Preface

**Section 5 Therapeutic Targets and Inhibitors 105**

**Visceral Leishmaniasis 133** Sushma Singh and N. Kishore Babu

**Section 6 Medicinal Plants as Source of Anti-leishmanial**

Chapter 9 **Alternative Treatment for Leishmaniasis 145**

Chapter 10 **Natural Compounds and Extracts from Mexican Medicinal**

Ariane Sousa-Batista and Bartira Rossi-Bergmann

Chapter 12 **Crossing Biological Barriers for Leishmaniasis Therapy: From Nanomedicinal Targeting Perspective 199**

Gul Shahnaz, Hafiz Shoaib Sarwar and Masoom Yasinzai

**Section 7 Nanomedicines for Anti-leishmanial Therapy 179**

Chapter 11 **Nanomedicines for Cutaneous Leishmaniasis 181**

**Chemotherapy 107**

**VI** Contents

**Metabolites 143**

Abreu-Silva

Chapter 7 **The Polyamine Pathway as a Potential Target for Leishmaniases**

Chapter 8 **3-Hydroxy-3-Methylglutaryl-CoA Reductase (HMGR) Enzyme of**

Fernandes and Lucile Maria Floeter-Winter

Juliana Ide Aoki, Sandra Marcia Muxel, Juliane Cristina Ribeiro

**the Sterol Biosynthetic Pathway: A Potential Target against**

Renata Mondêgo de Oliveira, Solange de Araújo Melo, Tatiane Aranha da Penha-Silva, Fernando Almeida-Souza and Ana Lucia

**Plants with Anti-Leishmanial Activity: An Update 163** María Adelina Jiménez-Arellanes and Rosalba León-Díaz

Leishmaniasis comprises a broad spectrum of neglected vector-borne diseases ranging in se‐ verity from self-healing but disfiguring and stigmatizing cutaneous lesions to mucocutane‐ ous and fatal visceral manifestations, depending on the species and host characteristics. The visceralizing species is the most devastating and listed as one of the major neglected tropical diseases. The syndrome primarily afflicts the impoverished population of low-income coun‐ tries, mainly in the tropics and subtropics. Despite intensive research, live vaccines are the only effective treatment till date against cutaneous leishmaniasis, while none exists for the visceral form. Moreover, there is an upward trend in development of resistance to most of the currently available chemotherapeutic arsenal. Combinations of drugs have also been ex‐ plored. Absence of vaccines, progressive emergence of HIV/*Leishmania* coinfection, and re‐ lapse after treatment delineate the gravity of leishmaniasis affliction.

Invasion of host macrophages by *Leishmania* triggers a multitude of signaling circuits to eliminate the pathogen. However, the parasite has evolved stratagems to neutralize macro‐ phage defensive arsenals, the very heart of the immune system's defensive machinery, creat‐ ing a safe niche for its survival. Identification of new drug targets can contribute towards designing inhibitors and strengthening the pipeline for disease elimination. Natural prod‐ ucts from medicinal plants have also shown leishmanicidal effects that in some cases are potentiated by immunomodulation. A plethora of nanoparticles has been reported to induce protection with modulation of the immune response. Another major challenge in the mitiga‐ tion of this endemic disease is to achieve safe, efficacious, and low-cost prophylactic and/or therapeutic vaccines with long-lasting protection.

This book encompasses the epidemiology of leishmaniasis, immune evasion strategies em‐ ployed by the *Leishmania* parasite, and current vaccination and immunotherapeutic ap‐ proaches, including prophylactic as well as therapeutic vaccines. The prospects of new drug targets and inhibitors and natural product-based antileishmanial drugs and nanomedicines have also been exemplified.

I would like to take this opportunity to express my deepest gratitude to my revered collea‐ gue Dr. Hassan Hemeg for his valuable guidance, perseverant support, and constructive criticism that gave impetus to the success of this book.

**Farhat Afrin and Hassan Abdullah Hemeg**

Department of Clinical Laboratory Sciences Faculty of Applied Medical Sciences Taibah University Madina, Kingdom of Saudi Arabia

**Section 1**

**Introductory Chapter**

**Section 1**

**Introductory Chapter**

**Chapter 1**

**Provisional chapter**

**Introductory Chapter: Leishmaniasis: An Emerging**

Leishmaniasis comprises a broad-spectrum of neglected vector-borne diseases ranging in severity from the self-healing but disfiguring and stigmatizing cutaneous lesions to mucocutaneous and fatal visceral manifestations, depending on the species and host characteristics. This syndrome primarily afflicts the impoverished population of low-income countries falling in the tropics and subtropics. Globally, 0.7–1.2 million new cases of cutaneous leishmaniasis (CL) occur every year while for visceral leishmaniasis (VL), 200,000–400,000 new cases and 20,000–40,000 deaths are reported each year, with 95% of fatal cases occurring in only six countries, namely, India, Bangladesh, Sudan, South Sudan, Ethiopia and Brazil [1]. The disease is transmitted by the bite of female *Phlebotomus* sandflies that transmit the promastigotes, which are then transformed into amastigotes within the mammalian macrophages. The goal of World Health Organization is to eliminate this public health problem in the South-east Asia Region by 2020 [2]. Despite intensive research, live vaccines are the only effective vaccines till date against CL while none exists for the visceral form that is the most severe of the various clinical forms of leishmaniasis. Moreover, there is an upward trend in development of resistance to most of the currently available drugs [3]. The chemotherapeutic arsenal is associated with need for hospitalization and prolonged periods of treatment, coupled with high toxicity, which limits the application and patient compliance. Combinations of drugs have also been explored. Absence of vaccines, progressive emergence of HIV-*Leishmania* co-infection and relapse after treatment delineate the gravity of leishmaniasis affliction [4]. A recent report indicated relapse of post kala-azar dermal leishmaniasis (PKDL) 1 year after successful treatment of VL with miltefosine and paromomycin [5]. Antimony therapy is also not advised in elderly patients with CL due to severe adverse side effects [6]. The potential of

**Introductory Chapter: Leishmaniasis: An Emerging**

© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

© 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use,

distribution, and reproduction in any medium, provided the original work is properly cited.

DOI: 10.5772/intechopen.79662

**Clinical Syndrome**

**1. Introduction**

**Clinical Syndrome**

Farhat Afrin and Hassan A. Hemeg

Farhat Afrin and Hassan A. Hemeg

http://dx.doi.org/10.5772/intechopen.79662

Additional information is available at the end of the chapter

Additional information is available at the end of the chapter

#### **Introductory Chapter: Leishmaniasis: An Emerging Clinical Syndrome Introductory Chapter: Leishmaniasis: An Emerging Clinical Syndrome**

DOI: 10.5772/intechopen.79662

Farhat Afrin and Hassan A. Hemeg Farhat Afrin and Hassan A. Hemeg

Additional information is available at the end of the chapter Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/intechopen.79662

## **1. Introduction**

Leishmaniasis comprises a broad-spectrum of neglected vector-borne diseases ranging in severity from the self-healing but disfiguring and stigmatizing cutaneous lesions to mucocutaneous and fatal visceral manifestations, depending on the species and host characteristics. This syndrome primarily afflicts the impoverished population of low-income countries falling in the tropics and subtropics. Globally, 0.7–1.2 million new cases of cutaneous leishmaniasis (CL) occur every year while for visceral leishmaniasis (VL), 200,000–400,000 new cases and 20,000–40,000 deaths are reported each year, with 95% of fatal cases occurring in only six countries, namely, India, Bangladesh, Sudan, South Sudan, Ethiopia and Brazil [1]. The disease is transmitted by the bite of female *Phlebotomus* sandflies that transmit the promastigotes, which are then transformed into amastigotes within the mammalian macrophages. The goal of World Health Organization is to eliminate this public health problem in the South-east Asia Region by 2020 [2]. Despite intensive research, live vaccines are the only effective vaccines till date against CL while none exists for the visceral form that is the most severe of the various clinical forms of leishmaniasis. Moreover, there is an upward trend in development of resistance to most of the currently available drugs [3]. The chemotherapeutic arsenal is associated with need for hospitalization and prolonged periods of treatment, coupled with high toxicity, which limits the application and patient compliance. Combinations of drugs have also been explored. Absence of vaccines, progressive emergence of HIV-*Leishmania* co-infection and relapse after treatment delineate the gravity of leishmaniasis affliction [4]. A recent report indicated relapse of post kala-azar dermal leishmaniasis (PKDL) 1 year after successful treatment of VL with miltefosine and paromomycin [5]. Antimony therapy is also not advised in elderly patients with CL due to severe adverse side effects [6]. The potential of

© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

the visceralizing species, *Leishmania donovani* to cause localized cutaneous lesions is also not fully understood [7].

system. The plethora of candidate vaccines range from the live non-pathogenic vectors to the recombinant subunit vaccines, alone or together with adjuvants and/or delivery systems for induction of cell-mediated immunity. Some of these include *Leishmania*-activated C-kinase antigen (LACK) [12], *Leishmania* cysteine peptidase A, B in poly-lactic-co-glycolic acid (PLGA) nanoparticles [13], soluble *Leishmania* antigens in nanoliposomes co-delivered with saponin and imiquimod [14], DNA vaccine encoding ornithine decarboxylase [15]. Inclusion of salivary proteins in antileishmanial vaccines has been reported to result in a synergistic protective effect [16]. A live recombinant amastigote 2 antigen vaccine vector using *Trypanosoma cruzi* non-virulent strain, and live attenuated centrin gene–deleted *Leishmania donovani* [17] have been reported to induce strong T cell-mediated protective immune responses against VL and hence could represent promising alternatives for translation to human clinical trials [18]. Recombinant small myristoylated protein-3, a virulence factor has been found to be immunogenic in both mice and humans, with induction of protective immunity against murine VL

Introductory Chapter: Leishmaniasis: An Emerging Clinical Syndrome

http://dx.doi.org/10.5772/intechopen.79662

[19]. In case of CL, intranasal immunization has been found to reduce numbers of CD4+

(aldolase, enolase, p45 and triose phosphate isomerase) has also been attempted [23].

membrane potential [24].

**4. Therapeutic targets and inhibitors**

been implicated as an essential therapeutic target [34].

Immunotherapy on the other hand has been found to promote sterilizing cure. However, immunotherapeutic intervention with *L. amazonensis* antigens plus saponin was not found to maintain long-lasting low parasitism in dogs naturally infected with *Leishmania infantum* [21]. Therapy with anti-PDL-1 antibody has been found to promote parasite clearance with concomitant induction of protective immunity against VL by inhibiting autophagy, that is hijacked by *Leishmania* [22]. Immunotherapeutic approach with Th1 stimulating antigens

An emerging therapeutic modality for CL is photodynamic therapy of zinc porphyrin that results in loss of plasma membrane integrity and hyperpolarization of the mitochondrial

Identification of new drug targets can contribute towards designing inhibitors and strengthen the pipeline for disease elimination. DNA topoisomerases that control the over- or underwinding of DNA have been reported as deadly targets for topoisomerase inhibitors that may act as potential antileishmanial drugs [25]. Computational tools using *in silico* approaches targeting key enzymes in metabolic pathways of *Leishmania* have led to identification of several potential druggable targets such as cytochrome P450 sterol 14α-demethylase [26], dihydrofolate reductase-thymidylate synthase [27], methylglyoxal degradation superpathway [28], trypanothione reductase [29]. Trypanothione reductase is absent in humans and neutralizes the reactive oxygen species generated inside the infected macrophages. Inhibitors such as chalcones that block the activity of these trypanosomatid enzymes may be effective in treatment of leishmaniasis [29]. β-carbonic anhydrase [30], acid phosphatases [31], uracil DNA glycosylase [32] and Type 2 NADH dehydrogenase [33] are other potential therapeutic targets that are being explored. NLR (NOD-Like Receptor) family member NOD2 has also

regulatory T cells with increased Th1 response and associated protection [20].

