Background

Leishmaniases are vector-borne diseases of significant public health concern, affecting millions of people across the tropics and subtropics (https://www.cdc.gov/dpdx/leishmaniasis/index.html). They present a wide spectrum of clinical manifestations, from cutaneous, diffuse cutaneous and mucocutaneous forms to the potentially fatal visceral leishmaniasis (VL). A vast majority of cases are linked to a limited number of Leishmania species. Traditionally, distinct Leishmania species have been linked to specific clinical syndromes: L. donovani and L. infantum are most often associated with VL, while L. major, L. tropica, and L. mexicana are typical causes of cutaneous leishmaniasis (CL) [1]. However, advances in molecular diagnostics have brought attention to a broader spectrum of disease presentations and causative agents. Increasingly, reports describe unconventional species, taxa not historically associated with human infection or that fall outside the small group of well-established species. Some of these are newly characterized or geographically restricted, such as members of the Mundinia subgenus, L. martiniquensis or L. orientalis for example [2,3]. In parallel, a growing number of cases involve non-classical species, including organisms generally considered classical but behaving unexpectedly. Mucocutaneous leishmaniasis (MCL) is a severe, destructive condition primarily caused by L. braziliensis, which affects mucous membranes of the nose, mouth, and throat, nevetheless L. infantum presenting with mucocutaneous (MCL) forms in North Africa have been described [4]. Diffuse cutaneous leishmaniasis (DCL), is characterized by widespread non-ulcerative skin lesions, associated with an anergic immune response, is most commonly linked to L. amazonensis or L. aethiopica, but can be caused by other taxa in immunocompromised individuals [1,5]. These cases challenge existing diagnostic categories and reflect a more complex biological and epidemiological landscape. Finally, infections involve atypical presentations, in which clinical features deviate from established syndromes. This may include unusual disease manifestations, infections in non-traditional hosts (e.g., domestic cats, wild carnivores). Together, these forms, whether involving unusual species, unexpected hosts, or non-canonical symptoms, highlight the need for updated frameworks for diagnosis, surveillance, and treatment.

Rationale

No global synthesis currently exists to map the diversity, geographic distribution, diagnostic features, and knowledge gaps related to unconventional clinical presentations, atypical Leishmania species, and emerging pathogens affecting animals of veterinary interest. These infections often present diagnostic and therapeutic challenges and may be underrecognized within routine surveillance systems [1–3,5,6]. Despite documentation in the scientific literature, these complexities remain underrepresented in the guidance of major stakeholders such as the World Health Organization (WHO), the Centers for Disease Control and Prevention (CDC), and regional health bodies. For example, reports from the European Centre for Disease Prevention and Control (ECDC) and the Pan American Health Organization (PAHO) highlight the lack of standardized diagnostic and treatment protocols across many settings [7–9]. Furthermore, molecular diagnostic methods such as PCR are not widely available in resource-limited regions, posing challenges for the detection and management of infections caused by non-classical Leishmania species. This disconnect between emerging evidence and formal guidance underscores the need for a comprehensive synthesis to inform evidence-based policy, strengthen diagnostic and surveillance frameworks, and guide future research priorities. The non-mandatory nature of CL reporting in many endemic countries likely contributes to the underrecognition of atypical presentations and infections involving unconventional or non-classical Leishmania species. Without compulsory notification and species-level diagnostics, such cases may go undocumented, obscuring the true diversity and distribution of leishmaniasis and limiting the visibility of emerging epidemiological patterns. Additionally, reports of leishmaniasis emerging in non-endemic regions, whether as imported cases or potential instances of local transmission, further highlight the evolving epidemiological landscape. Such cases often involve atypical clinical forms, unfamiliar Leishmania species, or novel reservoir hosts and may be underrecognized due to limited diagnostic capacity and clinical awareness outside traditional endemic zones. These infections are of particular importance for surveillance systems, clinical preparedness, and risk assessment in regions not historically considered at risk. Given the dynamic nature of leishmaniases transmission and the evolving understanding of its causative agents, a scoping review is warranted to compile existing evidence. By identifying and characterizing reports of unconventional Leishmania infections in humans and in animals of veterinary relevance, this review will provide a foundational resource for researchers, clinicians, and policymakers. Such mapping is especially timely given the emergence of novel or hybrid strains, shifting ecological patterns, and the increasing application of genomic tools, which have revealed hidden diversity within the Leishmania genus [10,11]. A comprehensive overview will help clarify the spectrum of pathogens involved, identify regions at risk, and address the diagnostic and surveillance limitations that currently hinder effective public health responses.

