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• 17 August 2023

In search of a vaccine for leishmaniasis

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doi: https://doi.org/10.1038/d41586-023-02580-y

This article is part of Nature Outlook: Neglected tropical diseases , a supplement funded by a grant from Merck Sharp & Dohme and with financial support from Moderna . Nature maintains full independence in all editorial decisions related to the content. About this content .

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• Published: 30 June 2021

Cutaneous Leishmaniasis in Pakistan: a neglected disease needing one health strategy

• Behzad Kayani 1 ,
• Shakera Sadiq 1 ,
• Hamad Bin Rashid 2 ,
• Naseer Ahmed 3 ,
• Altaf Mahmood 4 ,
• Muhammad Shakeel Khaliq 4 ,
• Rubab Maqsood 1 ,
• Haroon Rashid 5 ,
• Saima Hasan 1 ,
• Muhammad Hassan Mushtaq 1 ,
• Ubaid-ur-Rehman Zia 1 &
• Mamoona Chaudhry 1  

BMC Infectious Diseases volume  21 , Article number:  622 ( 2021 ) Cite this article

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Cutaneous Leishmaniasis (CL) is a neglected tropical disease, which mainly affects poor communities. It is one of the major vector-borne disease and endemic in Pakistan.

A case-control study to evaluate potential risk factors of human-CL was conducted in Khewra region, District Jhelum, Pakistan from January–April 2014. Case data about 90 cases registered during October 2012 to November 2013 was retrieved from Municipal Hospital. Controls were matched (1,1 ratio) on the date of registration with cases from same hospital. Both cases and controls were invited to participate and data was collected in a face-to-face interview. A prospective study of canine leishmaniasis (canine-CL) was also conducted at Civil Veterinary Hospital in the same area. Suspected dogs with skin ulceration signs were included in the study and blood samples were collected. Statistical analyses were conducted to determine association between various parameters and outcome of interest.

The ages of cases ranged from 1 to 76 years (median = 15 years) and proved to be protective factor i.e. increase in each year in age reduced the likelihood of being infected with human-CL [Odds Ratio (OR) = 0.4, 95% Confidence Interval (CI) = 0.25–0.76]. People sleeping outsides in an open area were more likely to become a case (OR = 8.7, 95% CI = 2.90–26.37) than a control. Poor sanitary condition inside the house (OR = 3.3, 95% CI 1.03–10.56) and presence of other animals in house (livestock, poultry) (OR = 3.6, 95% CI = 1.07–12.12) also identified as risk factors of high significance. The proportion of positive dogs with canine-CL was 21.05% and was significantly associated with human-CL cases in the same area ( p  < 0.05).

Conclusions

We concluded that adopting self-protections measures against sand-fly, and maintaining good hygiene may lower the risk of human-CL. One-Health Strategy is suggested to control leishmaniasis in human and dog population.

Peer Review reports

Cutaneous Leishmaniasis (CL) is a parasitic disease transmitted via the bite of female sand-flies belonging to the genera Phlebotomus in the Old World and Lutzomyia in the New World. It is a skin disease ranging from self-healing lesions to single or large skin ulcers and is caused by protozoan parasites of the genus Leishmania [ 1 ] . Leishmania major is a main cause of CL in humans in an area that stretches from India through Central Asia, the Middle East, to North and West Africa [ 2 , 3 ].

The epidemiology of leishmaniases is dynamic and the conditions of transmission are continually changing depending on change in environment, demography, human behavior, socioeconomic status, and immunogenic profile of affected human populations [ 2 , 4 ]. Among the most important zoonotic diseases, leishmaniasis is a major concern for public health [ 5 ]. In terms of burden of diseases, it is estimated to be the third most important vector-borne disease. Despite this fact, it is one of the “neglected diseases”. The tropical and sub-tropical parts of the world are endemic with leishmaniasis [ 3 ]. The disease occurs in 88 countries of the world with 70 being endemic. Afghanistan, Algeria, Brazil, Pakistan, Peru, Saudi Arabia, and Syria are the countries where 90% of the cases occur [ 6 ]. According to an estimate, 1.3 million new cases and 20,000 to 30,000 deaths occur annually [ 5 ]. The disease is disfiguring skin affliction as reported by U.S Centre of Disease Control and Prevention (CDC). Leishmaniasis can be divided into two forms based on epidemiology of disease: zoonotic which includes animal reservoir hosts in the transmission cycle of the disease, and anthroponotic, in which humans are considered to be the sole source of infection for the sand-fly vector [ 7 ].

In Pakistan, leishmaniasis has been reported in human and animal population [ 8 , 9 ]. Human-CL is endemic in several parts of Pakistan and is the second most prevalent vector-borne disease in the country after malaria [ 10 ]. There are 37 out of 70 species of the sand-fly inhabitant in Pakistan, which can transmit disease to healthy hosts [ 11 ]. Endemic areas of disease in Pakistan include areas of Baluchistan, Interior Sindh, South Punjab and Khyber Pakhtunkhwa [ 11 , 12 , 13 , 14 ]. Currently, the progression of the disease is a public health issue and represents a challenge for health professionals. Epidemiological studies might help planning for effective strategies to control human-CL. Several factors such as climatic and environmental changes, the movement or migration of infected people, animal reservoirs and female infected sand-flies play important role in the transmission of leishmaniasis [ 15 ].

In Pakistan, cases of human-CL have been reported from different districts of Punjab province, however, data is scant about the identification of risk factors specifically in District Jhelum. Few studies have been carried out in Baluchistan, Khyber Pakhtunkhwa and Azad Kashmir [ 11 , 12 , 16 ]. In the present study, we aimed to quantify risk factors associated with human-CL in Khewra region of District Jhelum, Pakistan, with an objective to inform policy makers for evidence-based disease control recommendations to prevent future outbreaks. To study the presence of zoonotic risk of human-CL, we also conducted a prospective study in dogs, suspected for canine leishmaniasis (canine-CL) in the same geographical area.

The study was conducted in Khewra region, Tehsil Pind Dadan Khan, District Jhelum (Fig.  1 ). The district is administratively divided into four tehsils namely Jhelum, Dina, Sohawa and Pind Dadan Khan. Khewra region is divided into two union councils: Khewra no.1 and Khewra no.2 with a population of around 35,000 [ 17 ]. The area is surrounded by the famous Salt Range. It is located at 32°38′ 60″ N 73° 1′ 0″ E. Khewra City is also known as “The Kingdom of Salt” because of its rock salt, which is 98% pure and natural source of salt in Pakistan. Khewra Salt Mine is the second largest salt mine in the world [ 18 , 19 ]. Previously several outbreaks of human-CL in local population have been reported from this area between 2012 and 2013 [ 20 ].

Map showing study area in District Jhelum, Pakistan

Study design

Case-control study in human.

A case-control study was designed to evaluate the risk factors associated with human-CL between January to April 2014 in residents of Khewra region, District Jhelum. Patient records from outpatient and inpatient clinics of Municipal Hospital, Pind Dadan Khan, District Jhelum, were retrieved and reviewed for case selection.

Definition of case and control

Human-CL positive cases were diagnosed by medical physicians at the Municipal Hospital. A case was defined as a person having at least one leishmania lesion (presence of a skin ulcer with typical raised edges and depressed centre or a skin plaque-a circumscribed, nodular or palpable skin lesion) and/or a typical scar (a typical CL scar develop when a papule appears after biting of sand-fly, which may enlarge to become an indolent ulcerated nodule or plaque, and after self-healing of the plague, a depressed scar is left on skin) [ 21 ]. The trained medical officers used clinical diagnosis (leishmania lesion or/and CL scar) followed by confirmatory microscopy (impression smear) to confirm leishmaniasis. Case patients were visited in their house after getting their information from hospital records.

Human-CL negative controls were selected from the same hospital registered on the same day with different complain (visiting hospital to seek treatment for other diseases like trauma, accidents, surgeries, respiratory infections etc.) and had no typical skin lesions (ulcer, plaque, wound or scar) upon inquiry by investigation team.

All participants consented to participate in the study. Institutional Committee for Biomedical Research at University of Veterinary and Animal Sciences, Lahore, Pakistan (Letter no. 077/IRC/BMR) approved the study design. Permission to conduct study was obtained from Municipal Hospital authorities. Anonymity and confidentiality of patient data were assured.

Sample size calculation

A sample size of 180 individual (90 cases and 90 controls) was determined to give the study, 80% power at 5% significance to detect an odds ratio (OR) of > 2 for an exposure of human-CL in 30% of controls [ 22 ]. From the list of confirmed cases, 90 cases of human-CL were selected randomly and matched with 90 confirmed control on the date of registration in the hospital with a case–control ratio of 1:1. Sample size was calculated using epiR package version 1.0–14 [ 23 ] in R software.

Enrollment of cases and controls

We contacted and enrolled 180 participants for the case-control study (90 cases who could be reached during the study period were selected from the hospital records based on the case definition). Each enrolled case was matched with a hospital-based control (90 control) by the date of registration to the hospital.

Data collection and analyses

A predesigned questionnaire ( Supplementary Material ) was administered to cases and controls through face-to-face interviews. Questionnaire comprised of two sections namely general information and exposure information and closed question about potential risk factors were asked. Information about age, sex and different socio-demographic factors of cases and controls was collected.

The data was compiled by making a database in Microsoft Excel. R software version 2.14.0 [ 24 ] was used to statistically analyze the data. Simple proportions, means and medians were calculated for categorical data and continuous data respectively. To identify biologically plausible risk factors associated with the human-CL, conditional logistic regression was conducted by using survival package (version, 2.36.10) in R software, which effectively performs a Mantel-Haenszel matched-pair analysis [ 25 ]. Variables with p  < 0.25 in the univariable analyses were consequently included in multivariable analysis for final model building. To develop the final model, multivariable logistic regression was conducted using forward elimination method, starting with most significant factors having lowest p-value in the univariable analysis to determine independent risk factors [ 26 ]. Odds ratios and 95% confidence intervals (95% CI) were computed for significant risk factors to measure strength of association. All statistical tests were performed at a significance level of 0.05.

QGIS version 2.14.3 (available at https://www.qgis.org/en/site/forusers/download.html# ) was used to visualize the spatial distributions of cases in Khewra region, District Jhelum.

Prospective study in dogs

A prospective study of canine-CL in pet dogs attending Civil Veterinary Hospital from Khewra region, was conducted from January–April 2014. Owners of all suspected dogs with skin lesions (dermatitis, alopecia, cutaneous ulcerations, weight loss, ocular or nasal lesions) [ 27 , 28 ] attending the government veterinary hospital were requested to participate in study. Only those dogs were included whose owners consented to participate in the study. Peripheral blood samples were collected by a trained veterinarian from suspected dogs and thin dry smears were made using leishman’s stain. The amastigotes of Leishmania were detected by using a compound microscope [ 29 ].