Foxp3+

5

This chapter gives a brief glimpse of the recent advances in immunopathogenesis and immune evasion strategies employed by the *Leishmania* parasite, vaccination and immunotherapeutic approaches, natural product-based drugs, nanomedicines, therapeutic targets and diagnosis of leishmaniasis. We have included citations of the latest research articles presenting the most recent results.

## **2. Immunopathogenesis and immune evasion strategies**

Invasion of host macrophages by *Leishmania* triggers a multitude of signaling circuits to eliminate the pathogen. However, the parasite tries to subvert these defense mechanisms to create a safe haven for their survival. *Leishmania* secretes effector molecules to modulate the host immune transcriptome resulting in alterations in the host epigenome to alter cytokine and chemokine levels, their cross talks and downstream signaling hubs. This adversely affects the recruitment and activation of immune cells, respiratory burst and antigen presentation, leading to immune evasion. *Leishmania amazonensis* has been reported to induce histone deacetylase in infected macrophages, which contributes to down regulation of inducible nitric oxide synthase and subsequent parasite survival [8]. *L. donovani* infection causes hypoxic environment within the macrophages by activating hypoxia inducible factor-1α, that in turn up regulates micro RNA-210, while down regulating NF-κB mediated pro-inflammatory immune responses, to establish a safe niche for their survival [9].

*Leishmania* have evolved stratagems to neutralize macrophage defensive arsenals, the very heart of the immune system's defensive machinery, resulting in replication of the parasites within the phagolysosomal vacuoles of the infected macrophages. Unfolding of these host-pathogen interactions will help in development of effective drug targets that would enable to modulate the host immune system to ameliorate the pathogenesis of infection. Besides the host immune profile and the intrinsic parasite factors that may influence the clinical manifestations of the disease, *Leishmania* virus RNA 1 (LRV1) infecting *Leishmania guyanensis* has been implicated to contribute to immunopathogenesis of American tegumentary leishmaniasis [10]. Studies have also indicated that gut microbiota egested during infected sandfly bites is an important determinant of *Leishmania* dissemination via triggering of inflammasomes, leading to IL-1β production that sustains the neutrophilic infiltrate harboring the parasites [11].

## **3. Current vaccination and immunotherapeutic approach**

A major challenge to mitigation of this endemic disease is to achieve safe, efficacious and low-cost prophylactic or therapeutic vaccines with long-lasting protection. These vaccines should be effective against both stages of the parasite curbing its progression and accompanying pathology that stems from an imbalance between the pathogen and the host immune system. The plethora of candidate vaccines range from the live non-pathogenic vectors to the recombinant subunit vaccines, alone or together with adjuvants and/or delivery systems for induction of cell-mediated immunity. Some of these include *Leishmania*-activated C-kinase antigen (LACK) [12], *Leishmania* cysteine peptidase A, B in poly-lactic-co-glycolic acid (PLGA) nanoparticles [13], soluble *Leishmania* antigens in nanoliposomes co-delivered with saponin and imiquimod [14], DNA vaccine encoding ornithine decarboxylase [15]. Inclusion of salivary proteins in antileishmanial vaccines has been reported to result in a synergistic protective effect [16]. A live recombinant amastigote 2 antigen vaccine vector using *Trypanosoma cruzi* non-virulent strain, and live attenuated centrin gene–deleted *Leishmania donovani* [17] have been reported to induce strong T cell-mediated protective immune responses against VL and hence could represent promising alternatives for translation to human clinical trials [18]. Recombinant small myristoylated protein-3, a virulence factor has been found to be immunogenic in both mice and humans, with induction of protective immunity against murine VL [19]. In case of CL, intranasal immunization has been found to reduce numbers of CD4+ Foxp3+ regulatory T cells with increased Th1 response and associated protection [20].

Immunotherapy on the other hand has been found to promote sterilizing cure. However, immunotherapeutic intervention with *L. amazonensis* antigens plus saponin was not found to maintain long-lasting low parasitism in dogs naturally infected with *Leishmania infantum* [21]. Therapy with anti-PDL-1 antibody has been found to promote parasite clearance with concomitant induction of protective immunity against VL by inhibiting autophagy, that is hijacked by *Leishmania* [22]. Immunotherapeutic approach with Th1 stimulating antigens (aldolase, enolase, p45 and triose phosphate isomerase) has also been attempted [23].

An emerging therapeutic modality for CL is photodynamic therapy of zinc porphyrin that results in loss of plasma membrane integrity and hyperpolarization of the mitochondrial membrane potential [24].

## **4. Therapeutic targets and inhibitors**

the visceralizing species, *Leishmania donovani* to cause localized cutaneous lesions is also not

This chapter gives a brief glimpse of the recent advances in immunopathogenesis and immune evasion strategies employed by the *Leishmania* parasite, vaccination and immunotherapeutic approaches, natural product-based drugs, nanomedicines, therapeutic targets and diagnosis of leishmaniasis. We have included citations of the latest research articles presenting the most

Invasion of host macrophages by *Leishmania* triggers a multitude of signaling circuits to eliminate the pathogen. However, the parasite tries to subvert these defense mechanisms to create a safe haven for their survival. *Leishmania* secretes effector molecules to modulate the host immune transcriptome resulting in alterations in the host epigenome to alter cytokine and chemokine levels, their cross talks and downstream signaling hubs. This adversely affects the recruitment and activation of immune cells, respiratory burst and antigen presentation, leading to immune evasion. *Leishmania amazonensis* has been reported to induce histone deacetylase in infected macrophages, which contributes to down regulation of inducible nitric oxide synthase and subsequent parasite survival [8]. *L. donovani* infection causes hypoxic environment within the macrophages by activating hypoxia inducible factor-1α, that in turn up regulates micro RNA-210, while down regulating NF-κB mediated pro-inflammatory immune

*Leishmania* have evolved stratagems to neutralize macrophage defensive arsenals, the very heart of the immune system's defensive machinery, resulting in replication of the parasites within the phagolysosomal vacuoles of the infected macrophages. Unfolding of these host-pathogen interactions will help in development of effective drug targets that would enable to modulate the host immune system to ameliorate the pathogenesis of infection. Besides the host immune profile and the intrinsic parasite factors that may influence the clinical manifestations of the disease, *Leishmania* virus RNA 1 (LRV1) infecting *Leishmania guyanensis* has been implicated to contribute to immunopathogenesis of American tegumentary leishmaniasis [10]. Studies have also indicated that gut microbiota egested during infected sandfly bites is an important determinant of *Leishmania* dissemination via triggering of inflammasomes, leading to IL-1β production that sustains the neutrophilic infiltrate

A major challenge to mitigation of this endemic disease is to achieve safe, efficacious and low-cost prophylactic or therapeutic vaccines with long-lasting protection. These vaccines should be effective against both stages of the parasite curbing its progression and accompanying pathology that stems from an imbalance between the pathogen and the host immune

**2. Immunopathogenesis and immune evasion strategies**

responses, to establish a safe niche for their survival [9].

**3. Current vaccination and immunotherapeutic approach**

harboring the parasites [11].

fully understood [7].

4 Leishmaniases as Re-emerging Diseases

recent results.

Identification of new drug targets can contribute towards designing inhibitors and strengthen the pipeline for disease elimination. DNA topoisomerases that control the over- or underwinding of DNA have been reported as deadly targets for topoisomerase inhibitors that may act as potential antileishmanial drugs [25]. Computational tools using *in silico* approaches targeting key enzymes in metabolic pathways of *Leishmania* have led to identification of several potential druggable targets such as cytochrome P450 sterol 14α-demethylase [26], dihydrofolate reductase-thymidylate synthase [27], methylglyoxal degradation superpathway [28], trypanothione reductase [29]. Trypanothione reductase is absent in humans and neutralizes the reactive oxygen species generated inside the infected macrophages. Inhibitors such as chalcones that block the activity of these trypanosomatid enzymes may be effective in treatment of leishmaniasis [29]. β-carbonic anhydrase [30], acid phosphatases [31], uracil DNA glycosylase [32] and Type 2 NADH dehydrogenase [33] are other potential therapeutic targets that are being explored. NLR (NOD-Like Receptor) family member NOD2 has also been implicated as an essential therapeutic target [34].

## **5. Natural products as source of antileishmanial drugs**

In view of looming chemotherapeutic drug resistance, natural products and scaffolds from medicinal plants are being emphasized as leads for drug discovery. Plant-based bioactive compounds have merit over synthetic compounds, considering their unique structural variety, providing an unlimited source of molecules and biological activities [35]. A host of plant extracts or oils and their phytoconstituents (alkaloids, terpenoids, quinones, flavonoids, saponins, phenylpropanoids, flavonoids, lignoids, naphthoquinones, iridoids, and more) have shown promise *in vitro* and/or *in vivo* [36–41]. In some cases, the leishmanicidal effect is potentiated by immunomodulation [3, 42]. Besides plants, secondary metabolites from microorganisms such as fungi [43] and marine organisms have also been reported. Plant defensins have been found to eliminate *Leishmania* parasites via plasma membrane perturbation, mitochondrial membrane collapse, and reactive oxygen species induction [44].

**7. Diagnosis of leishmaniasis**

**8. Conclusions and future perspectives**

**Conflict of interest**

**Author details**

The authors declare no conflict of interest.

Farhat Afrin\* and Hassan A. Hemeg

\*Address all correspondence to<EMAIL_ADDRESS>
University, Al Madinah Al Munawarah, Kingdom of Saudi Arabia

A definitive diagnosis of leishmaniasis is crucial to guide timely and appropriate therapy. The disease is often confused with other co-endemic diseases and HIV co-infections may result in atypical clinical presentation [4]. Differential diagnosis of VL should be considered in patients of endemic areas after organ transplantation [56]. This underscores the need for highly sensitive and specific diagnostic modalities. In this regard, molecular techniques such as real-time polymerase chain reaction (qPCR)-based methods are gaining ground for detection and quantification of *Leishmania* as well as for species identification [57]. However, to rule out false negatives, combination of two PCR techniques is advisable in patients with cutaneous lesions [58]. For VL, serological diagnosis with recombinant antigen rK39-based immunochromatography and direct agglutination test based on the whole parasite antigens have been reported to have high sensitivity and specificity [59]. Nonetheless, amastigote detection in bone marrow aspirates and positive rK39 immunochromatographic test should be further validated by nested PCR [60]. Recently, a loop-mediated isothermal amplification (LAMP) assay based on 18S rDNA and the conserved region of minicircle kDNA has been implicated with high sensitivity for visceral as well as CL diagnostics [61]. Further, *Leishmania* urine antigen has been explored as a probable biomarker for predicting treatment failure and relapse in VL/HIV-coinfected patients [62].