Objective

The objective of this scoping review is to examine the body of peer-reviewed literature and publications from governmental or non-governmental international sources on unconventional presentations, and pathogens associated with Leishmania infections in humans and animals of veterinary importance. This includes infections caused by novel or non-classical Leishmania species, atypical clinical manifestations caused by well-known species, and unconventional infections in animal hosts not traditionally associated with the disease. The aim is to define the diversity and global distribution of these occurrences, describe associated clinical and diagnostic patterns, and identify current knowledge gaps. This will be achieved through a multiphase screening and data extraction process. The study aims to answer one overarching research question and several secondary questions.

What is the current global evidence on infections involving unconventional Leishmania species, atypical clinical manifestations, or non-traditional Leishmania infections in reservoir hosts of medical or veterinary importance and others, with regard to pathogen diversity, geographic distribution, and diagnostic and clinical characteristics?

• What Leishmania species, novel, hybrid, or rarely implicated, have been reported in human and animal cases of visceral leishmaniasis (VL), cutaneous leishmaniasis (CL), mucocutaneous leishmaniasis (MCL), diffuse cutaneous leishmaniasis (DCL), or post-kala-azar dermal leishmaniasis (PKDL)?
• What unconventional or atypical clinical manifestations have been associated with either classical or non-classical Leishmania species?
• Which animal reservoir hosts, particularly of medical or veterinary importance, have been identified as harboring non-classical or atypically behaving Leishmania species?
• In which geographic regions have atypical Leishmania infections been reported, and what patterns in spatial distribution can be observed?
• What diagnostic techniques or molecular methods have been used to detect and identify these atypical Leishmania infections in both clinical or veterinary contexts?
• What evidence exists in the literature regarding genetic diversity, hybridization events, or adaptative traits among the implicated Leishmania strains?
• What treatment strategies have been documented for managing infections caused by non-classical Leishmania species or atypical clinical manifestations, and what is known about their outcome or efficacy?
• How have environmental or ecological factors (e.g., climate change, land use changes, urbanization) have been associated with the occurence or detection of atypical Leishmania infections?
• What integrated surveillance systems or One Health strategies have been implemented or proposed to monitor and control infections involving unconventional Leishmania species?
• What research, diagnostic, or surveillance gaps hinder the detection, understanding, or control of non-classical Leishmania infections?

Inclusion and exclusion criteria

For clarity and consistency, we defined the core concepts guiding our inclusion criteria in Table 1. These definitions helped ensure standardized screening and classification of cases across studies.

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Table 1. Operational definitions of key terms related to unconventional and atypical Leishmania infections.

https://doi.org/10.1371/journal.pone.0332874.t001

Inclusion Criteria:

• Studies involving human or animal cases (domestic or wild) of leishmaniasis caused by unconventional Leishmania species, including newly described, geographically restricted, or rarely implicated taxa (e.g., L. martiniquensis, L. orientalis, Mundinia species).
• Studies reporting atypical clinical presentations or non-classical infections, such as: Unusual anatomical or clinical forms (e.g., mucosal involvement by L. infantum, disseminated cutaneous disease), Infections in non-traditional hosts (e.g., cats, rodents, wildlife), infections occurring in non-endemic regions or described as imported.
• All study designs (case reports, case series, observational studies, surveillance studies, clinical trials).
• Studies with species-level identification using molecular, isoenzymatic, or parasitological confirmation (e.g., PCR, DNA sequencing, culture, isoenzyme typing).
• No restriction in language, non-English studies will be translated when feasible.

Exclusion Criteria:

• Studies without species-level identification.
• Reviews, editorials, or commentaries.
• Studies focused solely on classical species (e.g., L. donovani in VL, L. major in CL).

