasitic infection in the insect, including classical and molecular methods.
The classical method to detect natural infection is based on the direct observation of parasites under microscopy, after sandfly gut dissection. However, this in loco identification is laborious, time consuming and requires experience. Another limiting factor is the difficulty in processing the large number of samples required in epidemiological studies [70, 71]. In addition, since other flagellated parasites can be found in the digestive tract of the insects, infection needs to be confirmed by in vitro culture of Leishmania or by inoculation into laboratory animals [72, 73]. Furthermore, low parasitemia may underestimate the rates of natural sandfly infection, which are usually about 0.2% using the classical approach, often contrasting with the high frequency of VL in endemic areas [64, 74–76]. However, the dissection method has the advantage of allowing to determine the course and location of infection by Leishmania in the sandfly digestive tract [77].
Alternatively, molecular approaches represent a more specific and sensitive technique, allowing the DNA detection of a single Leishmania parasite, regardless of its stage and localization in the insect gut [78, 79]. Indeed, PCR‐based technique was eight times more efficient in detecting trypanosomatids than the dissection method and two times more efficient in identifying natural infection by Leishmania [80]. However, molecular methods have the disadvantage of not being able to distinguish between viable and dead parasites [81]. To access the genetic material of the parasite, DNA/RNA is extracted generally using a pool of about 10 female phlebotomine sandflies [82, 83].
Multiple molecular markers from nuclear and kinetoplast Leishmania DNA have been used to detect naturally infected phlebotomines, including the miniexon‐derived RNA gene, rRNA gene, repeated genomic sequences and the kinetoplast minicircle DNA (kDNA), which is present at thousands of copies per cell [84–87]. These molecular markers are assessed by PCR methods using specific primers to amplify conserved regions, with kDNA amplification having greater reliability as a marker for the parasite when compared to miniexon and 18S rRNA [88]. Currently, PCR assays are able to detect and identify the parasite (L. (L.) i. chagasi) and vector (Lu. longipalpis) responsible for VL [82, 89–91]. Besides that, qPCR combines the identification of genetic material with the quantification of parasites present in the phlebotomine, which is important for VL transmission and the establishment of infection [83].
4.3. Disease cases and natural infection rates in Latin America
The magnitude of VL in Latin America is not completely known, mainly because most countries do not have effective surveillance systems [92–94]. VL was reported in at least 12 countries in Latin America, with Brazil having the highest number of cases, followed by Paraguay, Argentina and Colombia [21, 25] (Figure 3).
Figure 3.
Visceral leishmaniasis cases in four Latin American countries: Brazil, Paraguay, Colombia and Argentina (2001–2013). Source: PAHO/WHO [21, 25].
The Brazilian Ministry of Health declared a total of 78,444 VL cases in 25 years of notification (1990–2014), with approximately 67% of them in the Northeast region. In this period, the annual mean in the country was 3137 cases and the incidence was two cases/100,000 inhabitants [22]. In addition, an increase of 3.2–6.6% in mortality rate caused by leishmaniasis was reported in Brazil from 2000 to 2014 [23].
Although resources have been invested in the VL control and establishment of protocols for specific treatment, important territorial expansion of VL in Latin America countries has been registered [21, 25, 95]. In Brazil, it was initially restricted to poor rural areas in the northeast of the country; however, since 1980s, the disease has gradually spread to major cities and peri‐urban areas in North, Southeast, South and Midwest regions [3, 96], occurring in 23 of the 27 Brazilian states [97] (Figure 4).
Figure 4.
Distribution of visceral leishmaniasis cases in Latin America countries in 2013. Source: PAHO/WHO [97].
Current control strategies to limit the VL expansion are directed against the vector, using insecticides; the canine reservoir by serological screening, by euthanasia in seropositive dogs and by the use of vaccine in asymptomatic animals with negative serological results, in addition to the diagnosis and treatment of human cases. Unfortunately, the results of those interventions have been shown to be modest [3, 96]. Since VL epidemiological data are generally based only on the prevalence of human infection [98], surveillance strategies based on a better definition of transmission, risk areas and rates of naturally infected sandflies are necessary in order to provide better control of the disease.
Natural infection rates by L. (L.) i. chagasi in phlebotomine are still poorly investigated even in VL endemic areas (Table 2). Literature has shown that infection ratios are usually low, ranging around 1–3% in Latin America, often contrasting with the high incidence of the disease in these regions [74, 76, 99].