Introductory Chapter: Leishmaniasis: An Emerging Clinical Syndrome

http://dx.doi.org/10.5772/intechopen.79662

7

To strengthen the leishmaniasis elimination drive, particular emphasis has to be laid on the diagnosis, chemotherapeutics and new targets identification and vaccination strategies for control of this endemic disease. This underscores renewed efforts to combat upcoming challenges in the quest for new drug targets in achieving definitive cure and/or safe, cost-effective prophylactic vaccines with long-lasting immunity against leishmaniasis. An effective therapeutic vaccine may further boost the immunosuppressed state and thus control the visceral-

Department of Clinical Laboratory Sciences, Faculty of Applied Medical Sciences, Taibah

izing form of leishmaniasis that is mainly harbored in the South Asian region.

Antimicrobial peptides have been reported to improve the therapeutic outcome of antileishmanial drugs [45]. Synergistic drug-natural product combinations have also been explored [46, 47].

## **6. Nanomedicines**

In recent years, numerous advances in drug discovery have been made for treating leishmaniasis, exploiting nanotechnological approaches to target the immune cell phagolysosomes that harbors the *Leishmania* amastigotes. A plethora of nanoparticles have been reported to elicit protection with modulation of the immune response via reduction in anti-inflammatory cytokine IL-10, and increased nitric oxide production [48]. Recently, antileishmanial activity of sulphonamide nanoemulsions have been reported that target the leishmanial β-carbonic anhydrase [30]. Linalool-loaded gold nanoparticles have also been found to exhibit therapeutic effectiveness against *Leishmania* [49]. A shortcourse AmBisome regimen has been found to be safe and effective in the treatment of clinically diagnosed PKDL patients in Bangladesh, and may be considered as a viable option for routine programmatic use, contributing towards the VL elimination drive [50]. Biodegradable PLGA microparticles loaded with an antileishmanial nitrochalcone has proved therapeutic effectiveness when administered subcutaneously in BALB/c mice with cutaneous lesions [51].

Green nanoparticles, that is, plant-based synthesis of nanoparticles have an upper edge over the synthetic nanoparticles owing to their biosynthesis being rapid, eco-friendly, nonpathogenic and economical. An array of biogenic nanoparticles from plant extracts has been reported to have antileishmanial activity with boosting of anti-oxidant activity [52, 53].

Miltefosine- and ketoconazole-loaded nanoniosomes with improved antileishmanial activity have also been reported [54]. AmBisome-miltefosine combination therapy for VL-HIV coinfected patients has been reported in Ethiopia with 83.8% cure rate [55].

## **7. Diagnosis of leishmaniasis**

**5. Natural products as source of antileishmanial drugs**

chondrial membrane collapse, and reactive oxygen species induction [44].

explored [46, 47].

**6. Nanomedicines**

6 Leishmaniases as Re-emerging Diseases

cutaneous lesions [51].

In view of looming chemotherapeutic drug resistance, natural products and scaffolds from medicinal plants are being emphasized as leads for drug discovery. Plant-based bioactive compounds have merit over synthetic compounds, considering their unique structural variety, providing an unlimited source of molecules and biological activities [35]. A host of plant extracts or oils and their phytoconstituents (alkaloids, terpenoids, quinones, flavonoids, saponins, phenylpropanoids, flavonoids, lignoids, naphthoquinones, iridoids, and more) have shown promise *in vitro* and/or *in vivo* [36–41]. In some cases, the leishmanicidal effect is potentiated by immunomodulation [3, 42]. Besides plants, secondary metabolites from microorganisms such as fungi [43] and marine organisms have also been reported. Plant defensins have been found to eliminate *Leishmania* parasites via plasma membrane perturbation, mito-

Antimicrobial peptides have been reported to improve the therapeutic outcome of antileishmanial drugs [45]. Synergistic drug-natural product combinations have also been

In recent years, numerous advances in drug discovery have been made for treating leishmaniasis, exploiting nanotechnological approaches to target the immune cell phagolysosomes that harbors the *Leishmania* amastigotes. A plethora of nanoparticles have been reported to elicit protection with modulation of the immune response via reduction in anti-inflammatory cytokine IL-10, and increased nitric oxide production [48]. Recently, antileishmanial activity of sulphonamide nanoemulsions have been reported that target the leishmanial β-carbonic anhydrase [30]. Linalool-loaded gold nanoparticles have also been found to exhibit therapeutic effectiveness against *Leishmania* [49]. A shortcourse AmBisome regimen has been found to be safe and effective in the treatment of clinically diagnosed PKDL patients in Bangladesh, and may be considered as a viable option for routine programmatic use, contributing towards the VL elimination drive [50]. Biodegradable PLGA microparticles loaded with an antileishmanial nitrochalcone has proved therapeutic effectiveness when administered subcutaneously in BALB/c mice with

Green nanoparticles, that is, plant-based synthesis of nanoparticles have an upper edge over the synthetic nanoparticles owing to their biosynthesis being rapid, eco-friendly, nonpathogenic and economical. An array of biogenic nanoparticles from plant extracts has been reported to have antileishmanial activity with boosting of anti-oxidant activity [52, 53].

Miltefosine- and ketoconazole-loaded nanoniosomes with improved antileishmanial activity have also been reported [54]. AmBisome-miltefosine combination therapy for VL-HIV co-

infected patients has been reported in Ethiopia with 83.8% cure rate [55].

A definitive diagnosis of leishmaniasis is crucial to guide timely and appropriate therapy. The disease is often confused with other co-endemic diseases and HIV co-infections may result in atypical clinical presentation [4]. Differential diagnosis of VL should be considered in patients of endemic areas after organ transplantation [56]. This underscores the need for highly sensitive and specific diagnostic modalities. In this regard, molecular techniques such as real-time polymerase chain reaction (qPCR)-based methods are gaining ground for detection and quantification of *Leishmania* as well as for species identification [57]. However, to rule out false negatives, combination of two PCR techniques is advisable in patients with cutaneous lesions [58]. For VL, serological diagnosis with recombinant antigen rK39-based immunochromatography and direct agglutination test based on the whole parasite antigens have been reported to have high sensitivity and specificity [59]. Nonetheless, amastigote detection in bone marrow aspirates and positive rK39 immunochromatographic test should be further validated by nested PCR [60]. Recently, a loop-mediated isothermal amplification (LAMP) assay based on 18S rDNA and the conserved region of minicircle kDNA has been implicated with high sensitivity for visceral as well as CL diagnostics [61]. Further, *Leishmania* urine antigen has been explored as a probable biomarker for predicting treatment failure and relapse in VL/HIV-coinfected patients [62].

## **8. Conclusions and future perspectives**

To strengthen the leishmaniasis elimination drive, particular emphasis has to be laid on the diagnosis, chemotherapeutics and new targets identification and vaccination strategies for control of this endemic disease. This underscores renewed efforts to combat upcoming challenges in the quest for new drug targets in achieving definitive cure and/or safe, cost-effective prophylactic vaccines with long-lasting immunity against leishmaniasis. An effective therapeutic vaccine may further boost the immunosuppressed state and thus control the visceralizing form of leishmaniasis that is mainly harbored in the South Asian region.

## **Conflict of interest**

The authors declare no conflict of interest.

## **Author details**

Farhat Afrin\* and Hassan A. Hemeg

\*Address all correspondence to<EMAIL_ADDRESS>
Department of Clinical Laboratory Sciences, Faculty of Applied Medical Sciences, Taibah University, Al Madinah Al Munawarah, Kingdom of Saudi Arabia

## **References**

[1] Alvar J, Velez 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

[13] Noormehr H, Hosseini AZ, Soudi S, Beyzay F. Enhancement of Th1 immune response against Leishmania cysteine peptidase A, B by PLGA nanoparticle. International Immu-

Introductory Chapter: Leishmaniasis: An Emerging Clinical Syndrome

http://dx.doi.org/10.5772/intechopen.79662

9

[14] Emami T, Rezayat SM, Khamesipour A, Madani R, Habibi G, Hojatizade M, et al. The role of MPL and imiquimod adjuvants in enhancement of immune response and protection in BALB/c mice immunized with soluble Leishmania antigen (SLA) encapsulated in

[15] Kumar A, Dikhit MR, Amit A, Zaidi A, Pandey RK, kumar Singh A, et al. Immunomodulation induced through ornithine decarboxylase DNA immunization in Balb/c

[16] Martin-Martin I, Chagas AC, Guimaraes-Costa AB, Amo L, Oliveira F, Moore IN, et al. Immunity to LuloHya and Lundep, the salivary spreading factors from Lutzomyia longipalpis, protects against *Leishmania major* infection. PLoS Pathogens. 2018;**14**(5):e1007006

[17] Banerjee A, Bhattacharya P, Dagur PK, Karmakar S, Ismail N, Joshi AB, et al. Live attenuated *Leishmania donovani* centrin gene–deleted parasites induce IL-23–dependent IL-17–protective immune response against visceral leishmaniasis in a murine model.

[18] Almeida APM, Machado LF, Doro D, Nascimento FC, Damasceno L, Gazzinelli RT, et al. New vaccine formulations containing a modified version of the amastigote 2 antigen and the non-virulent *Trypanosoma cruzi* CL-14 strain are highly antigenic and protective

[19] Oliveira MP, Martins VT, Santos TT, Lage DP, Ramos FF, Salles B, et al. Small myristoylated protein-3, identified as a potential virulence factor in *Leishmania amazonensis*, proves to be a protective antigen against visceral leishmaniasis. International Journal of

[20] Bezerra IPS, Abib MA, Rossi-Bergmann B. Intranasal but not subcutaneous vaccination with LaAg allows rapid expansion of protective immunity against cutaneous leishmani-

[21] Viana KF, Lacerda G, Teixeira NS, Cangussu ASR, Aguiar RWS, Giunchetti RC. Therapeutic vaccine of killed *Leishmania amazonensis* plus saponin reduced parasite burden in dogs naturally infected with *Leishmania infantum*. Veterinary Parasitology.