Data analysis

Data was statistically analyzed by using R software version 2.14.0 [ 24 ]. Chi square test was used to asses any association between canine-CL, area, and presence of any positive human-CL case. Proportion of canine-CL was calculated.

The human-CL cases enrolled in current study were registered in Municipal Hospital, Pind Dadan Khan, District Jhelum from October 2012 to November 2013. All of them visited hospital after the development of the lesions. Therefore, the date of the sand-fly bite was not accurately known by the cases and the time of exposure to human-CL could not be specified.

Demographic characteristics of cases

Among the cases, the individuals between the age group 1-15 years, had the greatest frequency (51%). The median of the age of human-CL patients was 15 (range: 1–76) (Fig.  2 ). The gender distribution was equal among cases (Male = 45; Female = 45). Most of the cases ( n  = 69, 76.7%) belonged to the income level category of PKRs 5000–10,000 (ranged from PKRs 5000-30,000). The hospital registration of human-CL patients was lower in winter months (December 2012-February-2013) and it peaked during summer and monsoon months (May–September 2013) followed by decline during October and November months (2013) (χ 2  = 20.4, p  < 0.05). The highest peak observed was in June and September 2013 ( n  = 12), whereas the lowest was in December 2012 and February 2013 ( n  = 2) (Fig.  3 ). The geographical locations of cases are marked on map in Fig.  4 (a) and showed that most of the cases were concentrated near Jotania (16.7%) and Sultania (16%) areas followed by Rehan Colony (Fig.  5 ). Locations of controls were not retrieved.

Age of study participants

Distribution of reported cases of human-CL per month

Locations of enrolled cases of human-CL (a) and canine-CL (b) in Khewra Region, District Jhelum

Number of human-CL cases according to areas and canine-CL cases

Potential risk factors

A total of 180 individuals were contacted and interviewed (90 cases, 90 controls) from the study area. Ten variables were screened in univariable analysis and 8 were associated with being a case or control (Table  1 ). Poor sanitary conditions, presence of other Leishmania infected persons in the house, sleeping outsides in open areas, other animal on premises, and house type, gender (being female), using protections like insecticide sprays, bed nets, screens etc. and age (in years) were selected for multivariable analysis based on selection criteria ( p  < 0.025). Two variables ‘income of the participant’ and ‘keeping a dog’ having p  > 0.25 were excluded from further analysis. One variable namely ‘other human-CL patient in house’ was excluded from analysis due to insufficient number of discordant pairs (Table 1 ).

In the final multivariable model, four variables were identified as significantly associated with the human-CL in Khewra residents (Table  2 ). Cases keeping other animals in house (livestock, poultry) were 3.6 times (95% CI: 1.07–12.12, p  < 0.05) more likely to have human-CL compared to controls. Similarly, cases having poor sanitation conditions at home were more likely to have human-CL (OR: 3.3, 95% CI 1.03–10.56, p  < 0.05) as compared to controls. The odds of being diagnosed with human-CL were 8.7 time more in cases who slept outside in open area (95% 2.90–26.37, p  < 0.001) when compared to exposure in controls. The increasing age showed to have decreased the likelihood of human-CL 0.4 times (95% CI: 0.25–0.76, p  < 0.005) (Table  2 ).

During the study period (January–April 2014), 15 blood samples of the dogs brought to Civil Veterinary Hospital with skin lesions were collected. A dry thin stained smear was made from the blood sample for the detection of amastigote forms of Leishmania in macrophages of the dogs. Leishmania amastigotes forms were found in 4 out of 15 samples (21%). The presence of positive dogs was significantly associated ( p  < 0.001) with the positive cases of human-CL in the same area. The spatial distribution of the canine-CL cases with human-CL cases is shown in Fig. 4 (b). The dogs from Jotania, Islamganj and Karimpura areas were tested positive for canine leishmaniasis (Fig. 5 ). The status of the dogs from other areas was unknown.

The epidemiological triad of CL is complex with various epidemiological risk factors associated with host, agent and environment. Early recognition of these risk factors may prevent the further transmission to susceptible population. Results of our study support the findings of other studies from Pakistan that CL cases are increasing in the local human and dog population in Pakistan [ 9 , 12 , 13 , 30 , 31 ] suggesting that a one-health approach would be needed to reduce the disease burden.

Published literature about risk factors for human-CL in Pakistan in generally sparse or obsolete [ 8 , 32 , 33 ]. The current study was aimed to determine the risk factors associated with human-CL that prevailed in the local environment and detection of canine-CL in dogs in Khewra region, District Jhelum. After extensive literature review, age, sex, income, keeping dog, keeping other animals (livestock, poultry), poor sanitary conditions, sleeping outside in open areas, using protections and presence of other Leishmania infected persons in the house were included as risk factors [ 2 , 12 , 30 , 34 , 35 , 36 ].

Seasonal pattern of transmission is useful to establish disease surveillance and control activities [ 37 ]. Human-CL patients registered in the current study, visited the hospital over a period of 12 months. There was a significant increase in the patient visits to the hospital during summer and monsoon months (May–September 2013). This reflects seasonal activity of sand-fly vector during summer and rainy season. Jhelum experience monsoon season from June to September which brings heavy rain, while the dry season in this region is from November to January. Varied transmission patterns have been reported by various studies suggesting seasonal trends in different geographical locations [ 37 , 38 , 39 ].

Previous studies have reported clustering of leishmaniasis at household level [ 33 , 38 , 40 ]. In current study, among all cases, 59% ( n  = 53) confirmed the presence of other human-CL patient in their house or in the neighbors. Presence of an infected person in the household increases the risk of getting infected because sand-flies have limited fly zone and they remain in same vicinity and could bite multiple hosts living at the same place [ 32 , 38 , 40 ]. L. tropica transmission has also been known to be characterized by clustering of cases [ 32 ].

In the current study, we identified a set of risk factors that might significantly contribute to the web of causation of human-CL in the region. Age (increasing in years) was identified as a protective factor (OR < 1). The majority of the cases in our study were children and young people < 15 years of age and human-CL was less reported in adults compared to children age groups. Increasing each year in age reduced the likelihood of human-CL 0.4 times. This could be correlated to the outdoor activities of the children (playing outdoor games) with minimum precautions to cover their body, which might have exposed them to bites of sand-flies, while adults adopt more precautions during outdoor activity [ 38 , 41 , 42 ].

Keeping other animals in house (livestock, poultry) showed association with CL (OR > 1). Presence of other animals e.g. livestock and poultry, could attract vector of CL due to presence of barn and dried dung, and may expose residents to the female sand-flies. Previously, presence of sand-flies was reported to be associated with cattle and cattle blood was found in Phlebotomus tobbi females [ 41 , 43 , 44 ].

Patients reporting poor sanitary condition were 3.3 times more likely to diagnosed with human-CL compared to those with better condition. Almost 80% of the cases reported unsatisfactory sanitary condition at home, which included, open toilets, open sewage, mud floors and unhygienic livings. Poor sanitary conditions provide suitable habitat for sand-flies to breed and spread human-CL [ 45 , 46 ]. Studies have consistently shown more cases of human-CL among poor, neglected populations, who are likely to be less educated and mostly unemployed [ 41 , 47 ]. Furthermore, most of cases (76.7%) in current study, belonged to families having an income of PKRs 10,000 or less. Families with lower income level have less resources to adopt protective measure and awareness about the protections against diseases, consequently increased risk of exposure to sand-flies and Leishmania infection [ 2 ]. Interventions such as poverty alleviation and improving living condition might aid significantly in controlling human-CL transmission in the region [ 21 ].

Sleeping outside in open air increased the odds of human-CL, probably due to their exposure to the sand-fly bites during the sleeping time as one cannot protect oneself. Sleeping outdoor in open space during summer months is very common in Pakistan. Our findings corroborated with the results of other studies that sleeping outside is a risk factor for CL [ 3 , 41 , 47 , 48 ]. In Pakistan, May–September are hot and humid months and people, especially in villages prefer to sleep outside the rooms in open air. Sand-fly activity is also increased through June and July, with peak in August. Entomological studies indicated nocturnal activity of sand-flies starts at the beginning of the night, and is strongly associated with relative humidity rather than with temperature [ 3 , 41 , 47 ]. Our data also supported the speculation that the most appropriate transmission period of CL is during the hot and humid nights from July to September.

During the period of 3 months, 15 suspected dogs for CL were brought to the local veterinary hospital. Their blood samples were taken and tested for presence of Leishmania protozoa. Among 15 suspected, 21% ( n  = 4) were detected positive for canine-CL. Although dogs are considered major reservoir for L. infantum, the possibility of clinical canine disease and their potential as secondary hosts for L. major should be investigated in endemic areas for human L. major infection [ 28 , 34 ]. Our results showed a significant association between the areas of reported cases of human-CL and canine-CL positive dogs. Areas with high burden of human-CL cases had presence of canine-CL positive dogs.

The findings of the study have some limitations due to case-control nature of the design as it is difficult to establish the temporal causality in case-control studies. Furthermore, these study designs are prone to selection bias and recall bias. Future investigations based on cohort study design would be more appropriate to ascertain the causal relationship between risk factors and outcome.

Pakistan has a diverse landscapes and climates that may affect the transmission of Leishmania in the country. The key risk factor identified in present study may be extrapolated to design an early preparedness response for human-CL outbreaks at human-animal interface. The current study also provides initial evidence for the presence of canine-CL in Khewra region, District Jhelum.

Availability of data and materials

The data gathered and generated during the current study are available from the corresponding author (Mamoona Chaudhry) on reasonable request.

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Acknowledgments

We gratefully acknowledge the assistance of staff at Municipal Hospital, and Civil Veterinary Hospital, Pind Daden Khan. We would also like to thank study participants and owners of dogs for providing data and samples.

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Behzad Kayani, Shakera Sadiq, Rubab Maqsood, Saima Hasan, Muhammad Hassan Mushtaq, Ubaid-ur-Rehman Zia & Mamoona Chaudhry

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Conceived and designed the study: MC, MHM, HBR and BK. Collected data: BK and NA. Analyzed the data: MC, SS, SH, URZ, RM and MSK. Drafted paper: MC, BK, HBR, MHM, SS, SH, URZ, MSK, AM, HR, RM. All authors approved the draft.

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Correspondence to Mamoona Chaudhry .

