Advancement in Leishmaniasis Diagnosis and Therapeutics

A special issue of Tropical Medicine and Infectious Disease (ISSN 2414-6366). This special issue belongs to the section "Neglected and Emerging Tropical Diseases".

Deadline for manuscript submissions: closed (28 August 2022) | Viewed by 17606

Special Issue Editors

Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro 21040-360, Brazil
Interests: visceral leishmaniasis; canine leishmaniasis; cutaneous leishmaniasis; diagnostic; immunopathology; animal leishmaniasis
Special Issues, Collections and Topics in MDPI journals
Instituto Oswaldo Cruz, Fundacão Oswaldo Cruz, Rio de Janeiro 21040-360, Brazil
Interests: visceral leishmaniasis; canine leishmaniasis; cutaneous leishmaniasis; diagnostic; immunopathology; animal leishmaniasis
Special Issues, Collections and Topics in MDPI journals
Laboratory of Immunoparasitology, Oswaldo Cruz Institute, IOC/Fiocruz, Avenida Brasil 4365 Pavilhão 26 sala 408-Manguinhos, Rio de Janeiro 21040-360, Brazil
Interests: vaccine; infectious diseases; Protozoa; diagnosis; review; ELISPOT; mycosis
Special Issues, Collections and Topics in MDPI journals
Instituto Nacional de Infectologia Evandro Chagas, Fundação Oswaldo Cruz, Rio de Janeiro 21040-360, Brazil
Interests: Leishmaniasis
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Leishmaniasis is a complex of diseases that annually affect thousands of people in the world. Leishmanias are mainly zoonoses, affecting wild and domestic animals. According to their clinical manifestation, they are classified as tegumentary (TL) and visceral (VL) forms. The TL can lead to irreversible and inaesthetic sequelae, whereas VL can be lethal if not promptly diagnosed and treated. Correct diagnosis and adequate treatment constitute two important pillars of the control measures that demand: a) provision of specific and sensitive diagnostic tools widely available in the endemic regions, for the identification of human and animal cases; b) adequate treatment and management of humans and animals, reducing morbidity and mortality and allowing the interruption of the parasite transmission cycle. Advances in treatment have been limited to a few available drugs.

For decades, pentavalent antimony and amphotericin B have been considered the drugs of choice for most of Leishmania species, despite all side effects, for both cutaneous and visceral leishmaniasis. Pentamidine is the first option for L. (V.) guyanensis. Miltefosine and local therapeutic approaches have also been successfully used for cutaneous leishmaniasis. Efficient drugs are needed for the treatment of canine visceral leishmaniasis that may not result in resistant parasites. In many regions, only microscopic parasitological diagnosis is available. Despite many described molecular tools, they are almost limited to reference centers. Rapid tests have great potential in both cutaneous and visceral leishmaniasis due to the ease of storage and handling. However, studies focused on the development or improvement of diagnostic tools and treatment methods are needed.

This Special Topic aims to publish original articles, reviews and mini reviews, case reports, and short communications that are related to testing new drugs, new treatment strategies, identification of target molecules with potential use in treatment, serological, molecular and parasitological diagnosis applicable to improve control of human and animal leishmaniasis.

Dr. Fernanda Nazaré Morgado
Dr. Renato Porrozzi
Dr. Fatima Conceição-Silva
Dr. Maria Inês Fernandes Pimentel
Guest Editors

Manuscript Submission Information

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Keywords

  • serological diagnosis
  • molecular diagnosis
  • parasitological diagnosis
  • treatment
  • visceral leishmaniasis
  • cutaneous leishmaniasis
  • human leishmaniasis
  • animal leishmaniasis

Published Papers (11 papers)

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Editorial

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4 pages, 233 KiB  
Editorial
Advancement in Leishmaniasis Diagnosis and Therapeutics
Trop. Med. Infect. Dis. 2023, 8(5), 270; https://doi.org/10.3390/tropicalmed8050270 - 10 May 2023
Cited by 1 | Viewed by 1048
Abstract
Leishmaniasis is a complex of clinical manifestations that affects thousands of people in the world each year according to WHO [...] Full article
(This article belongs to the Special Issue Advancement in Leishmaniasis Diagnosis and Therapeutics)