Natural infection ratios by Leishmania (L.) chagasi in Lu. longipalpis females in Latin America.
Note: *Lu. longipalpis females evaluated in pools.
According to Cimerman and Cimerman [109], transmission depends on the presence of high densities of Lu. longipalpis, as observed during outbreaks of the disease. Several factors may be associated with the difference between natural infection rates detected and VL human cases reported. However, it is possible that even low infection rates are sufficient to maintain circulating infection, highlighting the importance of monitoring sandfly vectors in order to prevent the occurrence of VL, as well as for the definition of risk areas.
On the other hand, high rates of natural infection were observed by Freitas‐Lidani et al. [88] and Saraiva et al. [104], with 8.6 and 19%, respectively, in Pará and Minas Gerais states (North and Southeast regions of Brazil). Both rates were determined using molecular approaches by individual vector analysis. The local incidences of VL for the same period were 281 (Pará state, Brazil) and 407 (Minas Gerais state, Brazil) cases [22], respectively. Although the assessment of individual vectors may be more laborious, the great advantage over pooled samples is the achievement of more informative rates of infected sandflies, especially in areas where new cases are beginning to emerge in dogs and humans.
The epidemiology of leishmaniasis is complex due to the diversity of protozoan, vector and reservoirs species, associated to a variety of clinical events. Early diagnosis and treatment of infected patients is crucial to direct public policies of VL control, especially because the disease has common clinical manifestations and geographic distributions with other infections such as Chagas disease, malaria, schistosomiasis, typhoid fever and tuberculosis. In this context, molecular approaches to determine rates of Lu. longipalpis naturally infected with Leishmania allows the estimation of the transmission risk for VL and vectorial capacity in areas where many species of phlebotomine sandflies coexist.
References
1.Medeiros IM, Nascimento ELT, Hinrichsen SL. Leishmanioses (visceral e tegumentar). In: Hinrichsen SL., editor. DIP – Doenças Infecciosas e Parasitárias. Rio de Janeiro, Brazil: Guanabara Koogan; 2005. pp. 398–409.
2.Costa CHN, Tapety CMM, Werneck GL. Control of visceral leishmaniasis in urban areas: randomized factorial intervention trial. Rev Soc Bras Med Trop. 2007;40(4):415–9.
3.Ministério da Saúde. Manual de Vigilância e Controle da Leishmaniose Visceral. 1.a edição. Brasília – DF: Editora MS; 2006. 120 p.
4.Alvar J, Vélez ID, Bern C, Herrero M, Desjeux P, Cano J, et al. Leishmaniasis worldwide and global estimates of its incidence. PLoS One. 2012;7(5): e35671
5.Pigott DM, Bhatt S, Golding N, Duda KA, Battle KE, Brady OJ, et al. Global distribution maps of the leishmaniases. Elife. 2014;3(e02851):1–21.
6.Grimaldi G, Tesh RB, McMahon‐Pratt D. A review of the geographic distribution and epidemiology of leishmaniasis in the New World. Am J Trop Med Hyg. 1989;41(6):687–725.
7.Marcili A, Sperança MA, da Costa AP, Madeira MF, Soares HS, Sanches CO, Acosta IC, Girotto A, Minervino AH, Horta MC, Shaw JJ, Gennari SM. Phylogenetic relationships of Leishmania species based on trypanosomatid barcode (SSU rDNA) and gGAPDH genes: Taxonomic revision of Leishmania (L.) infantum chagasi in South America. Infect Genet Evol. 2014;25:44–51.
8.Akhoundi M, Kuhls K, Cannet A, Votýpka J, Marty P, Delaunay P, et al. A historical overview of the classification, evolution, and dispersion of Leishmania parasites and sandflies. PLoS Negl Trop Dis. 2016;10(3):e0004349.
9.Bates PA. Transmission of Leishmania metacyclic promastigotes by phlebotomine sand flies. Int J Parasitol. 2007;37(10):1097–106.
10.CDC. Global Health – Division of Parasitic Diseases and Malaria [Internet]. 2015 [cited 2016 Sep 8]. Available from: http://www.cdc.gov/parasites/leishmaniasis/
11.Lainson R, Shaw JJ. Evolution, classification and geographical distribution. W Peters & R Killick-Kendrick (eds). In: The leishmaniases in biology and medicine Volume I Biology and epidemiology. Academic Press, London. 1987. p. 120.
