*4.1.1 Uncommon variants of CL*

Uncommonly, CL variants are encountered that are associated with various underlying immune responses.

*L. recidivans* typically follows a healed *L. tropica* cutaneous infection and presents as new lesions encircling the old scar. The lesions show predominantly

#### **Figure 3.**

*This photograph depicts the volar surface of a patient's extended right arm, who had been ill with leishmaniasis, having been infected with* Leishmania *sp. protozoa, which had manifested itself as a cutaneous form of the disease (courtesy of Centers for Disease Control and Prevention/Dr. martins Castro and Dr. Lucille K. Georg) (https://phil.cdc.gov/Details.aspx?pid=12161).*

#### *Leishmaniasis DOI: http://dx.doi.org/10.5772/intechopen.90680*

Africa. CL is usually a limited cutaneous disease. The lesions develop as papules at the sand fly bite site and progress over weeks to months to develop larger nodules that eventually ulcerate (**Figure 3**). Lesions are often itchy and may have a hyperkeratotic wart-like appearance. These lesions often self-heal in 2–18 months, leaving a permanent, often disfiguring, scar, leading to major cosmetic concern and social stigma. Approximately 10% of CL cases may progress to severe disease such as diffuse

Uncommonly, CL variants are encountered that are associated with various

*L. recidivans* typically follows a healed *L. tropica* cutaneous infection and pre-

*This photograph depicts the volar surface of a patient's extended right arm, who had been ill with leishmaniasis, having been infected with* Leishmania *sp. protozoa, which had manifested itself as a cutaneous form of the disease (courtesy of Centers for Disease Control and Prevention/Dr. martins Castro and Dr. Lucille K. Georg)*

sents as new lesions encircling the old scar. The lesions show predominantly

CL, ML, disseminated CL, and/or *L. recidivans* [1, 20].

*4.1.1 Uncommon variants of CL*

*Parasitology and Microbiology Research*

underlying immune responses.

**Figure 3.**

**302**

*(https://phil.cdc.gov/Details.aspx?pid=12161).*

increased number of lymphocytes making it difficult to histologically distinguish from tuberculosis.

*Diffuse cutaneous leishmaniasis* presents with multiple widespread nontender, non-ulcerating lesions, resembling lepromatous leprosy, and a negative leishmanin skin test (LST). The skin is heavily infiltrated by organisms and the patients lack a cellular immune response. These are caused *by L. amazonensis, L. aethiopica, and L. mexicana.*

*Disseminated cutaneous leishmaniasis* presents with 10 or more mixed-type lesions in multiple body parts and is mostly seen in Latin America with frequent involvement of the mucosa. Histologically, the organisms are scant in the skin lesions, and patients show positive antibodies against *Leishmania* and positive LST test.

Most cases of diffuse cutaneous leishmaniasis and *L. recidivans* are chronic and resistant to treatment, may be exceedingly disfiguring, and can be associated with low mortality rates.

*L. infantum/L. chagasi* predominantly causes VL; however, it may lead to atypical cutaneous disease. Reported cases are autochthonous, seen in immunocompetent hosts, and diagnosed in different regions [19].

L. donovani is also mainly responsible for VL; however, some atypical autochthonous CL cases by *L. donovani* are reported [19].

## **4.2 Mucocutaneous leishmaniasis**

ML presents as destructive lesions involving oronasal mucosa with involvement of the nasal septum, lips, and palate. Ninety percent of ML cases show a previous CL scar. The disease is often chronic and progressive with destructive, disfiguring midfacial lesions leading to extensive mutilation. Secondary infection and respiratory tract invasion may lead to patient's demise. It is frequently seen in immunocompromised individuals and being a potentially life-threatening disease requires immediate/early diagnosis and treatment [21, 22]. Less than 5% of patients infected by *L. braziliensis* and a small percent of those infected by *L. panamensis* and *L. guyanensis* can develop mucosal involvement months to years after cutaneous disease resolution [13].