Research

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28 pages, 7857 KiB  
Article
A Novel Protocol for the Synthesis of 1,2,4-Oxadiazoles Active against Trypanosomatids and Drug-Resistant Leukemia Cell Lines
Trop. Med. Infect. Dis. 2022, 7(12), 403; https://doi.org/10.3390/tropicalmed7120403 - 28 Nov 2022
Cited by 2 | Viewed by 2787
Abstract
Cancer and parasitic diseases, such as leishmaniasis and Chagas disease, share similarities that allow the co-development of new antiproliferative agents as a strategy to quickly track the discovery of new drugs. This strategy is especially interesting regarding tropical neglected diseases, for which chemotherapeutic [...] Read more.
Cancer and parasitic diseases, such as leishmaniasis and Chagas disease, share similarities that allow the co-development of new antiproliferative agents as a strategy to quickly track the discovery of new drugs. This strategy is especially interesting regarding tropical neglected diseases, for which chemotherapeutic alternatives are extremely outdated. We designed a series of (E)-3-aryl-5-(2-aryl-vinyl)-1,2,4-oxadiazoles based on the reported antiparasitic and anticancer activities of structurally related compounds. The synthesis of such compounds led to the development of a new, fast, and efficient strategy for the construction of a 1,2,4-oxadiazole ring on a silica-supported system under microwave irradiation. One hit compound (23) was identified during the in vitro evaluation against drug-sensitive and drug-resistant chronic myeloid leukemia cell lines (EC50 values ranging from 5.5 to 13.2 µM), Trypanosoma cruzi amastigotes (EC50 = 2.9 µM) and Leishmania amazonensis promastigotes (EC50 = 12.2 µM) and amastigotes (EC50 = 13.5 µM). In silico studies indicate a correlation between the in vitro activity and the interaction with tubulin at the colchicine binding site. Furthermore, ADMET in silico predictions indicate that the compounds possess a high druggability potential due to their physicochemical, pharmacokinetic, and toxicity profiles, and for hit 23, it was identified by multiple spectroscopic approaches that this compound binds with human serum albumin (HSA) via a spontaneous ground-state association with a moderate affinity driven by entropically and enthalpically energies into subdomain IIA (site I) without significantly perturbing the secondary content of the protein. Full article
(This article belongs to the Special Issue Advancement in Leishmaniasis Diagnosis and Therapeutics)
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16 pages, 2858 KiB  
Article
Investigating the Leishmania donovani sacp Gene and Its Role in Macrophage Infection and Survival in Mice
Trop. Med. Infect. Dis. 2022, 7(11), 384; https://doi.org/10.3390/tropicalmed7110384 - 18 Nov 2022
Cited by 2 | Viewed by 1478
Abstract
The protozoan parasite Leishmania donovani is a causative agent of the neglected tropical disease known as visceral leishmaniasis, which can be lethal when untreated. Studying Leishmania viru-lence factors is crucial in determining how the parasite causes disease and identifying new targets for treatment. [...] Read more.
The protozoan parasite Leishmania donovani is a causative agent of the neglected tropical disease known as visceral leishmaniasis, which can be lethal when untreated. Studying Leishmania viru-lence factors is crucial in determining how the parasite causes disease and identifying new targets for treatment. One potential virulence factor is L. donovani’s abundantly secreted protein: secreted acid phosphatase (SAcP). Whole-genome analysis revealed that the sacp gene was present in three copies in wild type L. donovani. Using CRISPR-Cas9 gene editing; we generated a sacp gene knockout termed LdΔSAcP, which demonstrated a loss of both the SAcP protein and an associated reduction in secreted acid phosphatase activity. Genome sequencing confirmed the precise dele-tion of the sacp gene in LdΔSAcP and identified several changes in the genome. LdΔSAcP demonstrated no significant changes in promastigote proliferation or its ability to infect and survive in macrophages compared to the wildtype strain. LdΔSAcP also demonstrated no change in murine liver infection; however, survival was impaired in the spleen. Taken together these results show that SAcP is not necessary for the survival of promastigotes in culture but may support long-term survival in the spleen. These observations also show that the use of CRISPR gene editing and WGS together are effective to investigate the function and phenotype of complex potential drug targets such as multicopy genes. Full article
(This article belongs to the Special Issue Advancement in Leishmaniasis Diagnosis and Therapeutics)
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9 pages, 677 KiB  
Article
Assessment of Immune and Clinical Response in Patients with Mucosal Leishmaniasis Treated with Pentavalent Antimony and Pentoxifylline
Trop. Med. Infect. Dis. 2022, 7(11), 383; https://doi.org/10.3390/tropicalmed7110383 - 16 Nov 2022
Cited by 2 | Viewed by 958
Abstract
Mucosal leishmaniasis (ML) is a severe form of tegumentary leishmaniasis associated with a persistent inflammatory response. High levels of TNF, IFN-γ, CXCL9 and CXCL10 are found in ML patients, and the association of pentoxifylline with antimony is more effective in decreasing the healing [...] Read more.