12.Lopes UG, Wirth DF. Identification of visceral Leishmania species with cloned sequences of kinetoplast DNA. Mol Biochem Parasitol. 1986;20(1):77–84.
13.Cabezas Y, Legentil L, Robert‐Gangneux F, Daligault F, Belaz S, Nugier‐Chauvin C, et al. Leishmania cell wall as a potent target for antiparasitic drugs. A focus on the glycoconjugates. Org Biomol Chem. 2015;13(31):8393–404.
14.Marques PE, Amaral SS, Pires DA, Nogueira LL, Soriani FM, Lima BHF, et al. Chemokines and mitochondrial products activate neutrophils to amplify organ injury during mouse acute liver failure. Hepatology. 2012;56(5):1971–82.
15.Van Zandbergen G, Hermann N, Laufs H, Solbach W, Laskay T. Leishmania promastigotes release a granulocyte chemotactic factor and induce interleukin‐8 release but inhibit gamma interferon‐inducible protein 10 production by neutrophil granulocytes. Infect Immun. 2002;70(8):4177–84.
16.de Oliveira VVG, Alves LC, Silva Jr VA. Transmission routes of visceral leishmaniasis in mammals. Cienc Rural. 2015;45(9):1622–8.
18.Reithinger R, Dujardin J‐C, Louzir H, Pirmez C, Alexander B, Brooker S. Cutaneous leishmaniasis. Lancet Infect Dis. 2007;7(9):581–96.
19.Farrar J, Hotez P, Junghanss T, Kang G, Lalloo D, White N. Protozoan infections: leishmaniasis. In: Manson's Tropical Diseases. 22nd ed. Edinburgh: Elsevier Ltd; 2009. pp. 1341–67.
20.WHO. Control of the leishmaniases. World Health Organ Tech Rep Ser. 2010;(949):22–6.
21.PAHO/WHO. Informe Epidemiológico das Américas. Report Leishmaniasis No 3. 2015.
22.Sinan/SVS/MS. Sistema de Informação de Agravos de Notificação/Secretaria de Vigilância em Saúde/Ministério da Saúde [Internet]. 2016 [cited 2016 Sep 8]. Available from: http://portalsaude.saude.gov.br/images/pdf/2016/maio/20/LV‐Casos.pdf
23.Sinan/SVS/MS. Sistema de Informação de Agravos de Notificação/Secretaria de Vigilância em Saúde/Ministério da Saúde [Internet]. 2016 [cited 2016 Sep 8]. Available from: http://portalsaude.saude.gov.br/images/pdf/2016/maio/20/LV‐Letalidade.pdf
24.Harhay MO, Olliaro PL, Costa DL, Costa CHN. Urban parasitology: Visceral leishmaniasis in Brazil. Trends Parasitol. 2011;27(9):403–9.
25.Pan American Health Organization (PAHO). Regional Office of the World Health Organization. [Internet] Leishmaniasis: Epidemiological Report of the Americas 2013; n° 1, April. [Cited 2013 October 15]. Available from: http://www.paho.org/leishmaniasis/.
26.Chappuis F, Sundar S, Hailu A, Ghalib H, Rijal S, Peeling RW, et al. Visceral leishmaniasis: what are the needs for diagnosis, treatment and control? Nat Rev Microbiol. 2007;5(11):873–82.
27.Stark D, Pett S, Marriott D, Harkness J. Post‐kala‐azar dermal leishmaniasis due to Leishmania infantum in a human immunodeficiency virus type 1‐infected patient. J Clin Microbiol. 2006;44(3):1178–80.
28.Agenor ALVF, Araújo LVF, de Francesco DE, Martins DSG, Saboia NA, Mendoça LVE. Renal tubular dysfunction in human visceral leishmaniasis (Kala‐azar). Clin Nephrol. 2009;71(5):492–500.
29.Pagliano P, Carannante N, Gramiccia M, Ascione T, Stornaiuolo G, Gradoni L, et al. Visceral leishmaniasis causes fever and decompensation in patients with cirrhosis. Gut. 2007;56(6):893–4.