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[24] Andrade C, Figueiredo R, Ribeiro K, Souza L, Sarmento-Neto J, Rebouças J, et al. Photodynamic effect of zinc porphyrin on the promastigote and amastigote forms of *Leishmania braziliensis*. Photochemical & Photobiological Sciences. 2018;**17**(4):482-490

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30208-4

12 Leishmaniases as Re-emerging Diseases

**Section 2**

**Leishmaniasis: An Overview**

**Leishmaniasis: An Overview**

**Chapter 2**

Provisional chapter

**Visceral Leishmaniasis**

Visceral Leishmaniasis

Sujit K. Bhattacharya, Ajanta Ghosal, Sudeshna Ganguly, Sandipan Ganguly,

Sujit K. Bhattacharya, Ajanta Ghosal, Sudeshna Ganguly, Sandipan Ganguly,

Additional information is available at the end of the chapter

Clinically, leishmaniasis is of three types—visceral leishmaniasis (VL) or kala-azar, cutaneous leishmaniasis (CL) and mucocutaneous leishmaniasis (MCL). Post-kala-azar dermal leishmaniasis (PKDL) is considered as a complication of VL. VL is characterized by fever, anemia and splenomegaly in a VL-endemic area (malaria excluded). A subject with such symptoms should be subjected to an rK39 strip test. Confirmation of diagnosis is made by demonstration of the parasite (Leishmania donovani) from samples obtained by aspiration of bone marrow or iliac crest puncture. Miltefosine, stibogluconate, amphotericin B, liposomal amphotericin B and paromomycin are effective available anti-leishmaniasis drugs. Vector (Phleblotomus argentipes) control for reduction of transmission and early diagnosis and complete treatment are essential elements of case management. There is no effective vaccine against VL. This review on VL aims at providing state-art knowledge on epide-

DOI: 10.5772/intechopen.75907

The distinct clinical forms of leishmaniasis are visceral leishmaniasis (VL), cutaneous leishmaniasis (CL) and mucocutaneous leishmaniasis (MCL). PKDL is considered to be a complication of VL. Kala-azar is a neglected tropical disease (NTD). It affects the poorest of the poor living in endemic areas. Post-kala-azar dermal leishmaniasis (PKDL) is associated with stigma. Fortunately, it is not difficult to diagnose the disease and several drugs are available for

> © 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and eproduction in any medium, provided the original work is properly cited.

© 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use,

distribution, and reproduction in any medium, provided the original work is properly cited.

miology, diagnosis and case-management and vaccine development. Keywords: leishmaniasis, PKDL, rK39 strip test, kala-azar vaccine

Additional information is available at the end of the chapter

Sabahat Azim and Shanta Dutta

Sabahat Azim and Shanta Dutta

http://dx.doi.org/10.5772/intechopen.75907

Abstract

1. Introduction

treatment of the disease.

**Chapter 2** Provisional chapter

#### **Visceral Leishmaniasis** Visceral Leishmaniasis

Sujit K. Bhattacharya, Ajanta Ghosal, Sudeshna Ganguly, Sandipan Ganguly, Sabahat Azim and Shanta Dutta Sujit K. Bhattacharya, Ajanta Ghosal, Sudeshna Ganguly, Sandipan Ganguly, Sabahat Azim and Shanta Dutta

Additional information is available at the end of the chapter Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/intechopen.75907

#### Abstract

Clinically, leishmaniasis is of three types—visceral leishmaniasis (VL) or kala-azar, cutaneous leishmaniasis (CL) and mucocutaneous leishmaniasis (MCL). Post-kala-azar dermal leishmaniasis (PKDL) is considered as a complication of VL. VL is characterized by fever, anemia and splenomegaly in a VL-endemic area (malaria excluded). A subject with such symptoms should be subjected to an rK39 strip test. Confirmation of diagnosis is made by demonstration of the parasite (Leishmania donovani) from samples obtained by aspiration of bone marrow or iliac crest puncture. Miltefosine, stibogluconate, amphotericin B, liposomal amphotericin B and paromomycin are effective available anti-leishmaniasis drugs. Vector (Phleblotomus argentipes) control for reduction of transmission and early diagnosis and complete treatment are essential elements of case management. There is no effective vaccine against VL. This review on VL aims at providing state-art knowledge on epidemiology, diagnosis and case-management and vaccine development.

DOI: 10.5772/intechopen.75907

Keywords: leishmaniasis, PKDL, rK39 strip test, kala-azar vaccine

### 1. Introduction

The distinct clinical forms of leishmaniasis are visceral leishmaniasis (VL), cutaneous leishmaniasis (CL) and mucocutaneous leishmaniasis (MCL). PKDL is considered to be a complication of VL. Kala-azar is a neglected tropical disease (NTD). It affects the poorest of the poor living in endemic areas. Post-kala-azar dermal leishmaniasis (PKDL) is associated with stigma. Fortunately, it is not difficult to diagnose the disease and several drugs are available for treatment of the disease.

© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and eproduction in any medium, provided the original work is properly cited. © 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

#### 1.1. VL

VL is prevalent in 88 countries, and there is an estimated 2 million new cases per year, of which 5,00,000 are VL and 15,00,000 are CL. The disease burden is calculated at 23,57,000 disabilityadjusted life years, a significant ranking among communicable diseases [1]. More than 147 million people living in the Southeast Asia Region are at risk. In this region, the highest disease burden is seen in the northern part of the state of Bihar, India. A large number of VL cases are seen in the international cross-border areas between the countries. In view of this, cross-border collaboration is crucial for elimination of the disease [2]. VL prevails mostly among poor people in marginalized communities. It attacks the internal organs and can be fatal if left untreated as it affects the vital organs of the body. Symptoms include irregular bouts of fever, weight loss, enlargements of the spleen and liver and anemia. All patients diagnosed to be VL require prompt and complete specific medical treatment; otherwise, the patient may die.

1.4. Diagnosis

performed in special laboratories.

teratogenic and should not be given to pregnant mothers.

2. Management

2.1.1. Miltefosine

2.1.2. Paromomycin

2.1. Management of VL

Clinical features like prolonged fever (>14 days), anaemia and splenomegaly (malaria excluded) in a kala-azar-endemic area will constitute a suspect case. This can be supported by an rK39 strip test. Accurate VL diagnosis till 1990 required parasitological confirmation by microscopy or culture of the blood, bone marrow, lymph nodes or spleen. Splenic aspirate was sometimes fatal and this prompted development of rapid diagnostic tests (RDTs). An RK39 test had a sensitivity of 72.1% and a specificity of 76.9% and DAT sensitivity was 62.8% and its specificity was 69.2%, using initial diagnosis (confirmed on clinical and serological basis) as reference in both cases. Both rK39 and DAT have the potential in diagnosing VL using urine [9]. A polymerase chain reaction test (PCR) to detect the DNA is highly reliable and can be

Visceral Leishmaniasis

19

http://dx.doi.org/10.5772/intechopen.75907

This is the first ever oral drug developed against VL. Initially the drug was used in the treatment of skin metastases from breast cancer. Subsequently, it was found to be effective in vitro against the Leishmania donovani parasite [9]. Phase I–Phase III clinical trials conducted in India demonstrated that the drug was effective against VL to the extent of ~95% [10–12]. Most of the side-effects included nausea, vomiting, abdominal pain, diarrhea and fever [11]. These side-effects occur during the first week of treatment. A Phase IV trial was conducted involving 13 centres in Bihar (India). This pivotal trial clearly demonstrated that the drug can be dispensed in the kala-azar elimination programme in the first condition [13]. A few major side-effects that occurred affected the kidney, liver and bone marrow. The dose of the drug is 50 mg 2 times daily after food to avoid gastric irritation for 28 days. In children, the dose is 2.5 mg/kg daily for 28 days [12]. In summer time, these patients are usually dehydrated and they should be rehydrated with ORS or IV fluids depending upon the degree of dehydration. Anemia is very common in such patients. Blood transfusion may be required and should be given. If these simple measures are taken, the patients tolerate the drug better. Miltefosine is

This drug belongs to the group of aminoglycosides. Unlike miltefosine, this drug is administered by intramuscular injections. A full course comprises daily injections (11 mg/kg/day) for 21 days [14, 15]. Although paromomycin is an aminoglycoside, it does not exhibit much ototoxicity or nephrotoxicity. It is safe in pregnancy. The most common adverse effects associated with paromomycin are abdominal cramps, diarrhea, heartburn, nausea and vomiting. Long-term use of paromomycin increases the risk for bacterial or fungal infection. Signs of

#### 1.2. PKDL

PKDL is considered an important long-lasting complication of kala-azar. This is seen in about 1–15% in the Indian subcontinent and in about 60% of treated, partially treated and untreated or active cases of kala-azar in Sudan [3]. The lesions generally appear from 1 to 15–20 years of kala-azar. The typical lesions are most prominently seen in the face (macular, papular and nodular). In contrast to the Indian subcontinent, the nodular lesions generally ulcerate as they grow in Sudan. The macular lesions are sometimes confused with leprosy. Diagnosis is confirmed by demonstration of Leishmania donovani from the tissue obtained from the lesions. A polymerase chain reaction (PCR) test to detect the DNA is highly reliable and can be performed in special laboratories. Treatment is long-term use of sodium stibogluconate (sometimes in combination with rifampicin) [4]. A recent study showed that a 12-week course of miltefosine is safe and effective in the treatment of PKDL [5]. Another study showed that miltefosine 50 mg 3 times daily for 60 days or 50 mg twice daily for 90 days has been shown to be effective [6]. In 2008, Berman remarked that 'Miltefosine is effective and can be recommended for visceral disease in India and in Ethiopia, and for cutaneous disease in Colombia and Bolivia. For unusual forms of disease that require long periods of treatment such as diffuse CL, oral miltefosine is probably the treatment of choice'. In 2006, Simon and Engel remarked that 'Miltefosine is active against most Leishmania species, including those that cause CL'. It has been demonstrated that in 2015 the efficacy of miltefosine has declined. Paromomycin has been shown to be effective against PKDL [7]. Amphotericin B is effective in the treatment of PKDL and several courses, where gaps between the two courses are required.

#### 1.3. CL

CL and MCL are the most common manifestations of leishmaniasis. This is also known as oriental sore. MCL is seen in the tropics and subtropics. The variety of leishmaniasis causes disfigurement. CL is caused by L. tropica and L. major. L. braziliensis causes MCL transmitted by Phleblotomus argentipes, sand fly. A clinical diagnosis should be supported by a PCR test [8].

#### 1.4. Diagnosis

1.1. VL

18 Leishmaniases as Re-emerging Diseases

1.2. PKDL

1.3. CL

VL is prevalent in 88 countries, and there is an estimated 2 million new cases per year, of which 5,00,000 are VL and 15,00,000 are CL. The disease burden is calculated at 23,57,000 disabilityadjusted life years, a significant ranking among communicable diseases [1]. More than 147 million people living in the Southeast Asia Region are at risk. In this region, the highest disease burden is seen in the northern part of the state of Bihar, India. A large number of VL cases are seen in the international cross-border areas between the countries. In view of this, cross-border collaboration is crucial for elimination of the disease [2]. VL prevails mostly among poor people in marginalized communities. It attacks the internal organs and can be fatal if left untreated as it affects the vital organs of the body. Symptoms include irregular bouts of fever, weight loss, enlargements of the spleen and liver and anemia. All patients diagnosed to be VL require prompt and complete specific medical treatment; otherwise, the patient may die.