#### **4.3 Visceral leishmaniasis**

*L. donovani* is the main species causing VL and humans are the main reservoir for it. *L. infantum* also causes visceral disease; however, it is zoonotic. VL is characterized by a "pentad" of persistent irregular fever, hepatosplenomegaly, weight loss, pancytopenia, and hypergammaglobulinemia. The fever characteristically shows a double rise in 24 hours with spikes of fever and afebrile intervals in between. It is the most devastating and fatal forms of leishmaniasis. The spectrum ranges from asymptomatic infection to fulminant life-threatening disease. The disease may present with an acute or insidious onset, however the typical presentation is that of wasted, thin, cachectic appearance with prominent abdominal distention due to hepatosplenomegaly. Jaundice is considered to be a bad prognostic sign. The incubation period is 2 weeks–8 months. High parasite burden is often associated with malnutrition and wasting in particular in children [23, 24]. VL is often associated with hyperpigmentation of the skin most likely secondary to production of adrenocorticotropic hormones. In such cases it is referred to as kala-azar/black fever [25]. VL, if untreated, is fatal within 2 years; mortality is mostly due to secondary bacterial infection, immunosuppression, hemorrhage due to hematopoietic infiltration, and severe anemia [13].

#### *4.3.1 Uncommon variants of VL*

*Gulf War soldiers*: An uncommon form of VL is described in some US veterans who were infected while participating in Gulf war. These patients had only mild symptoms and light parasitic burden*. L. tropica* was identified as the causative agent in some of these cases [19, 26].

*Viscerotropic leishmaniasis*: This is an indolent form of disease that has a distinct clinical presentation; however it does not progress to or develop classic VL.

*VL-HIV coinfection*: HIV is considered to be responsible for the re-emergence of the VL. Both organisms share common pathologic immunologic system involving the reticular endothelial system, therefore leading to accelerated progression of the disease. VL in an HIV-infected person should be considered an acquired immune deficiency syndrome (AIDS)-defining illness, and HIV testing should be mandatory in all patients presenting with VL [1, 27]. Atypical disseminated leishmaniasis can be seen in these patients with lesions involving the gastrointestinal tract and the respiratory tract [21, 28].

L. tropica*, L. amazonensis, and* L. major generally associated with CL are reported to be viscerotropic and uncommonly may lead to visceral disease [19].

#### **4.4 Post-kala-azar dermal leishmaniasis**

PKDL was commonly seen in India and Africa as a late complication of VL secondary to *L. donovani* and rarely *L. infantum,* the latter typically in immunocompromised patients [29]. Patients often present months to as many as 20 years after VL with hypopigmented or erythematous skin lesions which over time progress to develop plaques and nodules over the face and trunk. These lesions are often nontender and have preserved sensation, a feature distinguishing this from lepromatous leprosy. The lesions often resolves spontaneously; however, relapse is common, and resistant forms to antimonial treatment have been reported [1, 13].

prominent cell-mediated immunity to the organism, especially when long-standing, isolation, identification, and culture of these organisms can be extremely challenging. In cutaneous disease the organism may be visualized in samples obtained by biopsy, scraping, or FNA in approximately 70% of cases, while the culture from the

*This photomicrograph of a subcutaneous tissue sample reveals the presence of numerous* Leishmania donovani *parasites (courtesy of Centers for Disease Control and Prevention/Dr. Martin D. Hicklin) (https://phil.cdc.gov/*

A skin punch biopsy is recommended for the CL to be taken from the raised edge of an active lesion where parasites exist. In addition to the formalin-fixed sections, touch preparations/tissue impression slides can also be prepared and examined. The diagnostic finding is to identify the amastigotes with their eosinophilic rod-like cytoplasmic kinetoplast (**Figures 5** and **6**). In long-standing lesions, biopsy of the necrotic center of the lesion, and cases with low burden disease, the biopsy may

Mucosal biopsies and/or dental scrapings are used for mucocutaneous lesions to

Invasive procedures such as aspirates or biopsies from the spleen, bone marrow,

Leishmanin skin test/Montenegro skin test, similar to purified protein derivative

(PPD) test used for *Mycobacterium tuberculosis*, is a marker of cellular immune response and tests for delayed-type hypersensitivity reaction. The test uses injection of killed promastigotes in the skin. If there is a skin induration of at least 5 mm after 48–72 hours, the test is considered positive. The test is negative in acute infection as it shows positive results after 2–3 months of infection. In addition the test is negative in active VL and immunosuppressed patients due to anergic response. In the United States, no skin tests for leishmaniasis are approved because of lack of standardization; however, it is used in developing countries and is useful in epide-

miological surveys as a marker of previous exposure [1].

advancement and development of rapid diagnostic tests (RDT) such as recombinant K39 assay with its high sensitivity and specificity made the above invasive procedures unnecessary. In general, the positivity rate for identification of amastigotes in splenic aspirate is 98% and in bone marrow aspirate/biopsy is 54–86% [31, 32]. Blood samples, except in HIV-infected patients, and lymph nodes have lower

lymph node, and/or liver were used to diagnose VL. However, technology

skin shows only 40% sensitivity [13, 30].

show false-negative results.

look for organisms.