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The study protocol and consent procedure were approved by the Institutional Review Committee for Biomedical Research, (Reference No. 077/IRC/BMR) (For Humans) and Advanced Study and Research Board (ASRB) of University of Veterinary and Animal Sciences, Lahore, Pakistan (for Animals).

For human subjects, all participants and their attendees were briefed about the purpose of research, interview and questions, voluntary participation and other aspects of the study. Confidentiality of data were maintained during study and analysis. All procedures and methods were carried out according to Helsinki Declaration 2013. A trained medical doctor or paramedic staff registered with Pakistan Medical and Dental Council (PMDC) collected the samples from human subjects.

For animal patients, a trained veterinary staff, registered with Pakistan Veterinary Medical Council (PVMC), collected the blood samples from dog according to standard guidelines and procedures. All suspected dogs were provided with adequate water and food. Animals were properly restrained and a trained staff collected peripheral blood from brachial vein. We followed guidelines published by University of Minnesota Institutional Animal Care and Use Committee, USA.

For human participants, Informed consent was obtained from the individual patients and the parents (in case of minors). For animal cases, informed consent was obtained from the owner of the animal before taking samples and data.

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Kayani, B., Sadiq, S., Rashid, H.B. et al. Cutaneous Leishmaniasis in Pakistan: a neglected disease needing one health strategy. BMC Infect Dis 21 , 622 (2021). https://doi.org/10.1186/s12879-021-06327-w

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Research Article

Developments in Leishmaniasis diagnosis: A patent landscape from 2010 to 2022

Roles Data curation, Formal analysis, Methodology, Writing – original draft, Writing – review & editing

Affiliation Instituto René Rachou—Fiocruz Minas, Belo Horizonte-MG, Brazil

Roles Data curation, Formal analysis, Writing – review & editing

Affiliation Instituto Nacional de Propriedade Intelectual–INPI, Rio de Janeiro-RJ, Brazil

Roles Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Project administration, Supervision, Validation, Visualization, Writing – original draft, Writing – review & editing

* E-mail: [email protected]

Affiliations Instituto René Rachou—Fiocruz Minas, Belo Horizonte-MG, Brazil, Fundação Oswaldo Cruz-Fiocruz, Centro de Desenvolvimento Tecnológico em Saúde, Instituto Nacional de Ciência e Tecnologia de Inovação em Doenças de Populações Negligenciadas, Rio de Janeiro, RJ, Brasil

• Daniel Moreira de Avelar, 
• Camila Chaves Santos, 
• Alice Fusaro Faioli

• Published: November 1, 2023
• https://doi.org/10.1371/journal.pgph.0002557
• Peer Review
• Reader Comments

The current study aims to contribute to the understanding of leishmaniasis diagnosis by providing an overview of patent filings in this field and analyzing whether the methods revealed are consistent with the needs described by the scientific community, in special the main gaps detected by the World Health Organization’s 2021–2030 Roadmap for Neglected Tropical Diseases. To this aim, a patent search was carried out focusing on documents disclosing leishmaniasis diagnostic methods supported by experimental evidence and with earliest priority date from 2010 onwards. Our results show that patenting activity is low and patent families are often formed by individual filings. Most R&D activity occurs in Brazil, which is also the main market of protection. Brazilian academic institutions are the main patent drivers, and collaboration between different institutions is rare. Most patent families describe immunological methods based on ELISA assays, using antibodies directed to K39 and homologues. kDNA is the primary gene for molecular testing. Experimental evidence of test performance in fulfilling critical diagnostic gaps is usually absent. The patent scenario suggests that leishmaniasis diagnostic gaps need to be more closely addressed to drive innovation directed to the control and/or elimination of leishmaniasis. From the public policy point of view, the following strategies are suggested: (i) strengthening collaborative networks, (ii) enhancing the participation of the private sector, and (iii) increasing funding, with special focus on the remaining diagnostic gaps.

Citation: de Avelar DM, Santos CC, Fusaro Faioli A (2023) Developments in Leishmaniasis diagnosis: A patent landscape from 2010 to 2022. PLOS Glob Public Health 3(11): e0002557. https://doi.org/10.1371/journal.pgph.0002557

Editor: Suma Thankamma Krishnasastry, T D Medical College, INDIA

Received: March 6, 2023; Accepted: October 9, 2023; Published: November 1, 2023

Copyright: © 2023 de Avelar et al. This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Data Availability: The dataset used for this work is provided as supplementary material .

Funding: This work was funded by FAPEMIG via the following grants: ACN-00110-21 (AFF), and APQ-00802-20 (DMA). Funding for publication was provided by CNPq, CAPES, and FAPERJ through the National Institutes of Science and Technology Program (INCT) to Carlos Morel (INCT/IDPN). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Competing interests: The authors have declared that no competing interests exist.

Introduction

Leishmaniasis is an important disease complex caused by protozoan parasites of the genus Leishmania . It is usually classified according to clinical presentation as tegumentary (TL) or visceral (VL) leishmaniasis. Cutaneous (CL) and mucocutaneous (MCL) leishmaniasis are clinical forms of TL, while Post Kala-azar Dermal Leishmaniasis (PKDL) is a late cutaneous manifestation of VL. Leishmaniasis is considered a neglected tropical disease (NTD), with an estimated 700,000 to 1 million cases annually.

Significant efforts have been made in the past decades to control and/or eliminate NTDs, leishmaniasis included. Among key global actions are stakeholder commitments such as the London Declaration and the 2030 Agenda for Sustainable Development [ 1 , 2 ], and WHO roadmaps for NTDs (the first encompassing the years of 2012 to 2020 and the second from 2021 to 2030) [ 3 , 4 ].

Specific goals for leishmaniasis set in WHO’s 2021–2030 roadmap are: eliminating VL as a public health problem in 85% of countries and controlling CL (85% of all cases detected and reported, and 95% of reported cases treated). The roadmap recognizes diagnostics play a central role towards the achievement of such goals [ 4 ]. Effective diagnostics accelerate case detection and treatment, reducing disease progression and ensuing disability, and contributing to disease eradication by reducing sources of infection. In addition, they are essential to improve surveillance, for monitoring transmission, disease burden and outbreaks, or to evaluate control measures. Considering diagnostics directly inform several targets set in the 2021–2030 roadmap, WHO established in 2019 a Diagnostic Technical Advisory Group for NTDs (DTAG-NTD) to address priority areas for NTD diagnostics, identify gaps in access, and advise on developments required for the diagnostic process to properly inform decisions on NTD treatment [ 5 , 6 ].

WHO’s 2021–2030 roadmap assessment of the current scenario for VL diagnosis is that (i) it lacks adequate diagnostics for surveillance, (ii) major changes are required on diagnostic tests available for screening and diagnosis confirmation, (iii) sensitivity of rapid tests is insufficient in certain regions, (iv) a viable test of cure for VL and PKDL is absent, and that (v) PCR is restrict to reference laboratories [ 4 ]. The specific priorities set for VL in the 2021–2030 roadmap were to develop: (i) more sensitive rapid diagnostic tests for use in East Africa, (ii) less invasive, highly specific tests to measure parasite level, and (iii) a minimally invasive test of cure for PKDL and VL. The following critical actions were defined: (i) enable early detection to ensure timely treatment, and (ii) develop more effective and user-friendly diagnostics, especially for East Africa [ 4 ]. The scientific literature adds to that the need for more reliable VL tests to detect acute phase, relapse, and Leishmania -HIV coinfection [ 7 ].

Target Product Profiles (TPPs) for point of care in vitro detection of active VL and for in vitro laboratory-based test of cure for VL post-treatment have recently undergone public consultation. Draft versions of the TPPs highlight the need of diagnostic tests with the following ideal features: detection of analytes specific to L . donovani or L . infantum , with more than 95% clinical sensitivity and 99% clinical specificity; qualitative result for detection of active VL and quantitative result to confirm VL cure; execution under zero-infrastructure conditions, at low cost, using peripheral whole blood from finger stick, urine or saliva as samples, and enabling test result within 30 minutes [ 8 ].

The roadmap assessment for CL is that (i) current diagnosis based on parasitological tests and/or clinical features is not sufficiently sensitive in several endemic areas and laboratory diagnosis is not always available, and (ii) PCR is only available in reference laboratories. Improving the affordability and sensitivity of rapid diagnostic tests available at the health center and community levels, including detection at species level, is one of the key actions identified for CL. This is especially important in foci where multiple Leishmania species coexist [ 4 ]. It should be emphasized that identification of the responsible Leishmania species can be crucial to prognosis, disease control and therapeutic interventions [ 9 , 10 ].

A 2019 TPP for a point of care test for dermal leishmaniasis considers the following specific optimal features: species-specific detection of any form of CL or PKDL with more than 95% specificity, the use of Leishmania antigens as targets, direct testing from lesion swab, and less than 20 minutes to result, with visual reading. Minimal features are genus-specific detection of active localized CL with more than 90% specificity, using aspirates/biopsies/skin scrapings as samples, and obtaining results in less than 1h upon visual reading or using a simple reading device [ 11 ].

Although several reviews describe recent advances in leishmaniasis diagnosis published in the scientific literature [ 9 , 12 – 16 ], we could not find recent patent landscape analyses on this subject. Patent landscapes give a snapshot of innovation in a technological field of choice at a given time, providing insight into the patenting dynamics, key players, R&D location, markets of protection, technological trends, emerging technologies, among others. Such analyses are a useful tool to support decision making and R&D investment.

The current study aims to contribute to the understanding of leishmaniasis diagnosis by providing an overview of the patent filings in this field and analyzing whether the developments revealed in these documents are consistent with the needs described by the scientific community, in special the main gaps detected by WHO’s roadmaps. We focus on patent documents disclosing experimental evidence of diagnostic use submitted within the past decade, rather than patent documents that claimed a diagnostic test for leishmaniasis but did not necessarily support such claims experimentally. This strategy allows for a comprehensive and more informative analysis of the diagnostic method disclosed. A limitation of this approach is that evidence for leishmaniasis diagnosis may be obtained after the patent application, in which cases relevant inventions will be ignored. Nonetheless, we believe that the overestimation resulting from including all documents, regardless of experimental evidence, is much more detrimental than the possible underestimation that could result from the use of an experimental evidence filter. This patent landscape can be used to inform policy discussions, guide direct investment and strategic research planning.

Materials and methods

This patent landscape follows OECD’s Patent Statistics Manual guidelines [ 17 ] and the checklist for Reporting Items for Patent Landscapes (RIPL) [ 18 ].

Dataset compilation S1 Data

Search scope and strategy..