30.de Albuquerque LCP, Mendonça IR, Cardoso PN, Baldaçara LR, Borges MRMM, Borges J da C, Pranchevicius MC. HIV/AIDS‐related visceral leishmaniasis: a clinical and epidemiological description of visceral leishmaniasis in northern Brazil. Rev Soc Bras Med Trop. 2014;47(January):38–46.
31.Sakkas H, Gartzonika C, Levidiotou S. Laboratory diagnosis of visceral leishmaniasis. J Vector Borne Dis. 2016;53:8–16.
32.Maia Z, Lírio M, Mistro S, Mendes CMC, Mehta SR, Badaro R. Comparative study of rK39 Leishmania antigen for serodiagnosis of visceral leishmaniasis: systematic review with meta‐analysis. PLoS Negl Trop Dis. 2012;6(1): e1484.
33.Gontijo CMF, Melo MN. Visceral Leishmaniasis in Brazil: current status, challenges and prospects Rev Bras Epidemiol. 2004;7:338–49.
34.Sundar S, Rai M. Laboratory diagnosis of visceral leishmaniasis. Clin Diagn Lab Immunol. 2002;9(5):951–8.
35.Disch J, Pedras MJ, Orsini M, Pirmez C, de Oliveira MC, Castro M, et al. Leishmania (Viannia) subgenus kDNA amplification for the diagnosis of mucosal leishmaniasis. Diagn Microbiol Infect Dis. 2005;51(3):185–90.
37.No JH. Visceral leishmaniasis: Revisiting current treatments and approaches for future discoveries. Acta Trop. 2016;155:113–23.
38.Gradoni L, Gramiccia M, Scalone A. Visceral leishmaniasis treatment, Italy. Emerg Infect Dis. 2003;9(12):1617–20.
39.Santos DO, Coutinho CER, Madeira MF, Bottino CG, Vieira RT, Nascimento SB, et al. Leishmaniasis treatment – A challenge that remains: A review. Parasitol Res. 2008;103(1):1–10.
40.Fanos V, Cataldi L. Renal transport of antibiotics and nephrotoxicity: a review. J Chemother. 2001 Oct;13(5):461–72.
41.Wong‐Beringer A, Jacobs RA, Guglielmo BJ. Lipid formulations of amphotericin B: clinical efficacy and toxicities. Clin Infect Dis. 1998;27(3):603–18.
42.Ministério da Saúde. Manual for the surveillance and control of visceral leishmaniasis. Brasilia; 2003.
43.Frézard F, Michalick MSM, Soares CF, Demicheli C. Novel methods for the encapsulation of meglumine antimoniate into liposomes. Brazilian J Med Biol Res. 2000;33(7):841–6.
44.Frézard F, Schettini DA, Rocha OGF, Demicheli C. Lipossomas: Propriedades físico‐químicas e farmacológicas, aplicações na quimioterapia à base de antimônio. Quim Nova. 2005;28(3):511–8.
45.Ministério da Saúde. Manual for the surveillance and control of visceral leishmaniasis. Brasilia; 2004.
46.Ministério da Saúde. Guia de Vigilância Epidemiológica. Série A. Normas e Manuais Técnicos. 2009. 819 p.
47.Killick‐Kendrick R. Phlebotomine vectors of the leishmaniases: a review. Med Vet Entomol. 1990;4(1):1–24.
48.de Souza MB, de Marzochi MCA, de Carvalho RW, Ribeiro PC, Pontes C dos S, Caetano JM, et al. Absence of Lutzomyia longipalpis in some endemic visceral leishmaniasis areas in Rio de Janeiro municipality. Cad Saúde Publica. 2003;19(6):1881–5.
49.de Carvalho MR, Valença HF, da Silva FJ, de Pita‐Pereira D, Pereira T de A, Britto C, Brazil RP, Brandão Filho SP. Natural Leishmania infantum infection in Migonemyia migonei (França, 1920) (Diptera:Psychodidae: Phlebotominae) the putative vector of visceral leishmaniasis in Pernambuco State, Brazil. Acta Trop. 2010;116(1):108–10.
50.Travi BL, Velez ID, Brutus L, Segura I, Jaramillo C, Montoya J. Lutzomyia evansi, an alternate vector of Leishmania chagasi in a Colombian focus of visceral leishmaniasis. Trans R Soc Trop Med Hyg. 1990;84(5):676–7.