**Figure 4.**

*Leishmaniasis*

*DOI: http://dx.doi.org/10.5772/intechopen.90680*

*Details.aspx?pid=330).*

sensitivity.

**305**

### **5. Diagnosis**

Centers for Disease Control and Prevention (CDC) has a practical guide for laboratory diagnosis of leishmaniasis at http://www.cdc.gov/parasites/leishmania sis/health\_professionals/index [18].

Cutaneous and mucocutaneous lesions usually show normal values in routine laboratory testing. VL, on the other hand, may exhibit normocytic normochromic anemia, leukopenia, and/or thrombocytopenia due to bone marrow or spleen involvement. In addition there may be involvement of other organs leading to their respective abnormal functions such as abnormal liver function test in patients with significant hepatic disease.

Characteristically the diagnosis is confirmed by visualizing the amastigote form of the protozoa from infected tissue by performing invasive procedure such as dermal scraping or biopsies for cutaneous lesions and/or fine-needle aspirates/ biopsies for visceral disease (**Figure 4**). The smears are often stained with Giemsa, Leishman, and/or Wright's stain and slides reviewed under oil immersion. Historically, splenic puncture was considered the most sensitive method and golden standard procedure; however it is potentially life-threatening, carries a high risk of complications such as hemorrhage, and therefore currently is considered unnecessary. In endemic areas with high clinical suspicion, clinical history and physical examination is often sufficient to reach the diagnosis. Since the localized disease has

#### **Figure 4.**

*4.3.1 Uncommon variants of VL*

*Parasitology and Microbiology Research*

in some of these cases [19, 26].

respiratory tract [21, 28].

been reported [1, 13].

sis/health\_professionals/index [18].

significant hepatic disease.

**5. Diagnosis**

**304**

**4.4 Post-kala-azar dermal leishmaniasis**

*Gulf War soldiers*: An uncommon form of VL is described in some US veterans who were infected while participating in Gulf war. These patients had only mild symptoms and light parasitic burden*. L. tropica* was identified as the causative agent

*Viscerotropic leishmaniasis*: This is an indolent form of disease that has a distinct

*VL-HIV coinfection*: HIV is considered to be responsible for the re-emergence of the VL. Both organisms share common pathologic immunologic system involving the reticular endothelial system, therefore leading to accelerated progression of the disease. VL in an HIV-infected person should be considered an acquired immune deficiency syndrome (AIDS)-defining illness, and HIV testing should be mandatory in all patients presenting with VL [1, 27]. Atypical disseminated leishmaniasis can be seen in these patients with lesions involving the gastrointestinal tract and the

clinical presentation; however it does not progress to or develop classic VL.

L. tropica*, L. amazonensis, and* L. major generally associated with CL are reported to be viscerotropic and uncommonly may lead to visceral disease [19].

PKDL was commonly seen in India and Africa as a late complication of VL secondary to *L. donovani* and rarely *L. infantum,* the latter typically in immunocompromised patients [29]. Patients often present months to as many as 20 years after VL with hypopigmented or erythematous skin lesions which over time progress to develop plaques and nodules over the face and trunk. These lesions are often nontender and have preserved sensation, a feature distinguishing this

however, relapse is common, and resistant forms to antimonial treatment have

Centers for Disease Control and Prevention (CDC) has a practical guide for laboratory diagnosis of leishmaniasis at http://www.cdc.gov/parasites/leishmania

Cutaneous and mucocutaneous lesions usually show normal values in routine laboratory testing. VL, on the other hand, may exhibit normocytic normochromic anemia, leukopenia, and/or thrombocytopenia due to bone marrow or spleen involvement. In addition there may be involvement of other organs leading to their respective abnormal functions such as abnormal liver function test in patients with