Mucosal leishmaniasis (ML) is a severe form of tegumentary leishmaniasis associated with a persistent inflammatory response. High levels of TNF, IFN-γ, CXCL9 and CXCL10 are found in ML patients, and the association of pentoxifylline with antimony is more effective in decreasing the healing time in ML patients when compared to antimony alone. The present study aimed to investigate the existence of a correlation between cytokine and chemokine production and ML severity and evaluate the potential value of cytokine and chemokine production as marker of therapeutic response in ML patients. This prospective study included 86 subjects in an area of endemic Leishmania braziliensis transmission. Patients diagnosed with ML were classified into clinical stages ranging from I to V according to disease severity. TNF, IFN-γ, CXCL9 and CXCL10 levels were quantified in the supernatant of the mononuclear cell cultures by ELISA before and after treatment with antimony alone or antimony plus pentoxifylline. The median TNF level in the group with mild disease (Stages I–II) was 1064 pg/mL (142–3738 pg/mL), while, in the group with moderate or severe disease (Stages III–V), it was 1941 pg/mL (529–5294 pg/mL) (p = 0.008). A direct correlation was observed between ML clinical severity and levels of TNF production (r = 0.44, p = 0.007). Patients who were treated with antimony and pentoxifylline healed significantly faster than those treated with antimony alone (52 vs. 77 days, hazard ratio = 0.60; 95% confidence interval = 0.38–0.95, p = 0.013). Therapeutic failure was higher in the group that received antimony alone (25% vs. 7%; p = 0.041). There was a significant decrease in CXCL9 after therapy of ML in both groups (p = 0.013; p = 0.043). TNF levels are associated with the severity of mucosal diseases, and pentoxifylline associated with antimony should be the recommended therapy for ML in countries where liposomal amphotericin B is not available. Full article
(This article belongs to the Special Issue Advancement in Leishmaniasis Diagnosis and Therapeutics)
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8 pages, 1049 KiB  
Article
Quantitative Detection of Leishmania in Rhipicephalus microplus and Amblyomma sabanerae in the Peruvian Amazon Basin
Trop. Med. Infect. Dis. 2022, 7(11), 358; https://doi.org/10.3390/tropicalmed7110358 - 07 Nov 2022
Cited by 2 | Viewed by 1200
Abstract
Leishmaniasis is a disease of public importance with a complex transmission cycle. A quantitative PCR was developed by using the small subunit of the ribosomal RNA gene (SSU rRNA) as a DNA target, which is conserved in all Leishmania species. A TaqMan ® [...] Read more.
Leishmaniasis is a disease of public importance with a complex transmission cycle. A quantitative PCR was developed by using the small subunit of the ribosomal RNA gene (SSU rRNA) as a DNA target, which is conserved in all Leishmania species. A TaqMan ® probe was designed to have a high specificity. In all, 22 out of 23 (95.7%) ticks classified as R. microplus tested positive for Leishmania sp. The quantification was between 34.1 and 2197.1 parasites per tick in a range of 12 to 769 fg/uL. In addition, 9 out of 10 (90%) ticks classified as Amblyomma sabanerae tested positive for Leishmania sp. The quantification was between 448.6 and 5428.6 parasites per tick in a range of 157 to 1900 fg/µL. Leishmania sp. was identified in very high percentages in Rhipicephalus microplus and Amblyomma sabanerae from wild Pecari tajacu and Chelonoidis denticulata, in quantities of 34.1 and 5428.6 parasites per arthropod, and this could suggest that the ticks were parasitized by sucking blood from the animals from which they were collected. This is the first report about Leishmania parasites found in wild Rhipicephalus microplus and Amblyomma sabanerae, adding new information about the distribution and epidemiology of the parasite in sylvatic areas. Full article
(This article belongs to the Special Issue Advancement in Leishmaniasis Diagnosis and Therapeutics)
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13 pages, 1054 KiB  
Article
Comparison between Colorimetric In Situ Hybridization, Histopathology, and Immunohistochemistry for the Diagnosis of New World Cutaneous Leishmaniasis in Human Skin Samples
Trop. Med. Infect. Dis. 2022, 7(11), 344; https://doi.org/10.3390/tropicalmed7110344 - 01 Nov 2022
Cited by 2 | Viewed by 1325
Abstract
New world cutaneous leishmaniasis (NWCL) is an anthropozoonosis caused by different species of the protozoan Leishmania. Colorimetric in situ hybridization (CISH) was shown to satisfactorily detect amastigote forms of Leishmania spp. in animal tissues, yet it was not tested for the diagnosis of [...] Read more.
New world cutaneous leishmaniasis (NWCL) is an anthropozoonosis caused by different species of the protozoan Leishmania. Colorimetric in situ hybridization (CISH) was shown to satisfactorily detect amastigote forms of Leishmania spp. in animal tissues, yet it was not tested for the diagnosis of human NWCL. The aim of this study was to compare CISH, histopathology (HP), and immunohistochemistry (IHC) techniques to diagnose NWCL in human cutaneous lesions. The sample comprised fifty formalin-fixed, paraffin-embedded skin biopsy specimens from patients with NWCL caused by L. (V.) braziliensis. These specimens were analyzed by CISH, using a generic probe for Leishmania, IHC, and HP to assess the sensitivity of these methods by using a parasitological culture as a standard reference. Additional specimens from three patients diagnosed with cutaneous mycoses were also included to evaluate cross-reactions between CISH and IHC. The sensitivities of IHC, CISH, and HP for detecting amastigotes was 66%, 54%, and 50%, respectively. IHC, unlike CISH, cross-reacted with different species of fungi. Together, these results demonstrate that CISH may be a complementary assay for the detection of amastigote in the laboratorial diagnosis routine of human NWCL caused by L. (V.) braziliensis. Full article
(This article belongs to the Special Issue Advancement in Leishmaniasis Diagnosis and Therapeutics)
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12 pages, 1127 KiB  
Article
Intralesional Meglumine Antimoniate: Safe, Feasible and Effective Therapy for Cutaneous Leishmaniasis in Bolivia
Trop. Med. Infect. Dis. 2022, 7(10), 286; https://doi.org/10.3390/tropicalmed7100286 - 07 Oct 2022
Cited by 2 | Viewed by 1332
Abstract
The standard of care for cutaneous leishmaniasis includes the intramuscular/intravenous administration of pentavalent antimonials that are toxic and poorly tolerated. Primary health care usually lacks trained health staff for the diagnosis and treatment of leishmaniasis in Cochabamba Bolivia. Taking these aspects into account, [...] Read more.