Searches were carried out in September 2022 using the proprietary database Orbit Intelligence (Questel, Paris, France). This database covers patent documents published by more than 100 patent authorities worldwide, encompassing more than 110 million patent publications at the time of writing. Our search strategy targeted patents filed after 2010 disclosing a method for diagnosing leishmaniasis. Therefore, we only included patent families for which the first patent application was filed after 01/01/2010, i.e., documents with earliest priority after this date. More specifically, we first searched for documents containing the words leishmania+ and (+diagnos+ or detec+) in their title, abstract, or claims. We also used the Cooperative Patent Classification (CPC) and International Patent Classification (IPC) codes to include documents containing the word leishmania+ in their title, abstract, or claims and classified as (i) “immunoassay or other binding assay” (under CPC or IPC G01N33/569), (ii) “a measuring/testing process involving enzymes, nucleic acids or microorganisms” (under CPC or IPC C12Q1+) or as (iii) a “test involving the analysis of chemical or physical properties” (under CPC or IPC G01N+); or containing the word leishmania+ in the claims and classified as “peptides derived from protozoa” (under CPC or IPC C07K14/44); or containing the word diagnos+ in their title, abstract, or claims and classified as “ Leishmania antigens” (under CPC or IPC A61K39/008). See S1 Text for the specific search strings used.

Patent grouping into families.

Documents retrieved by our searches were automatically grouped by Orbit Intelligence into FamPat patent families. Orbit rules for FamPat construction are designed to group together all patent publications related to a single invention, such as different stages of a patent application in a particular country or related applications filed in different countries.

Patent selection criteria.

Inventions outside the scope of our search (i.e., unrelated to leishmaniasis diagnosis) and inventions within our search scope but which did not show experimental evidence of leishmaniasis diagnosis were manually excluded. At this stage some patents classified by Orbit into different patent families were grouped as a single family, when they protected the same invention and had a priority document linking the family. Manually grouped families are listed in S2 Text . In addition, two patent documents from Brazil were excluded from our dataset because they were continuation of documents with priority dates before 01/01/2010.

Data extraction.

The following data was automatically extracted from the FamPat families: current standardized assignee, assignee country, assignee address, inventor name, inventor address, earliest priority date, family legal status (pending, granted, revoked, expired, lapsed), family legal state (alive, dead), countries/authorities. Patents families were automatically ungrouped to obtain individual patent application numbers and the legal state of individual filings (FullPat records).

Manual classification of data

Extracted data standardization..

Data was manually cleaned to harmonize assignee name and remove from this field the funding agency’s, university board of regents’, or technology transfer office’s name.

Assignee classification.

Assignees were classified as “Academy” (universities, research institutes, government, and other not-for-profit entities), “Corporate” (companies), or “Individuals” (where an individual was indicated as assignee without affiliation to any organization).

R&D collaborations.

The field “current standardized assignee” was used to determine whether the invention was developed in collaboration. When the assignee was an independent inventor, this classification was not considered applicable. When developed in collaboration, inventions were further classified to indicate whether they consisted in academy-only, corporate-only, or academy-corporate partnerships.

Classification of diagnostic methods.

Patent documents were thoroughly analyzed and classified based on the experimental evidence disclosed. It was determined whether the test consisted of a molecular or immunological method, the precise method used (e.g., PCR, RT-PCR, ELISA etc.), the antigen or target gene employed, the clinical presentation under investigation (VL, CL etc.), Leishmania species tested, test sample, and whether it demonstrated detection of asymptomatic infection or detection of leishmaniasis in individuals coinfected with HIV. For molecular methods, we also specified if species typing and parasite quantification were demonstrated. In the case of immunological methods, we further indicate whether the antigen is identical to its natural form (or parts of it) or whether it has been modified. The presence of accuracy results and level of evidence were analyzed based on [ 19 ], that being: 1. An independent, masked comparison with reference standard among an appropriate population of consecutive patients; 2. An independent, masked comparison with reference standard among nonconsecutive patients or confined to a narrow population of study patients; 3. An independent, masked comparison with an appropriate population of patients, but reference standard not applied to all study patients; 4. Reference standard not applied independently or masked; 5. Expert opinion with no explicit critical appraisal, based on physiology, bench research.

Patent data analyses

Patent timeline..

Patent counts . To obtain an overall picture of inventive activity, patent family counts were plotted by earliest priority year. Earliest priority year was chosen as the closest date to the invention and best indicator of inventive performance, following OECD’s recommendations [ 17 ].

Family size . The number of different authorities in which patents from each patent family were filed was assessed using Orbit’s field “Countries/authorities count”. This field was corrected for the patent families that were manually grouped. This is considered an indication of investment in the protection of each invention, as additional fees are required for each filing in a different authority.

Identification of R&D country.

The assignee country was used to infer where R&D activity took place. Inventors’ address was used when no assignee address was available or when further clarification was needed. When the above-mentioned information was not available, we Google searched assignee name to ascertain its location. For a small number of patents R&D location could not be identified by any of the previous strategies and priority country was used as R&D location.

Markets of protection.

For this analysis we considered the countries where patents are still alive, either granted or pending. To obtain this information, patent families were automatically ungrouped (Orbit’s Fullpat records). The individual patents were filtered by patent status and the country codes of alive patent documents were extracted.

Patent status.

A family is considered alive if it has at least one live member, either granted or pending. Thus, to count it as dead, all members must be dead.

Assignee type and collaboration.

The following was assessed: (i) the number of patent families per assignee type (“academy”, “corporations” or “individuals”); (ii) how many of these families are jointly owned by two or more assignees; and (iii) the precise type of collaboration (academy-only, corporate-only, or academy-corporate). When more than one individual assigned a patent family it was not considered a collaboration, as in many of such cases the patent family will be later reassigned to an academic institution or corporation where the invention was developed.

Top assignees.

A list of all patent assignees (n = 45) was gathered and the number of times each name is indicated as patent family assignee was assessed (totaling 101 occurrences). Eight assignees were individuals and were not considered in the present analysis.

Our search strategy resulted in the retrieval of 423 patent families. Each patent family contains one or more individual patent applications related to a single invention. Multiple filings under the same family often correspond to filings for the same invention in different countries. Of these 423 patent families, only 94 showed experimental evidence of leishmaniasis diagnosis (amounting to a total of 136 individual patent applications). These are the patent families that disclose a diagnostic method for leishmaniasis with experimental support first filed after 01/01/2010. Mere identification of immunogenic proteins without confirmation of diagnostic potential, by western blot for instance, was considered insufficient to meet the inclusion criteria. All our analyses are based on this specific set of patent families.

Patenting dynamics

Patenting activity for leishmaniasis diagnosis is low. In the most active year only 11 patents were filed, whereas lowest activity occurred in 2011 (4 patents filed). Given that most patent authorities publish patent applications up to 18 months after filing, the drop in filings observed in the last couple of years is expected ( Fig 1A ). An average of 8 filings per year is detected when the last two years are removed. In terms of patent family size, the vast majority (78%) of patent families consist of single patent applications, while 13% of patent applications were filed in two patent offices. Only 9% of patent families were filed in three or more patent authorities ( Fig 1B ).

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• TIFF original image

(A) Patent family counts. Each patent family is counted once, in the year the first patent in the family was filed i.e., the earliest priority year. (B) Patent family size. Patent families are accounted for by size (the number of different authorities in which each patent family was filed).

https://doi.org/10.1371/journal.pgph.0002557.g001

Most R&D activity (59%) took place in Brazil, followed by China (17%), the USA (7%) and India (6%). The remaining countries have smaller contributions (2% or less each) ( Fig 2A ). Regarding the actual markets of protection, most live patents are in force in Brazil (54%), China (13%), India (11%) and the US (10%) ( Fig 2B ).

(A) Patent family counts are assessed by R&D location. Patent family assignee country is used as an indication of R&D location. When assignee country was unknown, inventor’s address was used instead. (B) The country codes of live individual patent filings (Fullpat) are accounted for. Patents filed in Europe (EPO) or via PCT (WO) that can still enter the national phase are included.

https://doi.org/10.1371/journal.pgph.0002557.g002

The previous patent family counts include applications that are alive, either pending examination or granted, but also applications that are already dead, i.e., abandoned by the assignee, expired, or revoked. Patent legal status was analyzed to ascertain how many of the 94 patent families currently protect inventions or still have the potential to protect them. Our results showed that 70% of the patent families are alive (i.e., they have at least one live member, either granted or pending) ( Fig 3 ). From these live families, most (62%) are pending applications, whereas 38% contain at least one patent in force (i.e., granted).

Families are considered alive if they have at least one member still in force. When the live family contains at least one granted patent, the whole family is classified as granted. Otherwise the family is regarded as pending, indicating that applications belonging to this family are still under review by the respective national patent office(s).

https://doi.org/10.1371/journal.pgph.0002557.g003

Assignees were further classified according to the institutions supporting the inventive activity. Academic institutions appear as assignees in 80% of the patent families, corporations in 12% and individuals in 8% ( Fig 4 ). Only 16% of our patent families had more than one academic institution or corporation as assignee. Of these, 86% are co-assigned by the academic sector, 7% by corporations, and 7% by the academy and corporations.

Assignees were classified as “Academy” (universities, research institutes, and other not-for-profit entities), “Corporate” (companies), and “Inventor” (individual without affiliation to any organization). The number of patent families having each of these assignee types is shown. The number of patent families with a single assignee are represented in blue, whereas those with two or more assignees (indicating a collaboration) are depicted in orange. Patents assigned by individuals were considered as being owned by a single assignee.

https://doi.org/10.1371/journal.pgph.0002557.g004

Top applicants are mostly Brazilian academic institutions. Universidade Federal de Minas Gerais (UFMG) is by far the institution with the highest number of patents, assigning 33% of the patent families, followed by Universidade Federal de Uberlândia (UFU), Fundação Oswaldo Cruz (Fiocruz) and Universidade Federal do Paraná (UFPR) (assigning 6%, 5% and 5%, respectively). The institutions represented in Fig 5 are the only ones that own 2 or more patent families from the 45 institutions assigning patents in our dataset.