Characteristically the diagnosis is confirmed by visualizing the amastigote form

of the protozoa from infected tissue by performing invasive procedure such as dermal scraping or biopsies for cutaneous lesions and/or fine-needle aspirates/ biopsies for visceral disease (**Figure 4**). The smears are often stained with Giemsa, Leishman, and/or Wright's stain and slides reviewed under oil immersion. Historically, splenic puncture was considered the most sensitive method and golden standard procedure; however it is potentially life-threatening, carries a high risk of complications such as hemorrhage, and therefore currently is considered unnecessary. In endemic areas with high clinical suspicion, clinical history and physical examination is often sufficient to reach the diagnosis. Since the localized disease has

from lepromatous leprosy. The lesions often resolves spontaneously;

*This photomicrograph of a subcutaneous tissue sample reveals the presence of numerous* Leishmania donovani *parasites (courtesy of Centers for Disease Control and Prevention/Dr. Martin D. Hicklin) (https://phil.cdc.gov/ Details.aspx?pid=330).*

prominent cell-mediated immunity to the organism, especially when long-standing, isolation, identification, and culture of these organisms can be extremely challenging. In cutaneous disease the organism may be visualized in samples obtained by biopsy, scraping, or FNA in approximately 70% of cases, while the culture from the skin shows only 40% sensitivity [13, 30].

A skin punch biopsy is recommended for the CL to be taken from the raised edge of an active lesion where parasites exist. In addition to the formalin-fixed sections, touch preparations/tissue impression slides can also be prepared and examined. The diagnostic finding is to identify the amastigotes with their eosinophilic rod-like cytoplasmic kinetoplast (**Figures 5** and **6**). In long-standing lesions, biopsy of the necrotic center of the lesion, and cases with low burden disease, the biopsy may show false-negative results.

Mucosal biopsies and/or dental scrapings are used for mucocutaneous lesions to look for organisms.

Invasive procedures such as aspirates or biopsies from the spleen, bone marrow, lymph node, and/or liver were used to diagnose VL. However, technology advancement and development of rapid diagnostic tests (RDT) such as recombinant K39 assay with its high sensitivity and specificity made the above invasive procedures unnecessary. In general, the positivity rate for identification of amastigotes in splenic aspirate is 98% and in bone marrow aspirate/biopsy is 54–86% [31, 32]. Blood samples, except in HIV-infected patients, and lymph nodes have lower sensitivity.

Leishmanin skin test/Montenegro skin test, similar to purified protein derivative (PPD) test used for *Mycobacterium tuberculosis*, is a marker of cellular immune response and tests for delayed-type hypersensitivity reaction. The test uses injection of killed promastigotes in the skin. If there is a skin induration of at least 5 mm after 48–72 hours, the test is considered positive. The test is negative in acute infection as it shows positive results after 2–3 months of infection. In addition the test is negative in active VL and immunosuppressed patients due to anergic response. In the United States, no skin tests for leishmaniasis are approved because of lack of standardization; however, it is used in developing countries and is useful in epidemiological surveys as a marker of previous exposure [1].

assay (ELISA), and western blot. Although these tests show high sensitivity for acute VL, they are not specific for this disease and may show false positivity with

Detection of antibodies to recombinant K 39 antigen appears to correlate with active VL disease in species such as *L. donovani, L. chagasi*, and *L. infantum*. These RDTs however are not useful in cutaneous and mucocutaneous infection. Based on a Cochrane review of RDTs, the sensitivity for rK39 RDT assay is excellent at 97% in Indian subcontinent but low in East Africa and Sudan at 85%. More recently, an rK28 antigen-based RDT shows better sensitivity in Sudan [33, 34]. Recent efforts in developing tests that detect antigens show promising results but still with certain limitations; latex agglutination test has moderate sensitivity of 64% and higher specificity of 93%, while most recent ELISA test shows more than 90%

Molecular techniques including polymerase chain reaction (PCR), with significant advances in technology, show higher sensitivity; however, due to the higher cost and complexity of the procedure, they are not available in resource-limited settings. This is particularly true in VL. These tests have a higher sensitivity for cutaneous lesions: reverse transcriptase loop-mediated isothermal amplification

Multiple factors play a role in treatment decision-making for *Leishmania* that include the specific species, geographic location, comorbidities, and the type of disease whether CL, ML, PKLD, or VL. On most part, it is considered as a treatable and curable disease; however it requires an immunocompetent system. Despite multiple efforts and after all these years, the treatment of *Leishmania* still remains a problem. This is mostly because of indiscriminate treatment leading to frequent

emergence of parasite resistance, and the side effects of antileishmanial

been used throughout the history and are still being used as an alternative therapy to conventional health care, in particular in developing countries and mainly in rural areas that are often deprived of public health resources [37]. This

science of using medicinal plants as therapeutic agents is referred to as

promastigotes of *L. donovani* and *L. infantum* [36].