PKDL is considered an important long-lasting complication of kala-azar. This is seen in about 1–15% in the Indian subcontinent and in about 60% of treated, partially treated and untreated or active cases of kala-azar in Sudan [3]. The lesions generally appear from 1 to 15–20 years of kala-azar. The typical lesions are most prominently seen in the face (macular, papular and nodular). In contrast to the Indian subcontinent, the nodular lesions generally ulcerate as they grow in Sudan. The macular lesions are sometimes confused with leprosy. Diagnosis is confirmed by demonstration of Leishmania donovani from the tissue obtained from the lesions. A polymerase chain reaction (PCR) test to detect the DNA is highly reliable and can be performed in special laboratories. Treatment is long-term use of sodium stibogluconate (sometimes in combination with rifampicin) [4]. A recent study showed that a 12-week course of miltefosine is safe and effective in the treatment of PKDL [5]. Another study showed that miltefosine 50 mg 3 times daily for 60 days or 50 mg twice daily for 90 days has been shown to be effective [6]. In 2008, Berman remarked that 'Miltefosine is effective and can be recommended for visceral disease in India and in Ethiopia, and for cutaneous disease in Colombia and Bolivia. For unusual forms of disease that require long periods of treatment such as diffuse CL, oral miltefosine is probably the treatment of choice'. In 2006, Simon and Engel remarked that 'Miltefosine is active against most Leishmania species, including those that cause CL'. It has been demonstrated that in 2015 the efficacy of miltefosine has declined. Paromomycin has been shown to be effective against PKDL [7]. Amphotericin B is effective in the treatment of PKDL and several courses, where gaps between the two courses are required.

CL and MCL are the most common manifestations of leishmaniasis. This is also known as oriental sore. MCL is seen in the tropics and subtropics. The variety of leishmaniasis causes disfigurement. CL is caused by L. tropica and L. major. L. braziliensis causes MCL transmitted by Phleblotomus argentipes, sand fly. A clinical diagnosis should be supported by a PCR test [8].

Clinical features like prolonged fever (>14 days), anaemia and splenomegaly (malaria excluded) in a kala-azar-endemic area will constitute a suspect case. This can be supported by an rK39 strip test. Accurate VL diagnosis till 1990 required parasitological confirmation by microscopy or culture of the blood, bone marrow, lymph nodes or spleen. Splenic aspirate was sometimes fatal and this prompted development of rapid diagnostic tests (RDTs). An RK39 test had a sensitivity of 72.1% and a specificity of 76.9% and DAT sensitivity was 62.8% and its specificity was 69.2%, using initial diagnosis (confirmed on clinical and serological basis) as reference in both cases. Both rK39 and DAT have the potential in diagnosing VL using urine [9]. A polymerase chain reaction test (PCR) to detect the DNA is highly reliable and can be performed in special laboratories.

## 2. Management

## 2.1. Management of VL

#### 2.1.1. Miltefosine

This is the first ever oral drug developed against VL. Initially the drug was used in the treatment of skin metastases from breast cancer. Subsequently, it was found to be effective in vitro against the Leishmania donovani parasite [9]. Phase I–Phase III clinical trials conducted in India demonstrated that the drug was effective against VL to the extent of ~95% [10–12]. Most of the side-effects included nausea, vomiting, abdominal pain, diarrhea and fever [11]. These side-effects occur during the first week of treatment. A Phase IV trial was conducted involving 13 centres in Bihar (India). This pivotal trial clearly demonstrated that the drug can be dispensed in the kala-azar elimination programme in the first condition [13]. A few major side-effects that occurred affected the kidney, liver and bone marrow. The dose of the drug is 50 mg 2 times daily after food to avoid gastric irritation for 28 days. In children, the dose is 2.5 mg/kg daily for 28 days [12]. In summer time, these patients are usually dehydrated and they should be rehydrated with ORS or IV fluids depending upon the degree of dehydration. Anemia is very common in such patients. Blood transfusion may be required and should be given. If these simple measures are taken, the patients tolerate the drug better. Miltefosine is teratogenic and should not be given to pregnant mothers.

#### 2.1.2. Paromomycin

This drug belongs to the group of aminoglycosides. Unlike miltefosine, this drug is administered by intramuscular injections. A full course comprises daily injections (11 mg/kg/day) for 21 days [14, 15]. Although paromomycin is an aminoglycoside, it does not exhibit much ototoxicity or nephrotoxicity. It is safe in pregnancy. The most common adverse effects associated with paromomycin are abdominal cramps, diarrhea, heartburn, nausea and vomiting. Long-term use of paromomycin increases the risk for bacterial or fungal infection. Signs of overgrowth include white patches in the oral cavities. Other less common adverse events include myasthenia gravis, kidney damage, enterocolitis, malabsorption syndrome, eosinophilia, headache, hearing loss, ringing in the ear, itching, severe dizziness and pancreatitis.

results are encouraging [26]. Sitamaquine interacts with phospholipids and accumulates rapidly in the Leishmania. An advantage of sitamaquine is its short elimination half-life, preventing

Visceral Leishmaniasis

21

http://dx.doi.org/10.5772/intechopen.75907

In view of the drug resistance and toxicity [27], it was expected that using the combination of two drugs will prevent or delay appearance of drug resistance, minimize toxicity, enhance efficacy and shorten duration of therapy. A safety and efficacy trial of combinations were

All the combinations were non-inferior to the standard treatment with liposomal amphotericin B in usual doses. The combination therapy efficacy of all the regimens was ~95%. It was recommended that combination therapy would be an alternative to liposomal amphotericin B (10 mg/kg) in the context of kala-azar elimination programme in the Indian subcontinent.

Vector control is of paramount importance in combating VL. When malaria control programme was carried out in India, as a collateral benefit, the incidence of kala-azar came down. In India, generally DDT is used for vector control but in Bangladesh and Nepal, synthetic pyrithroids are used. The exact role of long-lasting net (LLN) or long-lasting impreg-

Keeping in view the high disease burden in India, Nepal and Bangladesh and availability of effective tools to diagnose the disease in the field situation and the effective and safe drug to treat the disease in an outpatient setting, the three countries embarked on eliminating the dreaded disease. In 2005, a memorandum of understanding was signed by India, Nepal and Bangladesh under the auspices of World Health Organization to cooperate and collaborate with each other to eliminate the disease from their respective countries. The target of elimination was less than 1 case per 10,000 people in an endemic area. Three countries of the WHO's Southeast Asian Region —Bangladesh, India and Nepal—are poised to eliminate VL (kala-azar) as a public health problem. The number of cases have reduced by 53%, from a high of 1,82,000 cases during 2005– 2008 to 85,000 cases during 2011–2014. The 10,209 new cases reported in 2014 represent a 75%

2. single dose of Liposomal amphotericin B (day 1) with miltefosine (day 2–8)

3. single dose of liposomal amphotericin B (day 1) with paromomycin (day 2–11)

a rapid emergence of resistance.

conducted in Bangladesh [28].

3. Vector control

nated nets (LLIN) is not completely clear [29].

4. Elimination of kala-azar from Southeast Asian region

1. Liposomal amphotericin B alone or a combination of:

4. combinations of miltefosine with paromomycin (day 1–10)

2.1.8. Combination therapy

## 2.1.3. Amphotericin B

This is an anti-fungal drug and has substantial activity against Leishmania donovani. When resistance to stibogluconate becomes high, amphotericin B became the first-line drug in many places. The dose is 15 alternate-day infusions of 1 mg/kg over 30 days (total dose, 15 mg/kg) or daily treatment with 1 mg/kg for 20 days (total dose, 20 mg/kg). The most common side-effects are chill, rigor and fever. Injection of antihistamine alleviates the symptoms. The drug exhibits nephrotoxicity and ototoxicity [16–18].

## 2.1.4. Liposomal amphotericin B

Liposomal amphotericin B is safer than amphotericin B and safest among all anti-VL drugs. It is given by intravenous infusion. The dose is 5 mg/kg 3 days or 3 mg/ kg 5 days. A single dose of 10 mg/kg has shown a cure rate of more than 95%. Liposomal amphotericin B replaced miltefosine as the first-line drug in the kala-azar elimination programme [19–21]. However, it is felt that this decision to switch over from miltefosine to liposomal amphotericin B could have been delayed as the programme was going on smoothly using miltefosine as the first-line drug.

## 2.1.5. Sodium stibogluconate

For more than last 6 decades, sodium stibogluconate was the effective drug treatment for visceral leishmaniasis and PKDL. The dose is 20 mg/kg/day given by intramuscular injection for 30 days [22]. Afterwards, the parasites developed resistance to the drug and it became ineffective. In order to overcome the drug resistance, the dose of the drug was increased but the cardiotoxicity of the drug increased. In Bihar, India, currently, the drug resistance is to the tune of 60% [23]. However, the drug is still used in places where the parasites are sensitive to the drug [24]. It can be given by both intramuscular and intravenous routes. The intramuscular injections are painful.

## 2.1.6. Urea stibamine

Urea stibamine was an effective anti-leishmanial drug. Since the developer did not keep any record of the compound, the drug had its natural death [25].

### 2.1.7. Anti-fungal agents

Anti-fungal agents like ketoconazole and anti-tuberculosis drugs were not found effective in the treatment of VL. However, both ketoconazole and pentostam were more effective than placebo against L. braziliensis panamensis cutaneous leishmaniasis. Oral ketoconazole is comparable in efficacy to this parenteral pentostam regimen and can be recommended as initial treatment for this disease. Sitamaquine is undergoing clinical trial for VL treatment and initial results are encouraging [26]. Sitamaquine interacts with phospholipids and accumulates rapidly in the Leishmania. An advantage of sitamaquine is its short elimination half-life, preventing a rapid emergence of resistance.

## 2.1.8. Combination therapy

overgrowth include white patches in the oral cavities. Other less common adverse events include myasthenia gravis, kidney damage, enterocolitis, malabsorption syndrome, eosinophilia, headache, hearing loss, ringing in the ear, itching, severe dizziness and pancreatitis.

This is an anti-fungal drug and has substantial activity against Leishmania donovani. When resistance to stibogluconate becomes high, amphotericin B became the first-line drug in many places. The dose is 15 alternate-day infusions of 1 mg/kg over 30 days (total dose, 15 mg/kg) or daily treatment with 1 mg/kg for 20 days (total dose, 20 mg/kg). The most common side-effects are chill, rigor and fever. Injection of antihistamine alleviates the symptoms. The drug exhibits

Liposomal amphotericin B is safer than amphotericin B and safest among all anti-VL drugs. It is given by intravenous infusion. The dose is 5 mg/kg 3 days or 3 mg/ kg 5 days. A single dose of 10 mg/kg has shown a cure rate of more than 95%. Liposomal amphotericin B replaced miltefosine as the first-line drug in the kala-azar elimination programme [19–21]. However, it is felt that this decision to switch over from miltefosine to liposomal amphotericin B could have been delayed as the programme was going on smoothly using miltefosine as the first-line

For more than last 6 decades, sodium stibogluconate was the effective drug treatment for visceral leishmaniasis and PKDL. The dose is 20 mg/kg/day given by intramuscular injection for 30 days [22]. Afterwards, the parasites developed resistance to the drug and it became ineffective. In order to overcome the drug resistance, the dose of the drug was increased but the cardiotoxicity of the drug increased. In Bihar, India, currently, the drug resistance is to the tune of 60% [23]. However, the drug is still used in places where the parasites are sensitive to the drug [24]. It can be given by both intramuscular and intravenous routes. The intramuscular

Urea stibamine was an effective anti-leishmanial drug. Since the developer did not keep any

Anti-fungal agents like ketoconazole and anti-tuberculosis drugs were not found effective in the treatment of VL. However, both ketoconazole and pentostam were more effective than placebo against L. braziliensis panamensis cutaneous leishmaniasis. Oral ketoconazole is comparable in efficacy to this parenteral pentostam regimen and can be recommended as initial treatment for this disease. Sitamaquine is undergoing clinical trial for VL treatment and initial

record of the compound, the drug had its natural death [25].