The number of times each assignee name is indicated as patent family assignee is represented. Legend: UFMG- Universidade Federal de Minas Gerais, UFU—Universidade Federal de Uberlândia, Fiocruz—Fundação Oswaldo Cruz, UFPR—Universidade Federal do Paraná, UFOP—Universidade Federal de Ouro Preto, Chinese CDC—Chinese Center For Diseases Control & Prevention, UFSJ—Universidade Federal de São João Del Rei, FUCRI—Fundação Educacional de Criciuma, UNESP—Universidade Estadual Paulista Júlio de Mesquita Filho, UFV—Universidade Federal de Viçosa.

https://doi.org/10.1371/journal.pgph.0002557.g005

Assessment of experimental evidence

A thorough analysis of experimental evidence contained in the 94 patent families of our dataset indicated that 61 of them disclosed immunological methods for leishmaniasis diagnosis whereas 32 disclosed molecular methods. One method that did not fit either category was classified as “other”. A total of 63 immunological and 33 molecular methods were revealed in these patent families, as some of them presented experimental evidence of more than one mode of implementing the invention. Most patents reveal a diagnostic method based on ELISA assays (50) or Polymerase Chain Reaction (PCR) (20). The specific methods disclosed are summarized in Table 1 .

https://doi.org/10.1371/journal.pgph.0002557.t001

Molecular methods.

A more detailed analysis of patent families disclosing molecular methods is summarized in Table 2 . Most of them target the kDNA minicircle (11) or 18S ribosomal RNA/DNA (4). Considering the form of the disease and species tested, most target VL (23) and TL (18, including CL data). The most tested species are L . donovani (19), L . infantum (16) or L . major (15). Leishmania quantification was demonstrated in 14 of these 32 families and another 14 evidence typing, though in one case at complex level only (not at species level). Seven families included experimental evidence demonstrating both quantification and species typing. Only one of the tests was assessed for detection of asymptomatic individuals and none for HIV/ Leishmania co-infection. Clinical validation is included in 15 of the patent families. From these, 12 are validated using human samples only, one used dog samples only, one used both human and dog samples, and one used human, dog, and insect vector. Only three of them presented accuracy results, one classified as level of evidence 4 and the other two as level 2 (based on Turlik, 2009 [ 19 ]).

https://doi.org/10.1371/journal.pgph.0002557.t002

Immunological methods.

A more detailed analysis of patent families disclosing immunological methods is summarized in Table 3 . Overall, there is a predominance of tests based on the detection of antibodies. Most tests are based on K39 or on a K39-homologue (12), either alone or in combination with other antigenic regions. Thirty-four of the patent families do not employ the whole protein as target antigens, but selected peptides and epitopes (alone or combined), 6 of which are chimeric proteins. Considering the form of the disease and species tested, most target VL (53) and TL (22, including CL data) and most tests are carried out with L . infantum (39) or L . braziliensis (19). From the 61 patent families, only 17 confirmed detection of asymptomatic individuals and 3 detected leishmaniasis in cases of HIV/ Leishmania co-infection. Clinical validation is included in 56 of the patent families. From these, 19 are validated using human samples only, 21 use dog samples only, and 16 use both human and dog samples. Accuracy results are included in 44 of them, 43 of which are classified as level of evidence 4 and one as level 2.

https://doi.org/10.1371/journal.pgph.0002557.t003

Other methods.

One method did not fit into the categories of molecular or immunological method and was classified as “others” ( Table 4 ).

https://doi.org/10.1371/journal.pgph.0002557.t004

Our results suggest very slight worldwide interest in patenting leishmaniasis diagnostic methods, with few patents filed per year (mostly protecting the invention in a single country). Although diagnosis is an essential component of any NTD control program, from disease confirmation to mapping, screening, surveillance, monitoring and evaluation, diagnostics are overall a neglected area in healthcare, receiving little attention and funding [ 20 ]. As patenting is a relatively expensive process, especially when protection is sought in multiple jurisdictions, the low interest in leishmaniasis diagnosis is not surprising.

Most applications come from institutions in Brazil, followed by China, India, and the USA. These are also major markets of protection. This finding is consisting with the outstanding contribution of Brazil, the USA and India to leishmaniasis research [ 21 – 25 ], the fact that these countries are endemic for leishmaniasis [ 26 ] and that China and the USA are the leading countries in overall patent filings and filings by residents [ 27 ]. The expressive contribution of Brazil and India is also in line with the impact of the disease in these countries. According to data from the Global Health Observatory, India and Brazil are among the top five countries in reported VL cases from 2005–2020. China appears in the 12 th position. Brazil is also among the top three countries in reported CL cases from 2005–2020 [ 28 ]. Most surprising is the lack of patents from the United Kingdom, Iran, Colombia, Venezuela and Spain, countries that significantly contribute to scientific research in the field, some of which are also affected by leishmaniasis [ 21 , 29 ].

Patent grant can be used as a quality indicator of innovation activities [ 30 ]. However, considering almost half of the 94 families are still under examination by patent offices, it is not known whether the invention disclosed in these applications are in fact new and inventive compared to the prior art [ 30 ].

According to our analyses, the R&D behind patenting is almost entirely carried out by universities and research institutions, with little contribution from companies. Such low private sector interest is expected, given the low financial return from interventions primarily targeting low-income populations. Universidade Federal de Minas Gerais (UFMG) is by far the leading assignee with 33% of patent families. Notably, the top five assignees, owing 54% of patent families, are all Brazilian universities/research institutions. Out of 45 assignees, only 11 hold two or more patent families. From these, nine are Brazilian and two are Chinese universities/research institutions.

Our patent data analyses indicate that the strong international collaborative research observed when analyzing scientific publications on leishmaniasis worldwide [ 23 , 25 ] does not lead to co-ownership of patent applications for leishmaniasis diagnosis. In fact, only 16% of our patent families contained some type of joint research (international or national), the vast majority of which occurred between two academic institutions from the same country. It seems that either collaboration is low for leishmaniasis in general, or it is more focused on basic research and other research topics rather than diagnostics, such as drug or vaccine development.

More detailed analysis of the methods disclosed in the patent documents showed that kDNA is the most used target region in the molecular method patent families. kDNA is often targeted for its abundance, specificity, and repetitiveness. A drawback of using this gene to quantify parasites is the uncertainty of whether kDNA copy number differs between Leishmania species, strains, and growth stages. While seven of the patent families disclosing a kDNA-based test give experimental evidence of parasite quantification, only three mention the Leishmania species used and only one of these uses more than two species. Therefore, it is not possible to ascertain that all seven kDNA based tests will quantify parasites regardless of Leishmania species, strain, and growth stage.

Our results indicate that K39 or K39-homologues are the most popular target genes in the patent families disclosing immunological tests (either alone or in combination with other antigenic regions). K39 is an antigen used in commercial tests. The efficiency of current rapid diagnostic antibody detection tests based on K39 varies by region. For instance, while 98% of patients with primary VL in South Asia can be diagnosed with such tests, this number drops to 85–90% in East Africa [ 31 ]. Many of the patent families disclosing a K39 (or homologue)-based test claim that their goal is to provide an improved test for human or canine VL. However, only five patent families included comparisons with K39 and demonstrated that higher sensitivity is obtained.

Regarding gaps identified in WHO’s 2021–2030 roadmap [ 4 ], none of the patent families in the current landscape include enough experimental evidence to validate a rapid test. Moreover, only half of the molecular patent documents retrieved presented evidence of species typing, less than half presented some evidence of parasite quantification and only two patent families show the validity of the test on patients from East Africa or using DNA samples from East Africa isolates. Regarding the request of a test of cure for VL and PKDL, while some documents retrieved indicated that the disclosed diagnostic method could be used to differentiate healthy from treated individuals, only one family discloses a possible test of cure for VL supported by experimental evidence, and none presented validation for PKDL. In fact, experimental demonstrations with PKDL patient samples are only available in four patent families. This could possibly be explained by the difficulty in obtaining individual samples prior and after treatment, the fact that patents are filed early in the R&D process to guarantee priority date, and/or that PKDL is most common in East Africa and South-East Asia while most R&D work behind these patents took place in Brazil.

HIV– Leishmania coinfection and identification of asymptomatic dogs are important topics to be addressed if we are to achieve the goal of eliminating VL as a public health problem. HIV infection poses a major threat to leishmaniasis control and increases the risk of developing VL by more than 100-fold [ 32 ]. Despite the clear need for a rapid test capable of detecting Leishmania -HIV coinfection, only three patent families demonstrate test efficacy in such case. Identification of asymptomatic dogs is included in 18% of patent families, all by immunological methods. Most use canine samples to validate the test.

Regarding test format, health professionals should be able to perform such tests in difficult field conditions without the need of specific scientific expertise. Affordability is an important issue given the limited resources in affected regions and the need for continuous surveillance to control and eradicate the disease. For epidemiological surveillance of canine visceral leishmaniasis, testing of a large number of animals in a short period of time with an acceptable precision is essential [ 33 ]. Tests that could satisfy these criteria include rapid antibody detection tests (with greater potential for VL), antigen detection tests (for VL and TL) and isothermal molecular methods (such as LAMP and RPA, for LV and LT). However, the experimental validation contained in our landscape documents is insufficient to make a recommendation as to which of the disclosed tests with these characteristics are more likely to pass clinical validation.

Considering the low levels of jointly owned patents, there is a need to strengthen collaborative networks focused on developing diagnostic tests for leishmaniasis. Partnerships between different players in the innovation process, such as governmental agencies, international organizations, academic and private sectors, can be used to maximize the strengths of each partner and combine the expertise in the technical field with know-how to develop a product that meets market needs. Such partnerships include, but are not limited to, product development partnerships (PDPs), open innovation, public–private partnerships (PPPs), joint ownership of laboratories, among others. FIND is a successful example of a not-for-profit organization using a PPP business model for the development and implementation of diagnostic tools for poverty-related diseases. It has developed 24 diagnostic tools since 2003, including a LAMP based diagnostic test for VL. Their work on marginalized populations focuses on developing a diagnostic pipeline aligned with needs identified in the WHO’s 2021–2030 roadmap to contribute to the elimination of NTDs [ 34 ].

Indeed, the experience gained in the globe response to NTDs suggests that, in addition to multisectoral efforts, international multilateral coordination is crucial: the Fifth Progress Report on the London Declaration on NTDs accredits progress made in the global combat of NTDs to (i) intricate public-private partnerships, involving coordination with non-governmental organizations, industry, donors, academic institutions, endemic country governments and front-line health workers and (ii) national and regional ownership, i.e., the translation of international targets into national goals and strategies, with the support of the international community [ 35 ].