therapeutic agents call for a search for alternative treatment including the use of natural products such as plants and herbs [36]. Traditionally, medicinal plants have

phytotherapy [38]. The alternate therapies, when studied, show different mechanisms of action. Plants have several secondary metabolites, for example, flavonoids, polysaccharides, lactones, alkaloids, diterpenoids, and glycosides that may activate the immunological system [39]. As an example, a combination of miltefosine and nanoparticles of curcumin, a component of turmeric, displayed lymphocyte proliferation and increased the phagocytic capacity of peritoneal macrophages [40]. Another example is tricin which is isolated from *Casearia arborea*, an evergreen tea, that was reported to modulate the respiratory burst, thus helping in parasite

Other mechanisms reported as possible mechanisms of action include reactive oxygen species generation and apoptosis-inducing potential. Examples of the latter include ethanolic extract of seeds and leaves of *Azadirachta indica* and essentials oils of *Artemisia campestris* and *Artemisia herba-alba* that act as an apoptosis inductor in

Several studies have been carried out to assess the efficacy of such alternate treatment; however, the results have not been very encouraging. Most of the plants show immunomodulatory effect, but no leishmanicidal effect has been validated,

(LAMP) technology exhibiting a sensitivity of 98% in CL.

other organisms.

*DOI: http://dx.doi.org/10.5772/intechopen.90680*

*Leishmaniasis*

sensitivity [1, 35].

**6. Treatment**

elimination.

**307**

#### **Figure 5.**

*This photomicrograph depicts some of the histopathologic details seen in a canine bone marrow smear, processed using Giemsa stain, in the case of leishmaniasis. This particular view displays* Leishmania donovani *parasites contained within one of the bone marrow histiocytes (courtesy of Centers for Disease Control and Prevention/Dr. Francis W. Chandler) (https://phil.cdc.gov/Details.aspx?pid=30).*

#### **Figure 6.**

*This is a transmission electron microscopic image of* Leishmania major *amastigotes, which had been grown in a cell culture. Note the dense kinetoplasts in the cytoplasm (courtesy of Centers for Disease Control and Prevention/Cynthia goldsmith and Luciana Flannery) (https://phil.cdc.gov/Details.aspx?pid=22001).*

Several serological assays for detection of antibodies against leishmaniasis have been developed using various techniques such as direct agglutination (DAT), immunofluorescence assay (IFA), enzyme-linked immunosorbent

#### *Leishmaniasis DOI: http://dx.doi.org/10.5772/intechopen.90680*

assay (ELISA), and western blot. Although these tests show high sensitivity for acute VL, they are not specific for this disease and may show false positivity with other organisms.

Detection of antibodies to recombinant K 39 antigen appears to correlate with active VL disease in species such as *L. donovani, L. chagasi*, and *L. infantum*. These RDTs however are not useful in cutaneous and mucocutaneous infection. Based on a Cochrane review of RDTs, the sensitivity for rK39 RDT assay is excellent at 97% in Indian subcontinent but low in East Africa and Sudan at 85%. More recently, an rK28 antigen-based RDT shows better sensitivity in Sudan [33, 34]. Recent efforts in developing tests that detect antigens show promising results but still with certain limitations; latex agglutination test has moderate sensitivity of 64% and higher specificity of 93%, while most recent ELISA test shows more than 90% sensitivity [1, 35].

Molecular techniques including polymerase chain reaction (PCR), with significant advances in technology, show higher sensitivity; however, due to the higher cost and complexity of the procedure, they are not available in resource-limited settings. This is particularly true in VL. These tests have a higher sensitivity for cutaneous lesions: reverse transcriptase loop-mediated isothermal amplification (LAMP) technology exhibiting a sensitivity of 98% in CL.