The standard of care for cutaneous leishmaniasis includes the intramuscular/intravenous administration of pentavalent antimonials that are toxic and poorly tolerated. Primary health care usually lacks trained health staff for the diagnosis and treatment of leishmaniasis in Cochabamba Bolivia. Taking these aspects into account, a Bolivian consortium set out to explore the intralesional administration of meglumine antimoniate to treat cutaneous leishmaniasis during primary care under programmatic conditions. A four-step strategy consisting of clinical training for intralesional treatment and the promotion and periodic follow-up of health staff was carried out. The training process was applied in situ to personnel of nine primary health care centres. The intralesional treatment was applied five times every other day. Clinical follow-up after six-months of treatment showed a 77% healing proportion and 5% of therapeutic failure among 152 enrolled patients. The drug volume used in the intralesional procedure was on average 1.7 mL/ulcer treated. In conclusion, the strategy used was successful and effective, accomplishing a healing proportion similar to the long standardized treatment with a reduced time of administration, no severe side effects, and it is feasible to conduct by trained health staff. Our study supports the current PAHO/WHO recommendation for the intralesional administration of pentavalent antimonials for the treatment of cutaneous leishmaniasis. Full article
(This article belongs to the Special Issue Advancement in Leishmaniasis Diagnosis and Therapeutics)
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8 pages, 675 KiB  
Communication
Characterization of Leishmania spp. Causing Cutaneous Lesions with a Negative Parasitological Diagnosis in Panama
Trop. Med. Infect. Dis. 2022, 7(10), 282; https://doi.org/10.3390/tropicalmed7100282 - 03 Oct 2022
Cited by 2 | Viewed by 1109
Abstract
A total of 123 DNA samples from Panamanian patients with cutaneous leishmaniasis (CL) lesions were evaluated. These samples were previously confirmed with CL by a specific KDNA-Viannia PCR but had a negative parasitological diagnosis (Group A). Epidemiological variables, such as age, sex, geographic [...] Read more.
A total of 123 DNA samples from Panamanian patients with cutaneous leishmaniasis (CL) lesions were evaluated. These samples were previously confirmed with CL by a specific KDNA-Viannia PCR but had a negative parasitological diagnosis (Group A). Epidemiological variables, such as age, sex, geographic origin, evolution time, and the number and location of the lesions, were analyzed. No significant differences (p < 0.05) were found when these variables were evaluated against a control panel of 123 CL lesion samples from CL patients with positive parasitological diagnoses (Group B). Of the 123 samples (Group A), 67% (82/123) gave positive results when re-analyzed by PCR-hsp70. An analysis of 69 of these samples via PCR-hsp70-RFLP showed that 59.4% (41/69) of the found restriction patterns corresponded to Leishmania (Viannia) panamensis and 40.6% (28/69) to Leishmania (Viannia) guyanensis. Finally, the sequence and phylogenetic analysis of 32 of the samples confirmed the species in 21 (65.6%, 21/32) samples, originally characterized as L. (V.) panamensis. However, 11 samples (34.4%, 11/32), initially identified via RFLP-Hsp70 as L. (V.) guyanensis, matched the sequence of a genetic variant known as Leishmania sp.1. These results point out the species/genetic variants of Leishmania in the case of CL lesions with an apparently low parasite load. Full article
(This article belongs to the Special Issue Advancement in Leishmaniasis Diagnosis and Therapeutics)
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14 pages, 2661 KiB  
Article
Visceral Leishmaniasis and Land Use and Cover in the Carajás Integration Region, Eastern Amazon, Brazil
Trop. Med. Infect. Dis. 2022, 7(10), 255; https://doi.org/10.3390/tropicalmed7100255 - 22 Sep 2022
Cited by 3 | Viewed by 1848
Abstract
Human visceral leishmaniasis is a major public health problem in the Amazon. Thus, we analyzed the spatial distribution of this disease and its relationship with epidemiological, socioeconomic, and environmental variables in the Carajás Integration Region, Pará state, from 2011 to 2020. Epidemiological data [...] Read more.
Human visceral leishmaniasis is a major public health problem in the Amazon. Thus, we analyzed the spatial distribution of this disease and its relationship with epidemiological, socioeconomic, and environmental variables in the Carajás Integration Region, Pará state, from 2011 to 2020. Epidemiological data for this ecological study were obtained from the State Public Health Secretariat, environmental data were obtained from the National Space Research Institute, and socioeconomic data were obtained from the Brazilian Geography and Statistics Institute. ArcGIS 10.5.1 software was used for classifying land use and cover and for the Kernel and Moran spatial analyses. It was observed in 685 confirmed cases that the epidemiological profile followed the national pattern of the disease occurrence, with a high prevalence in children who were not school-aged. The disease had a non-homogeneous distribution with clusters related to different human activities, such as urbanization, ranching, and mining. A spatial dependence between the disease prevalence and socioeconomic indicators was observed. The municipalities presented gradients of case densities associated with a direct relationship between areas with cases and deforestation. The disease is developing due to risk factors such as establishment and maintenance related to the non-sustainable development model implemented in the region, pointing to the need for its revision. Full article
(This article belongs to the Special Issue Advancement in Leishmaniasis Diagnosis and Therapeutics)
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Review