Given the low level of contribution of the private sector to patent filings and the fact that less than 1% of R&D funding comes from “industry” (pharmaceutical companies and biotechnology firms) [ 36 ], incentives should be given to enhance the participation of the corporate sector. One possible strategy is to use push-pull mechanisms to reduce R&D costs and increase market attractiveness, as already used for NTD drug development. These include targeted R&D tax credits (direct governmental contribution to companies, designed to promote R&D in specific areas), rewards and prizes awarded for the development of products that meet specific requirements, advance purchase commitments, open source models that encourage collaboration and resource sharing between the private sector and academia, support for requirements needed for regulatory approval and mechanisms to fast track analyses by regulatory agencies [ 6 , 37 , 38 ]. A more integrated approach focusing on multiple NTDs diagnostic platforms could also reduce the market failure inherent to NTDs. Such an approach is suggested by WHO’s 2021–2030 roadmap [ 4 ] and a strategic framework for the integrated control and management of skin NTDs, which includes CL and PKDL, was specifically launched in 2022 [ 39 ]. In fact, the need for a multiplex platform for skin NTD diagnosis is on DTAG’s agenda, the requirements of which are still to be defined [ 40 , 41 ]. At last, defining clear processes for test validation and adoption of tests by programs are also needed to improve the rate at which new tests can be introduced into public health programs.

Judging by the experimental evidence contained in patent documents, incentives are needed to (i) stimulate new inventions in the field of leishmaniasis diagnosis, (ii) align such inventions with market needs and (iii) help push existing inventions beyond the pre-clinical phase. These incentives include increased funding. Global leishmaniasis diagnosis research funding between 2007–2020 amounted to 33 million dollars, according to the G-finder data portal. This accounts for less than 5% of total R&D funding for the disease ($730 million) [ 36 ]. In view of the findings of the current patent landscape, it seems that not only more funds must be invested, but more funds allocated for the development of tests that meet market needs. A recent manifest by the Network of Researchers and Collaborators in Leishmaniasis (RedeLeish) recognizes the need for funding and calls attention to the fact that CL funding constraints are even more severe [ 42 ].

Finally, we must emphasize that patent landscapes reflect the current patent situation in each field, and do not consider ensuing experimental evidence obtained after patent application, unless they have been included in subsequent patent documents. Therefore, as with all patent landscape analyses, our results must be interpreted with caution. Overall, our results indicate that from a public policy perspective the development of diagnostic tests for leishmaniasis needs leveraging, as most tests revealed in the patent documents do not fulfill the critical gaps for disease control mentioned in the WHO roadmaps for NTDs. Although these results may be discouraging, we should acknowledge that recent developments on diagnostic methods in general, including rapid and low-cost approaches, offer a positive prospect for the development of new tools to address public health needs.

Supporting information

S1 data. dataset compilation..

https://doi.org/10.1371/journal.pgph.0002557.s001

S1 Text. Specific search strings used to gather our dataset.

https://doi.org/10.1371/journal.pgph.0002557.s002

S2 Text. List of patents that were manually grouped.

https://doi.org/10.1371/journal.pgph.0002557.s003

S3 Text. Full description of proteins listed on Table 3 under the heading “several”.

https://doi.org/10.1371/journal.pgph.0002557.s004

Acknowledgments

The authors would like to thank Dr Fabio Zicker for the corrections and constructive insights.

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Research review: frequency of ddgs supplementation impacts gains of yearlings on grass.

This article is a review of the 2024 Nebraska Beef Cattle Report, Strategies for DDGS Supplementation Frequency to Grazing Yearling Steers .

The situation

Protein supplementation can be provided to cows daily, once every three days, or once every six days without impacting body weight or body condition score. By reducing the frequency of feeding from every day to once every three or six days, producers can reduce labor and feeding expenses.

Distillers grains is often used to supplement cattle on pasture, but the impact of supplementation frequency on gains of yearlings has shown inconsistent results.

A recent study was completed by the University of Nebraska-Lincoln to further evaluate the performance of yearling steers grazing smooth bromegrass pasture supplemented with dry distillers grains plus solubles (DDGS) either daily or three times a week. Steers went to grass in May weighing 700 lb and either received no supplementation, 5.6 lb DDGS daily, or 13 lb DDGS three times a week (dry matter basis) for a 97-day grazing period. 

• Non-supplemented steers gained 1.86 pounds per day on grass.
• Steers supplemented DDGS three times a week gained 2.45 pounds per day.
• Steers supplemented daily gained 2.75 pounds per day.

The differences in gain were reflected in similar differences in ending weight: 878 lb for non-supplemented steers, 933 lb for steers supplemented three times a week, and 961 lb for steers supplemented daily. These results support previous research by the University of Nebraska-Lincoln ( 2003 Nebraska Beef Cattle Report ) which showed supplementing heifers DDGS three times a week reduced gain by approximately 10% compared to daily supplementation. 

While reducing supplementation frequency to yearlings on grass may reduce labor and feeding expenses, it is important to consider how much gain is being sacrificed and the impact on ending weight. Depending on the distance traveled to provide supplementation, only supplementing three times a week vs. daily may make up for the reduction in gain per pound of supplement provided. Daily supplementation costs and target weight gain during the growing phase should be evaluated when determining the appropriate supplementation strategy for an operation.   

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A Review of Leishmaniasis: Current Knowledge and Future Directions

Affiliations.

• 1 Division of Infectious Diseases, Department of Internal Medicine, University of Colorado-AMC, 12700 E. 19th Ave., B168, Aurora, CO 80045 USA.
• 2 Division of Dermatology, University of Colorado-AMC, Aurora, CO USA.
• 3 Gorgas Memorial Institute of Tropical Medicine, Panamá City, Panamá.
• PMID: 33747716
• PMCID: PMC7966913
• DOI: 10.1007/s40475-021-00232-7

Purpose of review: The goal of this review is to summarize the current knowledge of the epidemiology, clinical manifestations, diagnosis, and treatment of cutaneous, mucosal, and visceral leishmaniasis. We will describe the most recent findings and suggest areas of further research in the leishmaniasis field.

Recent findings: This article reviews newer leishmaniasis tests (including rapid diagnostic tests using rK39 antibodies), vaccine candidates, and updated treatment recommendations.

Summary: While leishmaniasis is a complex disease, learning the prominent clinical manifestations and major parasite species can guide the recommendations for diagnosis and treatment.

Keywords: Cutaneous leishmaniasis; Leishmania vaccine; Leishmaniasis; Mucocutaneous leishmaniasis; Visceral leishmaniasis.

© The Author(s), under exclusive licence to Springer Nature Switzerland AG part of Springer Nature 2021.

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Chemical Society Reviews

Applications of low-valent compounds with heavy group-14 elements.

* Corresponding authors

a Department of Chemistry, Indian Institute of Science Education and Research Pune, Dr Homi Bhabha Road, Pashan, Pune-411008, India E-mail: [email protected]

Over the last two decades, the low-valent compounds of group-14 elements have received significant attention in several fields of chemistry owing to their unique electronic properties. The low-valent group-14 species include tetrylenes, tetryliumylidene, tetrylones, dimetallenes and dimetallynes. These low-valent group-14 species have shown applications in various areas such as organic transformations (hydroboration, cyanosilylation, N-functionalisation of amines, and hydroamination), small molecule activation ( e.g. P 4 , As 4 , CO 2 , CO, H 2 , alkene, and alkyne) and materials. This review presents an in-depth discussion on low-valent group-14 species-catalyzed reactions, including polymerization of rac -lactide, L -lactide, DL -lactide, and caprolactone, followed by their photophysical properties (phosphorescence and fluorescence), thin film deposition (atomic layer deposition and vapor phase deposition), and medicinal applications. This review concisely summarizes current developments of low-valent heavier group-14 compounds, covering synthetic methodologies, structural aspects, and their applications in various fields of chemistry. Finally, their opportunities and challenges are examined and emphasized.

• This article is part of the themed collection: Applications of Main Group Chemistry in Synthesis, Catalysis, and Biomedical and Materials Research

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Venki Ramakrishnan.

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Science is making anti-aging progress. But do we want to live forever?

Nobel laureate details new book, which surveys research, touches on larger philosophical questions

Anne J. Manning

Harvard Staff Writer

Mayflies live for only a day. Galapagos tortoises can reach up to age 170. The Greenland shark holds the world record at over 400 years of life. 

Venki Ramakrishnan, Nobel laureate and author of the newly released “ Why We Die: The New Science of Aging and the Quest for Immortality ,” opened his packed Harvard Science Book Talk last week by noting the vast variabilities of lifespans across the natural world. Death is certain, so far as we know. But there’s no physical or chemical law that says it must happen at a fixed time, which raises other, more philosophical issues.

The “why” behind these enormous swings, and the quest to harness longevity for humans, have driven fevered attempts (and billions of dollars in research spending) to slow or stop aging. Ramakrishnan’s book is a dispassionate journey through current scientific understanding of aging and death, which basically comes down to an accumulation of chemical damage to molecules and cells.

“The question is whether we can tackle aging processes, while still keeping us who we are as humans,” said Ramakrishnan during his conversation with Antonio Regalado, a writer for the MIT Technology Review. “And whether we can do that in a safe and effective way.”

Even if immortality — or just living for a very, very long time — were theoretically possible through science, should we pursue it? Ramakrishnan likened the question to other moral ponderings.

“There’s no physical or chemical law that says we can’t colonize other galaxies, or outer space, or even Mars,” he said. “I would put it in that same category. And it would require huge breakthroughs, which we haven’t made yet.”

In fact, we’re a lot closer to big breakthroughs when it comes to chasing immortality. Ramakrishnan noted the field is moving so fast that a book like his can capture but a snippet. He then took the audience on a brief tour of some of the major directions of aging research. And much of it, he said, started in unexpected places.

Take rapamycin, a drug first isolated in the 1960s from a bacterium on Easter Island found to have antifungal, immunosuppressant, and anticancer properties. Rapamycin targets the TOR pathway, a large molecular signaling cascade within cells that regulates many functions fundamental to life. Rapamycin has garnered renewed attention for its potential to reverse the aging process by targeting cellular signaling associated with physiological changes and diseases in older adults.

Other directions include mimicking the anti-aging effects of caloric restriction shown in mice, as well as one particularly exciting area called cellular reprogramming. That means taking fully developed cells and essentially turning back the clock on their development.

The most famous foundational experiment in this area was by Kyoto University scientist and Nobel laureate Shinya Yamanaka, who showed that just four transcription factors could revert an adult cell all the way back to a pluripotent stem cell, creating what are now known as induced pluripotent stem cells.

Ramakrishnan , a scientist at England’s MRC Laboratory of Molecular Biology, won the 2009 Nobel Prize in chemistry for uncovering the structure of the ribosome. He said he felt qualified to write the book because he has “no skin in the game” of aging research. As a molecular biologist who has studied fundamental processes of how cells make proteins, he had connections in the field but wasn’t too close to any of it.