2.1.3. Amphotericin B

20 Leishmaniases as Re-emerging Diseases

nephrotoxicity and ototoxicity [16–18].

2.1.4. Liposomal amphotericin B

2.1.5. Sodium stibogluconate

injections are painful.

2.1.6. Urea stibamine

2.1.7. Anti-fungal agents

drug.

In view of the drug resistance and toxicity [27], it was expected that using the combination of two drugs will prevent or delay appearance of drug resistance, minimize toxicity, enhance efficacy and shorten duration of therapy. A safety and efficacy trial of combinations were conducted in Bangladesh [28].

All the combinations were non-inferior to the standard treatment with liposomal amphotericin B in usual doses. The combination therapy efficacy of all the regimens was ~95%. It was recommended that combination therapy would be an alternative to liposomal amphotericin B (10 mg/kg) in the context of kala-azar elimination programme in the Indian subcontinent.

## 3. Vector control

Vector control is of paramount importance in combating VL. When malaria control programme was carried out in India, as a collateral benefit, the incidence of kala-azar came down. In India, generally DDT is used for vector control but in Bangladesh and Nepal, synthetic pyrithroids are used. The exact role of long-lasting net (LLN) or long-lasting impregnated nets (LLIN) is not completely clear [29].

## 4. Elimination of kala-azar from Southeast Asian region

Keeping in view the high disease burden in India, Nepal and Bangladesh and availability of effective tools to diagnose the disease in the field situation and the effective and safe drug to treat the disease in an outpatient setting, the three countries embarked on eliminating the dreaded disease. In 2005, a memorandum of understanding was signed by India, Nepal and Bangladesh under the auspices of World Health Organization to cooperate and collaborate with each other to eliminate the disease from their respective countries. The target of elimination was less than 1 case per 10,000 people in an endemic area. Three countries of the WHO's Southeast Asian Region —Bangladesh, India and Nepal—are poised to eliminate VL (kala-azar) as a public health problem. The number of cases have reduced by 53%, from a high of 1,82,000 cases during 2005– 2008 to 85,000 cases during 2011–2014. The 10,209 new cases reported in 2014 represent a 75%

decrease from 2005 when the kala-azar elimination programme was launched. In fact, Nepal has already achieved elimination and sustained for 2 years. Bangladesh is approaching fast towards elimination and India is expected to catch up [30–32].

essentially to interrupt transmission of the parasite. The WHO HQ and WHO regional office of the Southeast Asian Region extended formidable technical support to the programme. The role

, Sudeshna Ganguly1

[1] WHO/Department of Control of Neglected Tropical Diseases. Global leishmaniasis update, 2006–2015: A turning point in leishmaniasis surveillance. Weekly Epidemiologi-

[2] WHO. South-East Asia poised to defeat visceral leishmaniasis (kala-azar). 2015. Available from: http://www.who.int/neglected\_diseases/news/SEARO\_poised\_to\_defeat\_VL/en /

[3] Desjeux P, Ghosh RS, Dhalaria P, Strub-Wourgaft N, Zijlstra E. Report of the post kalaazar dermal Leishmaniasis (PKDL) consortium meeting, New Delhi, India, 27–29 June

[4] Musa AM, Khalil EAG, Younis BM, Elfaki MEE, Elamin MY, Adam AOA, Mohamed HAA, Dafalla MMM, Abuzaid AA, El-Hassan AM. Treatment-based strategy for the management of post-kala-azar dermal leishmaniasis patients in the Sudan. Journal of

[5] Sundar S, Singh A, Chakravarty J, Rai M. Efficacy and safety of Miltefosine in treatment of post-kala-azar dermal Leishmaniasis. The Scientific World Journal. 2015;2015:1-6. Arti-

[6] Sundar S, Singh A, Tiwari A, Shukla S, Chakravarty J, Rai M. Efficacy and safety of paromomycin in treatment of post-kala-azar dermal Leishmaniasis. ISRN Parasitology.

[7] Ramesh V, Singh R, Kumar A, Verma A, Deep DK, Verma S, Salotra P, Chatterjee M. Decline in clinical efficacy of oral miltefosine in treatment of post kala-azar dermal leishmaniasis (PKDL) in India. PLoS Neglected Tropical Diseases. 2015;9(10):1-12. DOI:

Tropical Medicine. 2013;2013:1-5. Article ID: 708391. DOI: 10.1155/2013/708391

2012. Parasites & Vectors. 2013;6:196. DOI: 10.1186/1756-3305-6-196

2014;2014:1-4. Article ID: 548010. DOI: 10.1155/2014/548010

, Sandipan Ganguly2

,

Visceral Leishmaniasis

23

http://dx.doi.org/10.5772/intechopen.75907

played by international agencies is unforgettable.

\*, Ajanta Ghosal2

\*Address all correspondence to<EMAIL_ADDRESS>
2 National Institute of Cholera and Enteric Diseases, Kolkata, India

1 Glocal Healthcare Systems Pvt. Ltd, Kolkata, India

Author details

References

Sujit K. Bhattacharya1

Sabahat Azim2 and Shanta Dutta1

cal Record. 2017;92:557-572

cle ID: 414378. DOI: 10.1155/2015/414378

10.1371/journal.pntd.0004093

## 5. Kala-azar vaccine

Conceptually, it is ideal to have a vaccine which will provide long-lasting immunity and simultaneously protect against VL and CL. Vaccines against VL and CL should be costeffective. Currently, there are no effective and safe vaccines against VL but several are in various stages of developments. These candidate vaccines should be able to elicit balanced TH1- and TH2-mediated immune response. In view of safety concerns, live-oral vaccines are no longer recommended. The approach now is to insert a suicidal killed vector directly into the leishmania genome.

Research into first-generation vaccines based on whole-cell, killed leishmania parasites demonstrated that killed parasites showed efficacy as both therapeutic and prophylactic vaccines. Numerous preparations of killed parasites were tested. Although they showed good safety profiles, no first-generation vaccine using killed parasites has been demonstrated having sufficient efficacy as a prophylactic vaccine. The second generation of vaccines exploits the subunit, recombinant protein approach utilizing to augment the immune response. Thirdgeneration vaccines derived from antigen-encoding DNA plasmids including heterologous prime-boost Leishmania vaccine have been examined for control and prevention of visceral leishmaniasis [33–35]. Vaccines based on recombinant protein and antigen-encoding DNA plasmids have given promising results.

## 6. HIV/kala-azar

Kala-azar patients may acquire HIV infection. Both the diseases lower the immunity of the person and opportunistic infections supervene. These patients easily acquire cryptosporidial infection and they respond to paromomycin. Tuberculosis is also common in these patients. Treatment of the three diseases requires a large number of drugs and may cause drug-drug interactions [36].

## 7. Concluding remarks

VL is potentially a life-threatening disease affecting the poorest of the poor in several regions of the world. There was a dearth of drugs, diagnostics and vector control methods until recently. The active collaboration of the scientists of the three countries joined by several other national and international agencies was the culmination of reliable diagnostics, drugs and vector control methods to diagnose and treat the disease. The third arm is vector control which is essentially to interrupt transmission of the parasite. The WHO HQ and WHO regional office of the Southeast Asian Region extended formidable technical support to the programme. The role played by international agencies is unforgettable.

## Author details

decrease from 2005 when the kala-azar elimination programme was launched. In fact, Nepal has already achieved elimination and sustained for 2 years. Bangladesh is approaching fast towards

Conceptually, it is ideal to have a vaccine which will provide long-lasting immunity and simultaneously protect against VL and CL. Vaccines against VL and CL should be costeffective. Currently, there are no effective and safe vaccines against VL but several are in various stages of developments. These candidate vaccines should be able to elicit balanced TH1- and TH2-mediated immune response. In view of safety concerns, live-oral vaccines are no longer recommended. The approach now is to insert a suicidal killed vector directly into

Research into first-generation vaccines based on whole-cell, killed leishmania parasites demonstrated that killed parasites showed efficacy as both therapeutic and prophylactic vaccines. Numerous preparations of killed parasites were tested. Although they showed good safety profiles, no first-generation vaccine using killed parasites has been demonstrated having sufficient efficacy as a prophylactic vaccine. The second generation of vaccines exploits the subunit, recombinant protein approach utilizing to augment the immune response. Thirdgeneration vaccines derived from antigen-encoding DNA plasmids including heterologous prime-boost Leishmania vaccine have been examined for control and prevention of visceral leishmaniasis [33–35]. Vaccines based on recombinant protein and antigen-encoding DNA

Kala-azar patients may acquire HIV infection. Both the diseases lower the immunity of the person and opportunistic infections supervene. These patients easily acquire cryptosporidial infection and they respond to paromomycin. Tuberculosis is also common in these patients. Treatment of the three diseases requires a large number of drugs and may cause drug-drug

VL is potentially a life-threatening disease affecting the poorest of the poor in several regions of the world. There was a dearth of drugs, diagnostics and vector control methods until recently. The active collaboration of the scientists of the three countries joined by several other national and international agencies was the culmination of reliable diagnostics, drugs and vector control methods to diagnose and treat the disease. The third arm is vector control which is

elimination and India is expected to catch up [30–32].

5. Kala-azar vaccine

22 Leishmaniases as Re-emerging Diseases

the leishmania genome.

6. HIV/kala-azar

interactions [36].

7. Concluding remarks

plasmids have given promising results.

Sujit K. Bhattacharya1 \*, Ajanta Ghosal2 , Sudeshna Ganguly1 , Sandipan Ganguly2 , Sabahat Azim2 and Shanta Dutta1

\*Address all correspondence to<EMAIL_ADDRESS>

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DOI: 10.4172/2329-891X.1000106

First-in-human trial of ChAd63-KH. PLoS Neglected Tropical Diseases. 2017;11(5):1-24. DOI: 10.1371/journal.pntd.0005527

**Chapter 3**

**Provisional chapter**

**Leishmaniases in West Africa: Past and Current**

**Leishmaniases in West Africa: Past and Current**

DOI: 10.5772/intechopen.77009

Leishmaniases are vector-borne diseases. Cutaneous leishmaniasis (CL) is endemic in West Africa. Sporadic and anecdotal cases of visceral leishmaniasis (VL) have been reported in the past. Recent data showed the changing of epidemiology of leishmaniases in West Africa, with the occurrence of outbreak of CL due to *Leishmania major* in urban and rural areas. CL is transmitted by *Phlebotomus duboscqi.* The role of *Sergentomyia (Spelaeomyia) darlingi* as vector in rural areas has been evoked but not confirmed. Cases of VL due to *Leishmania spp.* have been described in West Africa; however, parasites species were not identified and dogs were suspected to be the reservoir. No humans' case of symptomatic VL due to *L. infantum* has been described in West Africa. Recent data in rural areas of Senegal confirmed dog as reservoir of *L. infantum.* In the same study in Senegal, *Sergentomyia* sandflies were found infected with *L. infantum*, indicating a possible role in leishmaniasis transmission. Coinfection leishmaniases-HIV is reported but rare. In this chapter, we included most recent publications and propose an updated

Leishmaniases are anthropozoonoses common in animals and humans. Leishmaniases are endemics in 98 countries. The annual incidence is 0.7–1.2 million cases of cutaneous leishmaniasis (CL) and 0.2–0.4 million of cases of visceral leishmaniasis (VL) causing 20,000–40,000 deaths annually [1]. In sub-Saharan African region, the estimated annual incidence of CL was between 770 and 1500 cases. *Leishmania* parasites are characterized by their enzyme electrophoretic profile that defines zymodemes. *L. major* is the main parasite causing CL and its

> © 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

© 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use,

distribution, and reproduction in any medium, provided the original work is properly cited.