51.Oviedo M, Moreno G GD. Bionomía de los vectores de leishmaniasis visceral en el Estado Trujillo, Venezuela. III. Colonización de Lutzomyia evansi. Bol Dir MalariolSaneam Ambient. 1995;35(Suppl 1):269–76.
52.Montoya‐Lerma J, Lane RP. Factors affecting host preference of Lutzomyia evansi (Diptera: Psychodidae), a vector of visceral leishmaniasis in Colombia. Bull Entomol Res. 1996 Feb 10;86(01):43.
53.Travi BL, Montoya J, Gallego J, Jaramillo C, Llano R, Velez ID. Bionomics of Lutzomyia evansi (Diptera: Psychodidae) vector of visceral leishmaniasis in northern Columbia. J Med Entomol. 1996;33(3):278–85.
54.Pifano F RM. Investigaciones epidemiológicas sobre la leishmaniasis visceral en la isla de Margarita. Estado Nueva Esparta, Venezuela. Gac Med Caracas. 1964;72:425–30.
55.Feliciangeli MD, Rodriguez N, de Guglielmo Z, Rodriguez A. The re‐emergence of American visceral leishmaniasis in an old focus in Venezuela: present situation of human and canine infections. Parasite. 1998;5(4):317–23.
56.Salomón OD, Quintana MG, Bezzi G, Morán ML, Betbeder E, Valdéz D V. Lutzomyia migonei as putative vector of visceral leishmaniasis in La Banda, Argentina. Acta Trop. 2010;113(1):84–7.
57.Silva RA, Santos FKM, Sousa LC, Rangel EF, Bevilaqua CML. Ecology of Lutzomyia longipalpis and Lutzomyia migonei in an endemic area for visceral leishmaniasis. Rev Bras Parasitol Veterinária. 2014;2961:320–7.
58.Rodrigues ACM, Melo LM, Magalhães RD, de Moraes NB, de Souza Júnior AD, Bevilaqua CML. Molecular identification of Lutzomyia migonei (Diptera: Psychodidae) as a potential vector for Leishmania infantum (Kinetoplastida: Trypanosomatidae). Vet Parasitol. 2016;220:28–32.
59.Guimarães VCFV, Pruzinova K, Sadlova J, Volfova V, Myskova J, Filho SPB, et al. Lutzomyia migonei is a permissive vector competent for Leishmania infantum. Parasit Vectors. 2016;9(1):159.
60.Ryan L, Silveira FT, Lainson R, Shaw JJ. Leishmanial infections in Lutzomyia longipalpis and Lu. antunesi (Diptera: Psychodidae) on the island of Marajó, Pará State, Brazil. Trans R Soc Trop Med Hyg. 1984;78(4):547–8.
61.Dos Santos SO, Arias J, Ribeiro AA, de Paiva Hoffmann M, de Freitas RA, Malacco MAF. Incrimination of Lutzomyia cruzi as a vector of American visceral leishmaniasis. Med Vet Entomol. 1998;12(3):315–7.
62.Montoya‐lerma J, Cadena H, O M, Ready PD. Comparative vectorial efficiency of Lutzomyia evansi and Lu. longipalpis for transmitting Leishmania chagasi. Acta Trop. 2003;85:19–29.
63.Missawa NA, Veloso MAE, Maciel GBML, Michalsky ÉM, Dias ES. Evidence of transmission of visceral leishmaniasis by Lutzomyia cruzi in the municipality of Jaciara, State of Mato Grosso, Brazil. Rev Soc Bras Med Trop. 2011;44(1):76–8.
64.de Pita‐Pereira D, Cardoso MAB, Alves CR, Brazil RP, Britto C. Detection of natural infection in Lutzomyia cruzi and Lutzomyia forattinii (Diptera: Psychodidae: Phlebotominae) by Leishmania infantum chagasi in an endemic area of visceral leishmaniasis in Brazil using a PCR multiplex assay. Acta Trop. 2008;107(1):66–9.
65.Dias ES, Michalsky EM, Nascimento JC, Ferreira EC, Lopes JV, Fortes-Dias CL. Detection of Leishmania infantum, the etiological agent of visceral leishmaniasis, in Lutzomyia neivai, a putative vector of cutaneous leishmaniasis. Journal of Vector Ecology. 2013. 38:1, 193–196.