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16 pages, 329 KiB  
Review
An Overview on Leishmaniasis in Romania: Diagnosis and Therapeutics
Trop. Med. Infect. Dis. 2022, 7(11), 334; https://doi.org/10.3390/tropicalmed7110334 - 28 Oct 2022
Cited by 2 | Viewed by 1540
Abstract
Leishmaniasis, a vector-borne disease considered to be one of the twenty neglected diseases by the World Health Organization, represents one of the public health concerns in endemic countries. In humans, as well as in animal counterparts, the infection can evolve with different clinical [...] Read more.
Leishmaniasis, a vector-borne disease considered to be one of the twenty neglected diseases by the World Health Organization, represents one of the public health concerns in endemic countries. In humans, as well as in animal counterparts, the infection can evolve with different clinical localizations, such as those that are cutaneous, mucocutaneous and visceral. Romania has been traditionally considered a nonendemic country for Leishmania species infection and has had sporadic positive human cases; however, the climate change recorded in recent decades has created potentially optimal conditions for the preponderant vectors of Phlebotomus spp., which has lately been identified in various parts of country. Moreover, with people and dogs (the prevailing hosts) traveling in endemic countries, the disease was imported and diagnosed in both species, and became a medical concern. In this review, we focused on the: (1) epidemiological data of leishmaniasis cases, both in humans and animals, reported by Romania; (2) diagnostic tools available for confirmation since there is a lack of gold-standard laboratory methods for human and dog patients; and (3) conventional antileishmanial therapy. Full article
(This article belongs to the Special Issue Advancement in Leishmaniasis Diagnosis and Therapeutics)