While researching the book, he took pains to avoid interviewing scientists with commercial ventures tied to aging.

The potential for conflicts of interest abound.

The world has seen an explosion in aging research in recent decades, with billions of dollars spent by government agencies and private companies . And the consumer market for products is forecast to hit $93 billion by 2027 .

As a result, false or exaggerated claims by companies promising longer life are currently on the rise, Ramakrishnan noted. He shared one example: Supplements designed to lengthen a person’s telomeres, or genetic segments that shrink with age, are available on Amazon.

“Of course, these are not FDA approved. There are no clinical trials, and it’s not clear what their basis is,” he said.

But still there appears to be some demand.

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Research: Negotiating Is Unlikely to Jeopardize Your Job Offer

• Einav Hart,
• Julia Bear,
• Zhiying (Bella) Ren

A series of seven studies found that candidates have more power than they assume.

Job seekers worry about negotiating an offer for many reasons, including the worst-case scenario that the offer will be rescinded. Across a series of seven studies, researchers found that these fears are consistently exaggerated: Candidates think they are much more likely to jeopardize a deal than managers report they are. This fear can lead candidates to avoid negotiating altogether. The authors explore two reasons driving this fear and offer research-backed advice on how anxious candidates can approach job negotiations.

Imagine that you just received a job offer for a position you are excited about. Now what? You might consider negotiating for a higher salary, job flexibility, or other benefits , but you’re apprehensive. You can’t help thinking: What if I don’t get what I ask for? Or, in the worst-case scenario, what if the hiring manager decides to withdraw the offer?

• Einav Hart is an assistant professor of management at George Mason University’s Costello College of Business, and a visiting scholar at the Wharton School. Her research interests include conflict management, negotiations, and organizational behavior.
• Julia Bear is a professor of organizational behavior at the College of Business at Stony Brook University (SUNY). Her research interests include the influence of gender on negotiation, as well as understanding gender gaps in organizations more broadly.
• Zhiying (Bella) Ren is a doctoral student at the Wharton School of the University of Pennsylvania. Her research focuses on conversational dynamics in organizations and negotiations.

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Using ideas from game theory to improve the reliability of language models

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Imagine you and a friend are playing a game where your goal is to communicate secret messages to each other using only cryptic sentences. Your friend's job is to guess the secret message behind your sentences. Sometimes, you give clues directly, and other times, your friend has to guess the message by asking yes-or-no questions about the clues you've given. The challenge is that both of you want to make sure you're understanding each other correctly and agreeing on the secret message.

MIT Computer Science and Artificial Intelligence Laboratory (CSAIL) researchers have created a similar "game" to help improve how AI understands and generates text. It is known as a “consensus game” and it involves two parts of an AI system — one part tries to generate sentences (like giving clues), and the other part tries to understand and evaluate those sentences (like guessing the secret message).

The researchers discovered that by treating this interaction as a game, where both parts of the AI work together under specific rules to agree on the right message, they could significantly improve the AI's ability to give correct and coherent answers to questions. They tested this new game-like approach on a variety of tasks, such as reading comprehension, solving math problems, and carrying on conversations, and found that it helped the AI perform better across the board.

Traditionally, large language models answer one of two ways: generating answers directly from the model (generative querying) or using the model to score a set of predefined answers (discriminative querying), which can lead to differing and sometimes incompatible results. With the generative approach, "Who is the president of the United States?" might yield a straightforward answer like "Joe Biden." However, a discriminative query could incorrectly dispute this fact when evaluating the same answer, such as "Barack Obama."

So, how do we reconcile mutually incompatible scoring procedures to achieve coherent, efficient predictions? 

"Imagine a new way to help language models understand and generate text, like a game. We've developed a training-free, game-theoretic method that treats the whole process as a complex game of clues and signals, where a generator tries to send the right message to a discriminator using natural language. Instead of chess pieces, they're using words and sentences," says Athul Jacob, an MIT PhD student in electrical engineering and computer science and CSAIL affiliate. "Our way to navigate this game is finding the 'approximate equilibria,' leading to a new decoding algorithm called 'equilibrium ranking.' It's a pretty exciting demonstration of how bringing game-theoretic strategies into the mix can tackle some big challenges in making language models more reliable and consistent."

When tested across many tasks, like reading comprehension, commonsense reasoning, math problem-solving, and dialogue, the team's algorithm consistently improved how well these models performed. Using the ER algorithm with the LLaMA-7B model even outshone the results from much larger models. "Given that they are already competitive, that people have been working on it for a while, but the level of improvements we saw being able to outperform a model that's 10 times the size was a pleasant surprise," says Jacob. 

"Diplomacy," a strategic board game set in pre-World War I Europe, where players negotiate alliances, betray friends, and conquer territories without the use of dice — relying purely on skill, strategy, and interpersonal manipulation — recently had a second coming. In November 2022, computer scientists, including Jacob, developed “Cicero,” an AI agent that achieves human-level capabilities in the mixed-motive seven-player game, which requires the same aforementioned skills, but with natural language. The math behind this partially inspired the Consensus Game. 

While the history of AI agents long predates when OpenAI's software entered the chat in November 2022, it's well documented that they can still cosplay as your well-meaning, yet pathological friend. 

The consensus game system reaches equilibrium as an agreement, ensuring accuracy and fidelity to the model's original insights. To achieve this, the method iteratively adjusts the interactions between the generative and discriminative components until they reach a consensus on an answer that accurately reflects reality and aligns with their initial beliefs. This approach effectively bridges the gap between the two querying methods. 

In practice, implementing the consensus game approach to language model querying, especially for question-answering tasks, does involve significant computational challenges. For example, when using datasets like MMLU, which have thousands of questions and multiple-choice answers, the model must apply the mechanism to each query. Then, it must reach a consensus between the generative and discriminative components for every question and its possible answers. 

The system did struggle with a grade school right of passage: math word problems. It couldn't generate wrong answers, which is a critical component of understanding the process of coming up with the right one. 

“The last few years have seen really impressive progress in both strategic decision-making and language generation from AI systems, but we’re just starting to figure out how to put the two together. Equilibrium ranking is a first step in this direction, but I think there’s a lot we’ll be able to do to scale this up to more complex problems,” says Jacob.   

An avenue of future work involves enhancing the base model by integrating the outputs of the current method. This is particularly promising since it can yield more factual and consistent answers across various tasks, including factuality and open-ended generation. The potential for such a method to significantly improve the base model's performance is high, which could result in more reliable and factual outputs from ChatGPT and similar language models that people use daily. 

"Even though modern language models, such as ChatGPT and Gemini, have led to solving various tasks through chat interfaces, the statistical decoding process that generates a response from such models has remained unchanged for decades," says Google Research Scientist Ahmad Beirami, who was not involved in the work. "The proposal by the MIT researchers is an innovative game-theoretic framework for decoding from language models through solving the equilibrium of a consensus game. The significant performance gains reported in the research paper are promising, opening the door to a potential paradigm shift in language model decoding that may fuel a flurry of new applications."

Jacob wrote the paper with MIT-IBM Watson Lab researcher Yikang Shen and MIT Department of Electrical Engineering and Computer Science assistant professors Gabriele Farina and Jacob Andreas, who is also a CSAIL member. They presented their work at the International Conference on Learning Representations (ICLR) earlier this month, where it was highlighted as a "spotlight paper." The research also received a “best paper award” at the NeurIPS R0-FoMo Workshop in December 2023.

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MIT researchers have developed a new procedure that uses game theory to improve the accuracy and consistency of large language models (LLMs), reports Steve Nadis for Quanta Magazine . “The new work, which uses games to improve AI, stands in contrast to past approaches, which measured an AI program’s success via its mastery of games,” explains Nadis. 

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StatPearls [Internet].

Leishmaniasis.

Luke Maxfield ; Jonathan S. Crane .

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Last Update: June 28, 2023 .

• Continuing Education Activity

Leishmaniasis is a protozoan disease transmitted by sandflies that is most commonly seen in Europe, Africa, Asia, and Latin America. As travel patterns shift it is a disease being more frequently introduced into developed areas. The disease may either be cutaneous or systemic. Identification of the organism and knowledge of endemic species will guide interprofessional team members toward accurate diagnosis and targeted therapy if indicated. This activity outlines the epidemiology, clinical manifestations, diagnosis, and treatment of leishmaniasis. This review highlights the role of the interprofessional team in caring for affected patients and preparing for the potential for future cases of leishmaniasis in developed nations.

• Describe the epidemiology of leishmaniasis.
• Summarize the cutaneous, mucocutaneous, and visceral leishmaniasis syndromes.
• Explain how to diagnose leishmaniasis.
• Identify the importance of improving care coordination, with particular emphasis on communication between interprofessional medical teams, to enhance prompt and thorough delivery of care to patients with leishmaniasis.
• Introduction

Leishmaniasis is a disease caused by the protozoa Leishmania and is most commonly transmitted by infected sandflies. It has been historically widespread in tropical climates across multiple continents including Europe, Africa, Asia, and America. In humans, these parasites replicate intracellular and present classically with a visceral or cutaneous disease.

Leishmaniasis has tremendous historical relevance, with recorded disease thousands of years before common era (BCE). [1]  An examination of ancient Egyptian and Christian Nubian mummies dating back to 3500 to 2800 BCE yielded successful amplification of Leishmaniasis donovani DNA. During a time period referred to as the Middle Kingdom, Egyptian trade and military excursions involving Nubia (modern Sudan) are thought to be responsible for the introduction of leishmaniasis into Egypt, as DNA-positive samples were not seen prior to this time period. Furthermore, some sources suspect Sudan as the original foci of visceral leishmaniasis (VL). [2] Additionally, medical manuscripts called Ebers Papyrus from 1500 BC described a cutaneous condition thought to be cutaneous leishmaniasis then termed “Nile Pimple.” With this ancient concept of disease in mind, an early form of vaccination was attempted in the Middle East and Central Asia. This was performed by taking exudates of active lesions and inoculating them into the buttocks of children. [1]

Over the next thousand years cutaneous sores consistent with leishmaniasis were described, and in historical northern Afghanistan, a disease termed the "Balkh sore" is now thought to have been caused by L. tropica . In Asia and the Middle East, the disease continued to be documented, and conditions termed the "Aleppo boil," "Jericho boil," and the "Baghdad boil." Many of these names remain relevant in modern times.