66.Saraiva L, Carvalho GML, Gontijo CMF, Quaresma PF, Lima ACVMR, Falcão AL, et al. Natural infection of Lutzomyia neivai and Lutzomyia sallesi (Diptera: Psychodidae) by Leishmania infantum chagasi in Brazil. J Med Entomol. 2009;46(5):1159–63.
67.Moya SL, Giuliani MG, Manteca Acosta M, Salomón OD, Liotta DJ. First description of Migonemyia migonei (França) and Nyssomyia whitmani (Antunes & Coutinho) (Psychodidae: Phlebotominae) natural infected by Leishmania infantum in Argentina. Acta Trop. 2015;152:181–4.
68.Galati E. Classificação de Phlebotominae. In: Rangel E, Lainson R, editors. Flebotomíneos do Brasil. Rio de Janeiro, Brazil: Editora Fiocruz; 2003. pp. 23–51.
69.Marcondes CB. A proposal of generic and subgeneric abbreviations for phlebotomine sandflies (Diptera: Psychodidae: Phlebotominae) of the world. Entomol News. 2007;118(4):351–6.
70.Aransay AM, Scoulica E, Tselentis Y. Detection and identification of Leishmania DNA within naturally infected sand flies by seminested PCR on minicircle kinetoplastic DNA. Appl Environ Microbiol. 2000;66(5):1933–8.
71.Perez JE, Veland N, Espinosa D, Torres K, Ogusuku E, Llanos‐Cuentas A, et al. Isolation and molecular identification of Leishmania (Viannia) peruviana from naturally infected Lutzomyia peruensis (Diptera: Psychodidae) in the Peruvian Andes. Mem Inst Oswaldo Cruz. 2007;102(5):655–8.
72.Ryan L, Brazil RP. Leishmania infections in Lutzomyia longipalpis (Diptera:Psychodidae) on the island of São Luis, Maranhão State, Brazil. Vol. 79, Mem. Inst. Oswaldo Cruz, Rio de Janeiro- Brazil. 1984;79:383–4.
73.Freitas RA, Naiff RD, Barrett T V. Species diversity and flagellate infections in the sand fly fauna near Porto Grande, State of Amapá, Brazil (Diptera: Psychodidae. Kinetoplastida: Trypanosomatidae). Mem Inst Oswaldo Cruz. 2002;97(1):53–9.
74.Luz BYE, Castro EA, Dereure J, Pratlong F, Medicale E, Broussonet RA. Lutzomyia whitmani (Diptera: Psychodidae) as vector of Leishmania (V.)braziliensis in Paraná state, southern Brazil. Ann Trop Med Parasitol. 2000;94(6):623–31.
75.Carvalho GML, Filho JDA, Falcão AL, Rocha Lima ACVM, Gontijo CMF. Naturally infected lutzomyia sand flies in a leishmania‐endemic area of Brazil. Vector‐Borne Zoonotic Dis. 2008;8(3):407–14.
76.Rodríguez N, Aguilar CM, Barrios MA, Barker DC. Detection of Leishmania braziliensis in naturally infected individual sandflies by the polymerase chain reaction. Trans R Soc Trop Med Hyg. 1999;93:47–9.
77.Sadlova J, Yeo M, Seblova V, Lewis MD, Mauricio I, Volf P, et al. Visualisation of Leishmania donovani fluorescent hybrids during early stage development in the sand fly vector. PLoS One. 2011;6(5): e19851.
78.de Pita‐Pereira D, Alves CR, Souza MB, Brazil RP, Bertho ÁL, de Figueiredo Barbosa A, et al. Identification of naturally infected Lutzomyia intermedia and Lutzomyia migonei with Leishmania (Viannia) braziliensis in Rio de Janeiro (Brazil) revealed by a PCR multiplex non‐isotopic hybridisation assay. Trans R Soc Trop Med Hyg. 2005;99(12):905–13.
79.Perez JE, Ogusuku E, Inga R, Lopez M, Monje J, Paz L, et al. Natural leishmania infection of lutzomyia spp. In peru. Trans R Soc Trop Med Hyg. 1994;88(2):161–4.