Abdoulaye Kassoum Kone, Mahamadou A. Thera,

Abdoulaye Kassoum Kone, Mahamadou A. Thera,

landscape of CL and VL epidemiology in West Africa. **Keywords:** leishmaniases, epidemiology, West Africa

Babacar Faye and Ogobara K. Doumbo†

Babacar Faye and Ogobara K. Doumbo†

http://dx.doi.org/10.5772/intechopen.77009

**Abstract**

**1. Introduction**

Additional information is available at the end of the chapter

Additional information is available at the end of the chapter

#### **Leishmaniases in West Africa: Past and Current Leishmaniases in West Africa: Past and Current**

DOI: 10.5772/intechopen.77009

Abdoulaye Kassoum Kone, Mahamadou A. Thera, Babacar Faye and Ogobara K. Doumbo† Abdoulaye Kassoum Kone, Mahamadou A. Thera, Babacar Faye and Ogobara K. Doumbo†

Additional information is available at the end of the chapter Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/intechopen.77009

#### **Abstract**

First-in-human trial of ChAd63-KH. PLoS Neglected Tropical Diseases. 2017;11(5):1-24.

[35] Evans KJ, Kedzierski L. Development of vaccines against visceral leishmaniasis. Journal

[36] Burza S, Mahajan R, Sinha PK, van Griensven J, Pandey K, Lima MA, Sanz MG, Sunyoto T, Kumar S, Mitra G, Kumar R, Verma N, Das P. Visceral Leishmaniasis and HIV co-infection in Bihar, India: Long-term effectiveness and treatment outcomes with liposomal amphotericin B (AmBisome). PLOS Neglected Tropical Diseases. 2014;8(8):

of Tropical Medicine. 2012;2012. http://dx.doi.org/10.1155/2012/892817

DOI: 10.1371/journal.pntd.0005527

26 Leishmaniases as Re-emerging Diseases

e3053. DOI: 10.1371/journal.pntd.0003053

Leishmaniases are vector-borne diseases. Cutaneous leishmaniasis (CL) is endemic in West Africa. Sporadic and anecdotal cases of visceral leishmaniasis (VL) have been reported in the past. Recent data showed the changing of epidemiology of leishmaniases in West Africa, with the occurrence of outbreak of CL due to *Leishmania major* in urban and rural areas. CL is transmitted by *Phlebotomus duboscqi.* The role of *Sergentomyia (Spelaeomyia) darlingi* as vector in rural areas has been evoked but not confirmed. Cases of VL due to *Leishmania spp.* have been described in West Africa; however, parasites species were not identified and dogs were suspected to be the reservoir. No humans' case of symptomatic VL due to *L. infantum* has been described in West Africa. Recent data in rural areas of Senegal confirmed dog as reservoir of *L. infantum.* In the same study in Senegal, *Sergentomyia* sandflies were found infected with *L. infantum*, indicating a possible role in leishmaniasis transmission. Coinfection leishmaniases-HIV is reported but rare. In this chapter, we included most recent publications and propose an updated landscape of CL and VL epidemiology in West Africa.

**Keywords:** leishmaniases, epidemiology, West Africa

## **1. Introduction**

Leishmaniases are anthropozoonoses common in animals and humans. Leishmaniases are endemics in 98 countries. The annual incidence is 0.7–1.2 million cases of cutaneous leishmaniasis (CL) and 0.2–0.4 million of cases of visceral leishmaniasis (VL) causing 20,000–40,000 deaths annually [1]. In sub-Saharan African region, the estimated annual incidence of CL was between 770 and 1500 cases. *Leishmania* parasites are characterized by their enzyme electrophoretic profile that defines zymodemes. *L. major* is the main parasite causing CL and its

© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

zymodemes MON-26, MON-25, MON-17 and MON-117 have been identified in West Africa [2–4]. CL has been cited earlier as endemic in rural areas. However, outbreaks of CL in urban areas have been recently reported, showing a change in CL epidemiology [5]. VL presents a different epidemiological pattern in West Africa. Previous data described VL as a rare condition, with occurrence of sporadic and anecdotal cases in limited areas [6–8]. Recent data on VL in West Africa showed the occurrence of several cases of canine visceral leishmaniasis and asymptomatic human infections [9–11]. We will describe an updated dynamics of CL and VL characteristics in West Africa.

investigation post-outbreak is conducted to determine the *Leishmania spp*., the vectors and reservoirs involved [5, 29]. In urban areas [30], outbreaks are occurring in larger population. Rapid urbanization is considered as a favoring factor that also makes uneasy out-

Leishmaniases in West Africa: Past and Current http://dx.doi.org/10.5772/intechopen.77009 29

Coinfection CL-HIV is rare in West Africa. In Mali, the frequency of coinfection was 1% [31]. Coinfection CL-HIV has been reported in Burkina Faso and Ghana [32, 33]. In patients with coinfection, diffuse CL, mucosal involvement and bone marrow invasion have been

In West Africa, VL has been described, and previous data have shown the scarcity of disease (**Figure 1**). For several years, anecdotal and sporadic cases of VL were reported. Up to today, the data reviewed identified most of the clinical cases of VL in Ivory Coast and Niger [6–8]. In the Gambia, a case of VL has been reported in humans and in dogs [37, 38]. Underreporting of diseases is a known feature of West African health care system. This is also true for VL. The underreporting of VL in West Africa could be favored by the absence of appropriate biological diagnosis and the absence of specificity of VL clinical symptoms. VL cases may be confounded with others frequent parasitic diseases such as malaria or schistosomiasis. It is also assumed that the parasite strains found in West Africa are less virulent than those found elsewhere (Asia and East Africa). The strain identified in Senegal and likely those in West

**Figure 1.** Modified map of West Africa from map (http://d-maps.com/carte.php?num\_car=36688&lang=fr) and status of leishmaniasis endemicity in West Africa (WHO weekly report 2017) [45]. : Cutaneous leishmaniasis endemic; : Cutaneous leishmaniasis previously reported; : Visceral leishmaniasis endemic; : Visceral leishmaniasis previously

break control.

reported.

reported [16, 34–36].

**2.2. Visceral leishmaniasis**

Africa are coming from Mediterranean basin [39].

## **2. Burden and characteristics**

## **2.1. Cutaneous leishmaniasis**

The overall burden of CL is poorly characterized, due mainly to paucity of data. The frequency of CL in suspected patients was 78.4% in Mali [12], and Niger it was 66.7% [13]. In Burkina Faso, CL was perceived as a public health problem due to occurrence of outbreaks with an average incidence of 0.1% [14] and hospital frequency of 1.1% [15]. In Senegal, the frequency of CL in hospital based study was 38 cases over 4 years (9.5 cases per year) [16].

In Mali, recent positive LST survey showed a higher prevalence (49.9%) in Diema, Kayes region [17]. LST prevalence in Kayes was 25.7% in 1969 [18]. This difference in LST prevalence in the region of Kayes over a period of more than 45 years is likely to indicate an increasing trend in CL transmission.

*L. major* is the main species of *Leishmania* reported in Mali and has been identified in humans as a causative agent of CL [19]. The reservoirs of *L. major* in West Africa are rodents in Senegal. *Mastomys erythrolocus*, *Tatera gambiana* and *Arvicanthis niloticus* were found infected by *L. major* [20, 21]. *Phlebotomus duboscqi* previously was cited as vector of CL. *L. major* DNA was identified recently in *P. duboscqi* confirming its role in CL transmission in Mali [22, 23]. *Sergentomyia (Spelaeomyia) darlingi* may also play a role in *L. major* transmission [22]. Other species of *Leishmania* causing CL such as *L. tropica* has been identified in *S. dissimillima, S. ingrami, S. simillima, S. dissimillima, and S. hamoni* in Ghana [24], but this species has been not identified in humans in West Africa.

Recent findings revealed *L. infantum* in a HIV-positive child suffering from CL in Senegal [25]. A new species of *Leishmania* classified as *Leishmania enrietti* complex was found in humans in Ghana [26]. These findings call to strengthen CL diagnosis and stimulate efforts to determine the causative *Leishmania* species in human infections.

The enzymes electrophoresis analysis identified several strains of *L. major* in West Africa. The most frequent strain in Mali was MON-26 and MON-74 was the more frequent in Burkina Faso [2, 4, 27]. Travelers visiting endemic areas in West Africa are at risk of getting infected with *Leishmania* [28].

In West African countries (**Figure 1**), CL outbreaks may occur in rural areas where health care centers personnel are not well trained for diagnosis or case management. Often, an investigation post-outbreak is conducted to determine the *Leishmania spp*., the vectors and reservoirs involved [5, 29]. In urban areas [30], outbreaks are occurring in larger population. Rapid urbanization is considered as a favoring factor that also makes uneasy outbreak control.

Coinfection CL-HIV is rare in West Africa. In Mali, the frequency of coinfection was 1% [31]. Coinfection CL-HIV has been reported in Burkina Faso and Ghana [32, 33]. In patients with coinfection, diffuse CL, mucosal involvement and bone marrow invasion have been reported [16, 34–36].

## **2.2. Visceral leishmaniasis**

zymodemes MON-26, MON-25, MON-17 and MON-117 have been identified in West Africa [2–4]. CL has been cited earlier as endemic in rural areas. However, outbreaks of CL in urban areas have been recently reported, showing a change in CL epidemiology [5]. VL presents a different epidemiological pattern in West Africa. Previous data described VL as a rare condition, with occurrence of sporadic and anecdotal cases in limited areas [6–8]. Recent data on VL in West Africa showed the occurrence of several cases of canine visceral leishmaniasis and asymptomatic human infections [9–11]. We will describe an updated dynamics of CL and VL

The overall burden of CL is poorly characterized, due mainly to paucity of data. The frequency of CL in suspected patients was 78.4% in Mali [12], and Niger it was 66.7% [13]. In Burkina Faso, CL was perceived as a public health problem due to occurrence of outbreaks with an average incidence of 0.1% [14] and hospital frequency of 1.1% [15]. In Senegal, the frequency of CL in hospital based study was 38 cases over 4 years (9.5 cases per year) [16]. In Mali, recent positive LST survey showed a higher prevalence (49.9%) in Diema, Kayes region [17]. LST prevalence in Kayes was 25.7% in 1969 [18]. This difference in LST prevalence in the region of Kayes over a period of more than 45 years is likely to indicate an increasing

*L. major* is the main species of *Leishmania* reported in Mali and has been identified in humans as a causative agent of CL [19]. The reservoirs of *L. major* in West Africa are rodents in Senegal. *Mastomys erythrolocus*, *Tatera gambiana* and *Arvicanthis niloticus* were found infected by *L. major* [20, 21]. *Phlebotomus duboscqi* previously was cited as vector of CL. *L. major* DNA was identified recently in *P. duboscqi* confirming its role in CL transmission in Mali [22, 23]. *Sergentomyia (Spelaeomyia) darlingi* may also play a role in *L. major* transmission [22]. Other species of *Leishmania* causing CL such as *L. tropica* has been identified in *S. dissimillima, S. ingrami, S. simillima, S. dissimillima, and S. hamoni* in Ghana [24], but this species has been not

Recent findings revealed *L. infantum* in a HIV-positive child suffering from CL in Senegal [25]. A new species of *Leishmania* classified as *Leishmania enrietti* complex was found in humans in Ghana [26]. These findings call to strengthen CL diagnosis and stimulate efforts to determine

The enzymes electrophoresis analysis identified several strains of *L. major* in West Africa. The most frequent strain in Mali was MON-26 and MON-74 was the more frequent in Burkina Faso [2, 4, 27]. Travelers visiting endemic areas in West Africa are at risk of getting infected

In West African countries (**Figure 1**), CL outbreaks may occur in rural areas where health care centers personnel are not well trained for diagnosis or case management. Often, an

characteristics in West Africa.