Other

17 pages, 639 KiB  
Systematic Review
Epidemiology, Clinical Characteristics, Diagnostic Work Up, and Treatment Options of Leishmania Infection in Kidney Transplant Recipients: A Systematic Review
Trop. Med. Infect. Dis. 2022, 7(10), 258; https://doi.org/10.3390/tropicalmed7100258 - 22 Sep 2022
Cited by 3 | Viewed by 1510
Abstract
Current knowledge on Leishmania infection after kidney transplantation (KT) is limited. In order to offer a comprehensive guide for the management of post-transplant Leishmaniasis, we performed a systematic review following the latest PRISMA Checklist and using PubMed, Scopus, and Embase as databases. No [...] Read more.
Current knowledge on Leishmania infection after kidney transplantation (KT) is limited. In order to offer a comprehensive guide for the management of post-transplant Leishmaniasis, we performed a systematic review following the latest PRISMA Checklist and using PubMed, Scopus, and Embase as databases. No time restrictions were applied, including all English-edited articles on Leishmaniasis in KT recipients. Selected items were assessed for methodological quality using a modified Newcastle–Ottawa Scale. Given the nature and quality of the studies (case reports and retrospective uncontrolled case series), data could not be meta-analyzed. A descriptive summary was therefore provided. Eventually, we selected 70 studies, describing a total of 159 cases of Leishmaniasis. Most of the patients were adult, male, and Caucasian. Furthermore, they were frequently living or travelling to endemic regions. The onset of the disease was variable, but more often in the late transplant course. The clinical features were basically similar to those reported in the general population. However, a generalized delay in diagnosis and treatment could be detected. Bone marrow aspiration was the preferred diagnostic modality. The main treatment options included pentavalent antimonial and liposomal amphotericin B, both showing mixed results. Overall, the outcomes appeared as concerning, with several patients dying or losing their transplant. Full article
(This article belongs to the Special Issue Advancement in Leishmaniasis Diagnosis and Therapeutics)
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