80.do Nascimento JC, de Paiva BR, Malafronte R dos S, Fernandes WD, Galati EAB. Natural infection of Phlebotomines (Diptera: Psychodidae) in a visceral‐leishmaniasis focus in Mato Grosso do Sul, Brazil. Rev Inst Med Trop S Paulo. 2007;49(2):119–22.
81.Cuvillier A, Miranda JC, Ambit A, Barral A, Merlin G. Abortive infection of Lutzomyia longipalpis insect vectors by aflagellated LdARL‐3A‐Q70L overexpressing Leishmania amazonensis parasites. Cell Microbiol. 2003;5(10):717–28.
82.Acardi SA, Liotta DJ, Santini MS, Romagosa CM, Salomón OD. Detection of Leishmania infantum in naturally infected Lutzomyia longipalpis (Diptera: Psychodidae: Phlebotominae) and Canis familiaris in Misiones, Argentina: The first report of a PCR‐RFLP and sequencing‐based confirmation assay. Mem Inst Oswaldo Cruz. 2010;105(6):796–9.
83.Rodrigues ACM, Silva RA, Melo LM, Luciano MCS, Bevilaqua CML. Epidemiological survey of Lutzomyia longipalpis infected by Leishmania infantum in an endemic area of Brazil. Rev Bras Parasitol veterinária. 2014;23:55–62.
84.de Bruijn MHL, Barker DC. Diagnosis of New World leishmaniasis: Specific detection of species of the Leishmania braziliensis complex by amplification of kinetoplast DNA. Acta Trop. 1992;52(1):45–58.
85.Castilho TM, Shaw JJ, Lucile M, Floeter‐Winter LM. New PCR assay using glucose‐6‐phosphate dehydrogenase for identification of leishmania species. J Clin Microbiol. 2003;41(2):540–6.
86.Paiva BR, Secundino NFC, Nascimento JC, Pimenta PFP, Galati EAB, Junior HFA, et al. Detection and identification of Leishmania species in field‐captured phlebotomine sandflies based on mini‐exon gene PCR. Acta Trop. 2006;99(2–3):252–9.
87.Salotra P, Sreenivas G, Pogue GP, Lee N, Nakhasi HL, Ramesh V, et al. Development of a species‐specific PCR assay for detection of Leishmania donovani in clinical samples from patients with kala‐azar and post‐kala‐azar dermal leishmaniasis. J Clin Micr. 2001;39(3):849–54.
88.Freitas‐Lidani KC, de Messias‐Reason IJ, Ishikawa EAY. A comparison of molecular markers to detect Lutzomyia longipalpis naturally infected with Leishmania (Leishmania) infantum. Mem Inst Oswaldo Cruz. 2014;109(4):442–7.
89.Francino O, Altet L, Sánchez‐Robert E, Rodriguez A, Solano‐Gallego L, Alberola J, et al. Advantages of real‐time PCR assay for diagnosis and monitoring of canine leishmaniosis. Vet Parasitol. 2006;137(3–4):214–21.
90.Lins RMMA, Oliveira SG, Souza NA, de Queiroz RG, Justiniano SCB, Ward RD, et al. Molecular evolution of the cacophony IVS6 region in sandflies. Insect Mol Biol. 2002;11(2):117–22.
91.Lopes EG, Alberto C, Junior G, Marcili A, Silva RD. Performance of conventional PCRs based on primers directed to nuclear and mitochondrial genes for the detection and identification of Leishmania spp. Rev Inst Med Trop Sao Paulo. 2016;58(41):1–7.
92.Werneck GL, Rodrigues L, Santos M V., Araújo IB, Moura LS, Lima SS, et al. The burden of Leishmania chagasi infection during an urban outbreak of visceral leishmaniasis in Brazil. Acta Trop. 2002;83(1):13–8.
93.Bern C, Maguire JH, Alvar J. Complexities of assessing the disease burden attributable to leishmaniasis. PLoS Negl Trop Dis. 2008;2(10): e313.
94.Zerpa O, Ulrich M, Borges R, Rodríguez V, Centeno M, Negrón E, et al. Epidemiological aspects of human and canine visceral leishmaniasis in Venezuela. Rev Panam Salud Publica. 2003;13(4):239–45.
95.Ministério da Saúde. Leishmaniose Visceral: Recomendações clínicas para redução da letalidade. Brasília; 2011.
96.Romero GAS, Boelaert M. Control of visceral leishmaniasis in latin America – A systematic review. PLoS Negl Trop Dis. 2010;4(1).