28 Leishmaniases as Re-emerging Diseases

**2.1. Cutaneous leishmaniasis**

trend in CL transmission.

identified in humans in West Africa.

with *Leishmania* [28].

the causative *Leishmania* species in human infections.

**2. Burden and characteristics**

In West Africa, VL has been described, and previous data have shown the scarcity of disease (**Figure 1**). For several years, anecdotal and sporadic cases of VL were reported. Up to today, the data reviewed identified most of the clinical cases of VL in Ivory Coast and Niger [6–8]. In the Gambia, a case of VL has been reported in humans and in dogs [37, 38]. Underreporting of diseases is a known feature of West African health care system. This is also true for VL. The underreporting of VL in West Africa could be favored by the absence of appropriate biological diagnosis and the absence of specificity of VL clinical symptoms. VL cases may be confounded with others frequent parasitic diseases such as malaria or schistosomiasis. It is also assumed that the parasite strains found in West Africa are less virulent than those found elsewhere (Asia and East Africa). The strain identified in Senegal and likely those in West Africa are coming from Mediterranean basin [39].

**Figure 1.** Modified map of West Africa from map (http://d-maps.com/carte.php?num\_car=36688&lang=fr) and status of leishmaniasis endemicity in West Africa (WHO weekly report 2017) [45]. : Cutaneous leishmaniasis endemic; : Cutaneous leishmaniasis previously reported; : Visceral leishmaniasis endemic; : Visceral leishmaniasis previously reported.

Parasite species identified in West Africa is *L. infantum* using serology method in asymptomatic Senegalese [11]*. L. donovani* has not yet been identified in West Africa. Cases of VL encountered in Niger and Ivory Coast had their parasite identified by microscopy [6–8]. It is known that microcopy cannot distinguish between *Leishmania* species. For species, diagnosis serology or molecular biology is required.

Africa. A surveillance system based on referral health care centers with training of health care personnel will help to better address clinical and diagnostic challenges imposed by leishmaniasis.

\*, Mahamadou A. Thera1

1 Malaria Research and Training Center, Department of Epidemiology of Parasitic Diseases/

2 Service de Parasitologie-Mycologie, Faculté de Médecine, Université Cheikh Anta DIOP,

[1] Alvar J, Velez ID, Bern C, Herrero M, Desjeux P, Cano J, et al. Leishmaniasis worldwide and global estimates of its incidence. PLoS One. 2012;**7**:e35671. DOI: 10.1371/journal.

[2] Izri MA, Doumbo O, Belazzoug S, Pratlong F. Presence of *Leishmania major* MON-26 in

[3] Garin JP, Peyramond D, Piens MA, Rioux JA, Godfrey DG, Lanotte G, et al. Presence of *Leishmania major* Yakimoff and Schokhor, 1914 in Mali. Enzymatic identification of a strain of human origin. Annales de Parasitologie Humaine et Comparée. 1985;**60**:93-94

[4] Pratlong F, Lami P, Ravel C, Balard Y, Dereure J, Serres G, et al. Geographical distribution and epidemiological features of old world *Leishmania infantum* and *Leishmania donovani* foci, based on the isoenzyme analysis of 2277 strains. Parasitology. 2013;**140**:423-434

[5] Kone AK, Delaunay P, Djimdé AA, Thera MA, Giudice PD, Coulibaly D, Traoré K, Goita SM, Abathina A, Izri A, Marty P, Doumbo OK. Epidemiology of cutaneous leishmaniasis in five villages of Dogon country, Mali. Bulletin De La Societe De Pathologie Exotique. 2012

Mali. Annales de Parasitologie Humaine et Comparée. 1989;**64**:510-511

Faculty of Medicine, and Dentistry/ UMI-3189/ University of Science, Technique and

\*Address all correspondence to<EMAIL_ADDRESS>
Technology of Bamako, BP, Bamako, Mali

, Babacar Faye2

and

Leishmaniases in West Africa: Past and Current http://dx.doi.org/10.5772/intechopen.77009 31

**Conflict of interest**

**Author details**

Dakar, Sénégal

† Deceased

**References**

pone.0035671

Feb;**105**(1):8-15

No conflict of interest declared.

Abdoulaye Kassoum Kone1

Ogobara K. Doumbo1†

Sandflies of the genus *Sergentomyia* (*Se. dubia*, *Se. schwetzi* and *Se. magna*) have been found infected with *L. infantum* in Mont-Roland district in Senegal [40]. This raises the possibility that *Sergentomyia spp.* may be involved in VL transmission in Senegal.

Canine visceral leishmaniasis is well described in West Africa. Recent studies in domestic dogs showed that *L. infantum* was the causal pathogen in Senegal, in Burkina Faso and Nigeria [9, 10, 41].

**Geographic diversity**: the area of transmission could be wider, therefore underestimating the cases of leishmaniasis. In Senegal, previous studies have shown that the vectors *Phlebotomus* or *Sergentomyia* are found in many areas of the country (Kédougou, South East, Keur Moussa in Dakar region, Ferlo area [42]. Environmental changes are risk factors of explosion.

## **3. Management and control**

VL is rarely encountered in West Africa. Most cases of human Leishmaniasis are cutaneous leishmaniasis. Often, CL cases are under-diagnosed, and their clinical management is poorly done. This is particularly true for cases encountered at peripheral health care centers with personnel poorly trained. For those encountered at referral health care facilities with good capacity for the diagnosis, treatment is available. In Mali, CL cases are referred to National Center for Diseases Control [CNAM acronym in French for Centre National d'Appui à Lutte contre la Maladie]. Treatment is done using either meglumine antimoniate locally or local thermotherapy [43]. In Burkina Faso, meglumine antimoniate is the first line treatment [15]. Treatment outcome is favorable with healing of lesions in 2–4 weeks. Treatment response in HIV coinfected patients is also favorable but hampered by the frequency of relapses [44].

In rural areas where these treatments are not available dermatologists advice to clean skin lesions and apply tetracycline ointment until healing [43]. Meglumine antimoniate and amphotericin B have been used to treat VL in West Africa [6–8].

## **4. Conclusion**

Compared to other endemic parts of the world, leishmaniases are not very common in West Africa. CL is widely distributed in few West African countries such as Burkina Faso, Mali, Nigeria and Senegal. Urbanization is the main risk factor. Human VL human is sporadic in few countries. Also, VL affects more domestic dogs. Our review acknowledged the changing of CL epidemiology with more report of outbreaks and description of new parasite species in West Africa. A surveillance system based on referral health care centers with training of health care personnel will help to better address clinical and diagnostic challenges imposed by leishmaniasis.

## **Conflict of interest**

Parasite species identified in West Africa is *L. infantum* using serology method in asymptomatic Senegalese [11]*. L. donovani* has not yet been identified in West Africa. Cases of VL encountered in Niger and Ivory Coast had their parasite identified by microscopy [6–8]. It is known that microcopy cannot distinguish between *Leishmania* species. For species, diagnosis

Sandflies of the genus *Sergentomyia* (*Se. dubia*, *Se. schwetzi* and *Se. magna*) have been found infected with *L. infantum* in Mont-Roland district in Senegal [40]. This raises the possibility

Canine visceral leishmaniasis is well described in West Africa. Recent studies in domestic dogs showed that *L. infantum* was the causal pathogen in Senegal, in Burkina Faso and Nigeria

**Geographic diversity**: the area of transmission could be wider, therefore underestimating the cases of leishmaniasis. In Senegal, previous studies have shown that the vectors *Phlebotomus* or *Sergentomyia* are found in many areas of the country (Kédougou, South East, Keur Moussa

VL is rarely encountered in West Africa. Most cases of human Leishmaniasis are cutaneous leishmaniasis. Often, CL cases are under-diagnosed, and their clinical management is poorly done. This is particularly true for cases encountered at peripheral health care centers with personnel poorly trained. For those encountered at referral health care facilities with good capacity for the diagnosis, treatment is available. In Mali, CL cases are referred to National Center for Diseases Control [CNAM acronym in French for Centre National d'Appui à Lutte contre la Maladie]. Treatment is done using either meglumine antimoniate locally or local thermotherapy [43]. In Burkina Faso, meglumine antimoniate is the first line treatment [15]. Treatment outcome is favorable with healing of lesions in 2–4 weeks. Treatment response in HIV coinfected patients is also favorable but hampered by the fre-

In rural areas where these treatments are not available dermatologists advice to clean skin lesions and apply tetracycline ointment until healing [43]. Meglumine antimoniate and

Compared to other endemic parts of the world, leishmaniases are not very common in West Africa. CL is widely distributed in few West African countries such as Burkina Faso, Mali, Nigeria and Senegal. Urbanization is the main risk factor. Human VL human is sporadic in few countries. Also, VL affects more domestic dogs. Our review acknowledged the changing of CL epidemiology with more report of outbreaks and description of new parasite species in West

amphotericin B have been used to treat VL in West Africa [6–8].

in Dakar region, Ferlo area [42]. Environmental changes are risk factors of explosion.

that *Sergentomyia spp.* may be involved in VL transmission in Senegal.

serology or molecular biology is required.

30 Leishmaniases as Re-emerging Diseases

**3. Management and control**

quency of relapses [44].

**4. Conclusion**

[9, 10, 41].

No conflict of interest declared.

## **Author details**

Abdoulaye Kassoum Kone1 \*, Mahamadou A. Thera1 , Babacar Faye2 and Ogobara K. Doumbo1†

\*Address all correspondence to<EMAIL_ADDRESS>
1 Malaria Research and Training Center, Department of Epidemiology of Parasitic Diseases/ Faculty of Medicine, and Dentistry/ UMI-3189/ University of Science, Technique and Technology of Bamako, BP, Bamako, Mali

2 Service de Parasitologie-Mycologie, Faculté de Médecine, Université Cheikh Anta DIOP, Dakar, Sénégal

† Deceased

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