## **6. Treatment**

Multiple factors play a role in treatment decision-making for *Leishmania* that include the specific species, geographic location, comorbidities, and the type of disease whether CL, ML, PKLD, or VL. On most part, it is considered as a treatable and curable disease; however it requires an immunocompetent system. Despite multiple efforts and after all these years, the treatment of *Leishmania* still remains a problem. This is mostly because of indiscriminate treatment leading to frequent emergence of parasite resistance, and the side effects of antileishmanial therapeutic agents call for a search for alternative treatment including the use of natural products such as plants and herbs [36]. Traditionally, medicinal plants have been used throughout the history and are still being used as an alternative therapy to conventional health care, in particular in developing countries and mainly in rural areas that are often deprived of public health resources [37]. This science of using medicinal plants as therapeutic agents is referred to as phytotherapy [38]. The alternate therapies, when studied, show different mechanisms of action. Plants have several secondary metabolites, for example, flavonoids, polysaccharides, lactones, alkaloids, diterpenoids, and glycosides that may activate the immunological system [39]. As an example, a combination of miltefosine and nanoparticles of curcumin, a component of turmeric, displayed lymphocyte proliferation and increased the phagocytic capacity of peritoneal macrophages [40]. Another example is tricin which is isolated from *Casearia arborea*, an evergreen tea, that was reported to modulate the respiratory burst, thus helping in parasite elimination.

Other mechanisms reported as possible mechanisms of action include reactive oxygen species generation and apoptosis-inducing potential. Examples of the latter include ethanolic extract of seeds and leaves of *Azadirachta indica* and essentials oils of *Artemisia campestris* and *Artemisia herba-alba* that act as an apoptosis inductor in promastigotes of *L. donovani* and *L. infantum* [36].

Several studies have been carried out to assess the efficacy of such alternate treatment; however, the results have not been very encouraging. Most of the plants show immunomodulatory effect, but no leishmanicidal effect has been validated,

Several serological assays for detection of antibodies against leishmaniasis have been developed using various techniques such as direct agglutination (DAT), immunofluorescence assay (IFA), enzyme-linked immunosorbent

*This is a transmission electron microscopic image of* Leishmania major *amastigotes, which had been grown in a cell culture. Note the dense kinetoplasts in the cytoplasm (courtesy of Centers for Disease Control and Prevention/Cynthia goldsmith and Luciana Flannery) (https://phil.cdc.gov/Details.aspx?pid=22001).*

*This photomicrograph depicts some of the histopathologic details seen in a canine bone marrow smear, processed using Giemsa stain, in the case of leishmaniasis. This particular view displays* Leishmania donovani *parasites contained within one of the bone marrow histiocytes (courtesy of Centers for Disease Control and Prevention/Dr.*

*Francis W. Chandler) (https://phil.cdc.gov/Details.aspx?pid=30).*

*Parasitology and Microbiology Research*

**Figure 6.**

**306**

**Figure 5.**

supporting the notion that substances obtained from plants may complement the treatment of leishmaniasis because of their immunomodulatory effects, but there is no direct effect against the parasite.

There are recommended guidelines for *Leishmania* treatment by the WHO [16]. In addition, a panel of the Infectious Diseases Society of America (IDSA) and the American Society of Tropical Medicine and Hygiene (ASTMH) have developed management guidelines for *Leishmania* patients. These guidelines are mainly for physicians practicing in North America and are based, whenever possible, on randomized clinical trials and a systematic method of grading the quality of evidence and strength of recommendation [41].

#### **6.1 Cutaneous leishmaniasis**

Most CL cases spontaneously regress in immunocompetent hosts over 2– 18 months, and therefore conservative approach can be used in particular for those caused by *L. major* and *L. mexicana*. On the other hand, *L. braziliensis* has a low spontaneous cure rate. The decision to treat CL and ML is often to reach a goal of reducing the risk of disfigurement, scarring, dissemination, accelerating cure, and subsequent progression to mucocutaneous disease in cases of CL. In addition it is important to classify cutaneous lesions into simple or complex cutaneous lesions based on certain criteria that are then used for treatment decision-making process. These include immunocompetent versus immunocompromised host status, regional lymphadenopathy, multiplicity of lesions (>4), lesions of >5 cm in size, lesions on sensitive areas (such as face, ears, eyelids, lips, fingers/toes, genitalia, or joints), more than 6 months duration, and *Leishmania* species that are more likely to be associated with ML, unusual presentations such as diffuse or disseminated CL, and *L. recidivans*. Traditional treatment for CL has been intralesional injections mostly sodium stibogluconate, thermotherapy, cryotherapy, and topical agents such as paromomycin. The combination of intralesional antimonials and cryotherapy is often the first-line treatment option for CL, resulting in higher cure rates. There has been lack of standardization and poor trial designs for therapeutic regimens in the past. Recently efforts are being carried out to develop unified criteria to define measurable endpoints for different treatment regimens. The treatment regimen decision regarding whether to give local or systemic therapy or choice of therapeutic modality is based on the geographic location and the infecting *Leishmania* species.