Search strategies

Articles will be gathered through searches of PubMed, Embase, Web of Science Core Collection, Cochrane Library, Global Index Medicus, and PROSPERO. PROSPERO will be searched to identify any registered or ongoing evidence syntheses related to atypical or unconventional leishmaniasis to avoid duplication and ensure the novelty of this review. A summary of the rationale for database selection is presented in Table 2. This strategy ensures broad thematic and geographical coverage across both clinical and veterinary domains, consistent with the objectives of this scoping review. There will be no publication date restrictions. Grey literature will be searched via Google Scholar and relevant conference proceedings. The search terms used for each database can be found in online S2 File search terms.

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Table 2. Justification for database selection.

https://doi.org/10.1371/journal.pone.0332874.t002

Record management

Deduplication of abstracts using the De-duplicator from Bond University’s Systematic Review Accelerator will be used [14]. Records will be screened using Rayyan, an article screening tool for evidence synthesis projects [15].

Screening strategy

The screening process will be conducted in two stages. In the first stage (title and abstract screening), records must meet the primary inclusion criteria and at least one secondary criterion to proceed. This broader approach is intended to avoid the premature exclusion of studies that may not explicitly reference unconventional Leishmania infections in the title or abstract but are still relevant. In the second stage (full-text screening), all predefined inclusion criteria must be fully met for a study to be included in the review. All records will be screened independently and in duplicate by two reviewers (excluding MJG). Any discrepancies will be resolved through consensus by a third reviewer (DS or TK). The study selection process will be documented using a PRISMA flow diagram.

Data extraction

Data extracted from the included texts will follow a standardized, piloted charting form (Table 3). Variables include bibliographic details, study design, clinical and diagnostic features, host species, and outcomes. We will also extract information on the funding source, to assess potential publication or sponsor-related bias and identify patterns in research investment related to non-classical or emerging Leishmania. Similarly, surveillance source (e.g., hospital reports, case registries, or active surveillance) will be recorded to contextualize case detection pathways and interpret the representativeness of reported findings.

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Table 3. Standardized, piloted charting form.

https://doi.org/10.1371/journal.pone.0332874.t003

Data summarization and presentation

Given the anticipated heterogeneity of included studies, spanning diverse host species (humans, domestic animals, others), study designs (case reports to surveillance studies), and diagnostic methods, we will adopt a structured approach to organize and synthesize data thematically and descriptively:

• Stratification by host type (e.g., human, canine, feline, others) to distinguish patterns by reservoir relevance.
• Categorization by clinical form (e.g., CL, VL, MCL, DCL, PKDL, disseminated or mixed presentations).
• Separation by diagnostic approach, noting molecular vs. parasitological confirmation and level of species identification.
• Grouping by geographical region, with attention to endemic vs. non-endemic settings.
• Study design labeling to contextualize the strength and type of evidence (e.g., single case vs. cross-sectional survey).

We will not conduct a formal quality appraisal, consistent with JBI guidance for scoping reviews. However, we will highlight diagnostic certainty and species identification method in the charting form to inform interpretation. We acknowledge potential limitations, including publication bias, inconsistent reporting standards, and challenges in species identification across studies.

Ethics and dissemination

This scoping review will use data extracted exclusively from publicly available sources, including peer-reviewed publications, surveillance reports, and grey literature such as theses, conference proceedings, and institutional reports. No individual-level or confidential data will be accessed, and no identifiable patient or animal data will be collected. Therefore, formal ethical approval is not required (S3 File).

We acknowledge that grey literature and informal surveillance data may vary in methodological rigor and completeness. To address this, we will extract and report data origin and surveillance type (e.g., passive hospital report, national registry, or academic thesis) and note diagnostic certainty and reporting context when interpreting the findings. These elements will be considered during data synthesis to ensure transparency and contextual clarity.

Findings will be disseminated through publication in a peer-reviewed, open-access journal, presentation at scientific conferences, and sharing with stakeholders in public health, tropical medicine, and veterinary networks.

Patient and public involvement

There is no applicable patient and public involvement in the study.

Ethic statement

Patient consent for publication; Not applicable

Strenghten and limitations of this study

This is the first scoping review to systematically map unconventional Leishmania infections across humans and animals, integrating emerging species, atypical clinical forms, and veterinary hosts within a One Health framework.

The protocol adopts a One Health perspective, enabling integrated analysis of human and animal cases to reflect the complex ecology of Leishmania transmission.

Challenges such as publication bias and inconsistent species-level identification may affect data comparability; to mitigate this, we include grey literature, apply broad inclusion criteria, and transparently report data limitations during synthesis.