97.PAHO/WHOb. Pan‐American Health Organization/World Health Organization [Internet]. 2013. Available from: http://www.paho.org/hq/images/ATLAS_CD/NID_Subnational/atlas.html
98.Felipe IMA, de Aquino DMC, Kuppinger O, Santos MDC, Rangel MES, Barbosa DS, et al. Leishmania infection in humans, dogs and sandflies in a visceral leishmaniasis endemic area in Maranhão, Brazil. Mem Inst Oswaldo Cruz. 2011;106(2):207–11.
99.Missawa N a, Michalsky EM, Fortes‐Dias CL, Santos Dias E. Lutzomyia longipalpis naturally infected by Leishmania (L.) chagasi in Várzea Grande, Mato Grosso State, Brazil, an area of intense transmission of visceral leishmaniasis. Cad saude publica/Minist da Saude, Fund Oswaldo Cruz, Esc Nac Saude Publica. 2010;26(12):2414–9.
100.de Oliveira DMS, Saraiva EM, Ishikawa EAY, de Sousa AAA, da Silva EO, da Silva IM. Distribution of phlebotomine fauna (Diptera: Psychodidae) across an urban–rural gradient in an area of endemic visceral leishmaniasis in Northern Brazil. Mem Inst Oswaldo Cruz. 2011;106(8):1039–44.
101.Soares MR, Carvalho CC, Silva LA, Lima MS, Barral AM, Rebelo JM, et al. Molecular analysis of natural infection of Lutzomyia longipalpis in an endemic area for visceral leishmaniasis in Brazil. Cad Saude Publica. 2010;26(12):2409–13.
102.Silva JGDE, Werneck GL, Cruz MDSPE, Costa CHN, Mendonça IL De. Infecção natural de Lutzomyia longipalpis por Leishmania sp. em Teresina, Piauí, Brasil. Cad Saude Publica. 2007;23(7):1715–20.
103.Silva EA, Andreotti R, Dias ES, Barros JC, Brazuna JCM. Detection of Leishmania DNA in phlebotomines captured in Campo Grande, Mato Grosso do Sul, Brazil. Exp Parasitol. 2008;119(3):343–8.
104.Saraiva L, Filho JDA, de Oliveira Silva S, de Andrade ASR, Melo MN. The molecular detection of different Leishmania species within sand flies from a cutaneous and visceral leishmaniasis sympatric area in Southeastern Brazil. Mem Inst Oswaldo Cruz. 2010;105(8):1033–9.
105.Michalsky ÉM, Guedes KDS, de Oliveira F, França‐silva JC, Latorre C, Dias F, et al. Natural infection with Leishmania infantum chagasi in Lutzomyia (Lutzomyia) longipalpis (Diptera: Psychodidae) sandflies captured in the municipality of Janaúba, State of Minas Gerais, Brazil. Rev Soc Bras Med Trop. 2011;44(1):58–62.
106.Flórez M, Patricia J, Reinaldo M, Katherine G, Luna P, Hugo V, et al. Lutzomyia longipalpis (Diptera: Psychodidae) en un foco suburbano de leishmaniosis visceral en el Cañón del Chicamocha en Santander, Colombia. Biomédica. 2006;26(Suppl. 1):109–20.
107.Corredor A, Gallego JF, Tesh RB, Morales A, de Carrasquilla CF, Young DG, et al. Epidermiology of visceral leishmaniasis in Colombia. Am Soc Trop Med Hyg. 1989;40(5):480–6.
108.Le Pont F, Desjeux P. Leishmaniasis in Bolivia. I. Lutzomyia longipalpis (Lutz & Neiva, 1912) as the vector of visceral leishmaniasis in Los Yungas. Trans R Soc Trop Med Hyg. 1985;79(2):227–31.
109.Cimerman S, Cimerman B. Medicina tropical. 1st ed. São Paulo: Atheneu; 2003. 690 p.
Written By
Kárita Cláudia Freitas Lidani, Fabiana A. Andrade, Maria R.P.A.
Tizzot, Magda C.V. Costa-Ribeiro, Marcia H. Beltrame and Iara J.
Messias-Reason
Submitted: March 24th, 2016Reviewed: September 15th, 2016Published: March 1st, 2017
Open access peer-reviewed chapter