Local treatment includes a combination of intralesional antimonials and cryotherapy, paromomycin ointment containing methylbenzethonium chloride, paromomycin containing 0.5% gentamicin, and paromomycin with allopurinol for *L. recidivans*.

Systemic regimens include oral fluconazole, pentavalent antimonials with or without pentoxifylline, ketoconazole, miltefosine, liposomal amphotericin B (LAMB), and pentamidine isethionate.

Systemic treatment for CL is usually used for immunosuppressed patients, mucocutaneous lesions, diffuse/extensive lesions, and refractory disease. In addition infection by *L. braziliensis* and *L. infantum* should be considered for systemic treatment (**Tables 2** and **3**) [1, 17, 18].

#### **6.2 Mucocutaneous leishmaniasis**

For mucocutaneous disease systemic regimens include pentamidine isethionate, pentavalent antimonials + pentoxyfilline, and LAMB (**Table 4**) [17, 18].

**Table 2**.

*Leishmaniasis*

*DOI: http://dx.doi.org/10.5772/intechopen.90680*

**309**

*Treatment regimens for cutaneous leishmaniasis, New World species, as per WHO recommendations (adopted from WHO) (https://www.who.int/leishmaniasis/research/978924129496\_pp67\_71.pdf?ua=1) [8].*

supporting the notion that substances obtained from plants may complement the treatment of leishmaniasis because of their immunomodulatory effects, but there is

Most CL cases spontaneously regress in immunocompetent hosts over 2– 18 months, and therefore conservative approach can be used in particular for those caused by *L. major* and *L. mexicana*. On the other hand, *L. braziliensis* has a low spontaneous cure rate. The decision to treat CL and ML is often to reach a goal of reducing the risk of disfigurement, scarring, dissemination, accelerating cure, and subsequent progression to mucocutaneous disease in cases of CL. In addition it is important to classify cutaneous lesions into simple or complex cutaneous lesions based on certain criteria that are then used for treatment decision-making process. These include immunocompetent versus immunocompromised host status, regional lymphadenopathy, multiplicity of lesions (>4), lesions of >5 cm in size, lesions on sensitive areas (such as face, ears, eyelids, lips, fingers/toes, genitalia, or joints), more than 6 months duration, and *Leishmania* species that are more likely to be associated with ML, unusual presentations such as diffuse or disseminated CL, and *L. recidivans*. Traditional treatment for CL has been intralesional injections mostly sodium stibogluconate, thermotherapy, cryotherapy, and topical agents such as paromomycin. The combination of intralesional antimonials and cryotherapy is often the first-line treatment option for CL, resulting in higher cure rates. There has been lack of standardization and poor trial designs for therapeutic regimens in the past. Recently efforts are being carried out to develop unified criteria to define measurable endpoints for different treatment regimens. The treatment regimen decision regarding whether to give local or systemic therapy or choice of therapeutic modality is based on the geographic location and the infecting

Local treatment includes a combination of intralesional antimonials and cryotherapy, paromomycin ointment containing methylbenzethonium chloride, paromomycin containing 0.5% gentamicin, and paromomycin with allopurinol for

Systemic regimens include oral fluconazole, pentavalent antimonials with or without pentoxifylline, ketoconazole, miltefosine, liposomal amphotericin B

Systemic treatment for CL is usually used for immunosuppressed patients, mucocutaneous lesions, diffuse/extensive lesions, and refractory disease. In addition infection by *L. braziliensis* and *L. infantum* should be considered for systemic

For mucocutaneous disease systemic regimens include pentamidine isethionate,

pentavalent antimonials + pentoxyfilline, and LAMB (**Table 4**) [17, 18].

There are recommended guidelines for *Leishmania* treatment by the WHO [16]. In addition, a panel of the Infectious Diseases Society of America (IDSA) and the American Society of Tropical Medicine and Hygiene (ASTMH) have developed management guidelines for *Leishmania* patients. These guidelines are mainly for physicians practicing in North America and are based, whenever possible, on randomized clinical trials and a systematic method of grading the quality of evidence

no direct effect against the parasite.

*Parasitology and Microbiology Research*

and strength of recommendation [41].

**6.1 Cutaneous leishmaniasis**

*Leishmania* species.

(LAMB), and pentamidine isethionate.

treatment (**Tables 2** and **3**) [1, 17, 18].

**6.2 Mucocutaneous leishmaniasis**

*L. recidivans*.

**308**


#### **Table 2**.

*Treatment regimens for cutaneous leishmaniasis, New World species, as per WHO recommendations (adopted from WHO) (https://www.who.int/leishmaniasis/research/978924129496\_pp67\_71.pdf?ua=1) [8].*


when patients require treatment, that include miltefosine, amphotericin B deoxycholate, and LAMB mainly for Indian subcontinent. As for East Africa, the WHO based on evidence grading recommends pentavalent antimonial, LAMB,

*Treatment regimens for mucocutaneous leishmaniasis as per WHO recommendations (adopted from WHO)*

Traditionally VL has been treated by pentavalent antimonials. Recently there is emergence of resistance in the Indian subcontinent. Current recommendations for VL in East Africa include pentavalent antimonials, LAMB, or combination treatment (including pentavalent antimonials with paromomycin). As for the Indian subcontinent, the recommendations include LAMB, amphotericin B deoxycholate, miltefosine, and one of the combination therapies: LAMB with miltefosine, LAMB with paromomycin, or miltefosine with paromomycin [1]. As for complicated VL, elderly patients, and pregnant patients in East Africa, it is recommended to have

**Recommended treatment regimens ranked by preference**

2. Liposomal amphotericin B: 2.5 mg/kg per day by infusion for 20 days, when indicated (C)

infusion, up to 60–80 doses over 4 months (C) 2.Miltefosine orally for 12 weeks at dosage as above in

intramuscularly or intravenously for 30–60 days, when

miltefosine, and combination treatment (pentavalent antimonial with

*(https://www.who.int/leishmaniasis/research/978924129496\_pp67\_71.pdf?ua=1) [8].*

LAMB treatment because of its better safety. LAMB monotherapy is not recommended in patients with less severe disease in Asia due to lack of proven efficacy in that region [42]. In Asia, sodium stibogluconate, rather than LAMB, is considered the first-line treatment for *L. infantum* and *L. donovani.* The WHO recommended LAMB therapy in the initial elimination phase for *L. donovani* in

East Africa 1. Pentavalent antimonials: 20 mg Sb5+/kg per day

Bangladesh, India, and Nepal 1. Amphotericin B deoxycholate: 1 mg/kg per day by

*Treatment regimens for post-kala-azar dermal leishmaniasis as per WHO recommendations (adopted from*

*WHO) (https://www.who.int/leishmaniasis/research/978924129496\_pp67\_71.pdf?ua=1) [8].*

indicated (C)

visceral leishmaniasis (A)

paromomycin) (**Table 5**) [17, 18].

**Geographic areas affected by postkala-azar dermal leishmaniasis**

**Table 5**.

**311**

**6.4 Visceral leishmaniasis**

**Table 4**.

*Leishmaniasis*

*DOI: http://dx.doi.org/10.5772/intechopen.90680*

#### **Table 3**.

*Treatment regimens for cutaneous leishmaniasis, Old World species, as per WHO recommendations (adopted from WHO) (https://www.who.int/leishmaniasis/research/978924129496\_pp67\_71.pdf?ua=1) [8].*

#### **6.3 Post-kala-azar dermal leishmaniasis**

Treatment regimens for PKDL are scant. In general, majority of cases from East Africa are self-healing and therefore do not require treatment. In contrast, in the Indian subcontinent, these patients are treated. Since vast majority of these patients are healthy and the risk is cosmetic, the risk benefit should be weighed before initiating therapy. Selected treatment regimens are recommended by the WHO,

## **Table 4**.

*Treatment regimens for mucocutaneous leishmaniasis as per WHO recommendations (adopted from WHO) (https://www.who.int/leishmaniasis/research/978924129496\_pp67\_71.pdf?ua=1) [8].*

when patients require treatment, that include miltefosine, amphotericin B deoxycholate, and LAMB mainly for Indian subcontinent. As for East Africa, the WHO based on evidence grading recommends pentavalent antimonial, LAMB, miltefosine, and combination treatment (pentavalent antimonial with paromomycin) (**Table 5**) [17, 18].