Early recognition of the infectious nature of leishmaniasis was first encountered by a Scottish physician who noticed the parasites in a Delhi boil, but it wasn’t until similar findings were seen by Russian physician Piotr Fokich Borovsky that these bodies in Asian sores were actually suspected to be protozoa as published in 1898. In 1900, a British pathologist noted ovoid bodies and suggested these represented degenerated trypanosomes. He then termed this illness “dum-dum fever.” Around the same time, Irish doctor Charles Donovan published a paper on similar ovoid bodies from the spleen of native Asian Indians. An investigation into the Indian disease kala-azar and splenic ovoid bodies described by the pathologist Leishman and clinician Donavan suggested that these ovoid bodies did not degenerate trypanosomes but a new protozoan species later termed Leishmania donovani. Over the next decades, subspecies would be identified including L. tropica, L. aethiopica, and many more. Classification of the disease into a new world and old world leishmaniasis would then be based on these organisms and their geographic distribution. [1]

Leishmaniasis is a disease caused by a protozoa in the family Trypanosomatidae, order Kinetoplastida, genus Leishmania. The two stages of development are the amastigote and the promastigote, with the former infecting lysosomal vacuoles in phagocytic cells. The promastigote is an extracellular form that attaches to the insect microvilli. The insect vector, the sandfly, has multiple species but distinct subsets. Those that most commonly transmit Old World disease are Phlebotomus and Sergentomyia . The sandfly species notorious for spreading New World disease is Lutzomyia. A summative list of common leishmaniasis sub-species involved in New and Old World disease can be seen in table 1. [3]

Adult sandflies are very small, about one-third the size of a small mosquito or < 3.5 mm in length. They are susceptible to dehydration and therefore thrive in moist climates, hence the distribution of disease. These flies are nocturnal, and during the day are found in burrows and under rocks or other shelters. They have a characteristic “V” shape over their backs when at rest and a distinct thoracic hump that pushes the head down. While males and females both obtain carbohydrates from plant juices, females require a blood meal. It is during this meal that the vector fly transmits the protozoa to the human host. [3]

• Epidemiology

Leishmaniasis is endemic to Asia, the Middle East, Northern Africa, the Mediterranean, and South and Central America. It is found in 89 countries, and worldwide 1.5 to 2 million new cases occur annually. Leishmaniasis may cause mucocutaneous or visceral disease and is attributed to 70,000 deaths per year. The World Health Organization (WHO) in 2012 reported the majority of visceral and cutaneous diseases were found in select countries.[Table 2]  [1] [2] [4]

• Pathophysiology

Leishmania parasites are transmitted by the bite of sandflies, with the genus Phlebotomus and Lutzomyia the most common vectors of Old World and New World disease, respectively. [1] As mentioned, only female sandflies require blood meals, and during these meals Leishmanis spp. are both acquired by the fly and transmitted to the host. When a disease-naive sand fly attacks an infected host, they use saw-like mouthparts inserted into the skin to create a small wound from which blood pools from injured capillaries. The infectious promastigote enters the sandfly foregut and replicates. [5] [6] [7] When the fly feeds on canines, rodents, marsupials, or humans it then leads to transmission of disease to the new host. [1]

Once protozoa gain access to the host, the protozoa enter the phagolysosomes. Based on which subtype of phagocytic cells are infected, Cutaneous leishmaniasis (CL) or visceral leishmaniasis (VL) occurs. In CL the parasites infect resident macrophages within the skin, and once each compromised cell is full of amastigotes, it bursts to allow rapid release and infection of neighboring macrophages. VL differs in that amastigotes are spread hematogenously to mononuclear cells of the liver, spleen, bone marrow, and lymph nodes of the intestine. [1]

• Histopathology

Identification of parasites by histopathologic examination of fixed tissue or parasite in vitro culture is the gold standard of diagnosis. Sampling tissue from the cutaneous ulcer margin provides the highest yield fromGiemsa-stained samples from biopsies or impression smears. [8]  Comparing scraping smears and fine needle aspiration cytology showed that needle aspiration improved both the detection of amastigotes and patient comfort. [9]  A simplified collection method called "press-imprint-smear" has also been used, and when compared to histopathology for cutaneous disease, it had significantly higher sensitivity than histopathologic studies. This technique is performed by utilizing a 3 mm punch biopsy similar to that obtained for formalin fixed histopathology. With the press-imprint-smear, however, the tissue fragment is placed between two glass slides longitudinally (the epidermis perpendicular to the slides) and squeezed. Pressure is focused on the center of the slide and allows “juice” and tissue to spread across both slides. Next, the slides are separated, the tissue is removed, and the slides are allowed to air dry. The slides are then fixed with menthol, stained with Giemsa, and examined microscopically with an oil immersion lens. [10]

Examination of either method reveals the classic organisms as 2 to 4 mcm, round, oval bodies with characteristic nuclei and kinetoplasts. [8] [10]

• History and Physical

Clinical manifestations are traditionally broken up into three main syndromes: cutaneous, mucocutaneous, and visceral. [11] [4] Organisms responsible for each clinical subset are listed in Table 1. Cutaneous disease is the most common manifestation of leishmaniasis and is further subdivided into localized cutaneous and diffuse cutaneous disease. The localized cutaneous lesions often have an incubation period from 2 to 4 weeks at which time an asymptomatic papule, multiple papules, or nodules occur at the site of inoculation. These enlarge and transform into well-circumscribed ulcers with a raised violaceous border and epidermal breakdown. These lesions often heal spontaneously within 2 to 5 years (depending on the species) with a secondary depressed scar. [5] [4]  The characteristics of limited cutaneous lesions associated with individual subspecies are listed in Table 3. [4]

Diffuse cutaneous leishmaniasis also begins as a painless nodule but may progress to involve the entire cutaneous surface. It does have a predilection for face, ears, and extensor surfaces such as the knees and elbows. Invasion of the nasopharyngeal and oral mucosa may be seen in up to a third of patients. Progressive disease may result in leonine facies. Organisms most associated with diffuse cutaneous leishmaniasis are L. aethiopica in Old World and L. mexicana in New World disease. Skin lesions may further progress to diffuse hypopigmented plaques and patches.

Mucosal disease is due to either hematogenous or lymphatic spread and often occurs after resolution of cutaneous lesions. The onset of mucosal manifestations usually occurs within two years but may have be delayed decades. L. braziliensis accounts for the majority of mucocutaneous disease although other organisms can be implicated (table 1). The oral and nasal mucosa is preferentially affected although ulcerative involvement may extend to vocal cords and tracheal cartilage, but bony structures are uninvolved. Mucosal disease may be severe and life-threatening. [4]

Visceral leishmaniasis is also known by the term kala-azar as initially described in India in the 1800’s. [1] [11] [4] With visceral involvement, there is often associated fever, splenomegaly, hypergammaglobulinemia, and pancytopenia. Often these clinical sequelae are secondary to organs directly infected including the liver, spleen, bone marrow, or other viscera. The organisms most commonly causative are L. donovani, L. infantum, and L. chagasi. [11] [4] Visceral involvement, similar to the cutaneous disease, has seasonal peaks in the spring that are likely due to temperature, humidity, and vector habits. [11]

Occasionally cutaneous involvement may manifest after treatment of the visceral disease as a papular rash on the face and upper extremities. A term "post-kala-azar dermal leishmaniasis" has been coined to describe this, and these skin lesions are nondisfiguring and self-limited. [4]

As mentioned, the gold standard for diagnosis is a histopathologic examination of tissue samples. Notably, the sensitivity of examined tissue is low, and sensitivity can be increased by utilizing the press-imprint-smear method. Parasite culture tubes with Novy-MacNeal-Nicolle medium can be used but is technically difficult with low sensitivity. Micro-culture technologies have increased sensitivity up to 98.4% and are 100% specific. Serologic studies including enzyme-linked immunosorbent assays, western blot, or direct agglutination are rarely used due to a poor humoral response by leishmaniasis and therefore low sensitivity. Purified antigen preparations or recombinant antigens increase the performance of these studies. Serum levels of anti-alpha-Gal IgG have been noted to be elevated in individuals infected with L. tropica and L. major . This test may be valuable as a marker of a cure for Old World CL. Intradermal skin tests have been used with good sensitivity and specificity with delayed-type hypersensitivity skin reactions equal to 5 mm is considered positive. A large disadvantage is the inability of skin testing to distinguish between prior or current infection. Polymerase chain reaction and nucleic acid amplification tests are being increasingly utilized and are both sensitive and specific. [8] Diagnosis of disease in the clinical setting often is determined by resources available.

For patients with suspected visceral disease, tissue samples may not easily be obtained, and testing with direct agglutination and rK39 dipstick testing may have more of a utility. Direct agglutination among patients with visceral/systemic involvement has a sensitivity of 97-100% and specificity of 86% to 92%. Bone marrow biopsy may be needed and is commonly positive among patients with suspected marrow involvement. [11]

• Treatment / Management

For infectious disease, initial measures are often aimed at prevention. Knowledge of endemic areas, awareness of nocturnal sandfly activity, and exposure to animals in areas known to harbor disease is important. As sandflies are very small, even smaller than mosquitos, a bed net with maze patterns three times smaller than standard is required. Further impregnation with permethrin may also decrease risk. Attempts at vaccinating dogs and utilizing insecticide dog collars has also been shown to decrease disease burden. [8]

For limited CL, disease often resolves spontaneously. However dermatologic disease can be destructive, increase secondary infections, or leave permanent disabling scars. First line treatment options for the limited cutaneous disease include intralesional forms of pentavalent antimonals, including sodium stibolgluconate and meglumine antimoniate. Alternative regimens include systemic miltefosine, amphotericin B, pentamidine isethionate, paromomycine, or granulocyte macrophage colony-stimulating factor. Many of these systemic agents are limited by severe adverse effects. Heat or cryotherapy are treatment options reserved for cases of < 5 cutaneous lesions. [8]

For patients with mucocutaneous leishmaniasis, systemic treatment is often required. Meglumine or stibogluconate have been first-line therapy and the WHO recommends antimonial pentavalent for a mucocutaneous disease. Treatment success rates have been as high 95% if high dosing strategies are utilized, although low dosing strategies are often used to minimize adverse effects. Azole therapies (i.e., fluconazole, ketoconazole, itraconazole) have been used in isolation and in combination with amphotericin B. Their use is limited by regional variants of the disease and resistance as well as having a minimal additive benefit to the already effective amphotericin. Agents established with good cure rates (= 90%) include amphotericin B (liposomal or colloidal dispersion), amphotericin B deoxicholate, and pentamidine. Other, less effective therapies include antimonial pentavalent and itraconazole. [12]

Visceral leishmaniasis requires treatment, and agents commonly used include antimony sodium stibogluconate, amphotericin, paromomycin, and oral miltefosine. The agent of choice is often determined by native species as resistances vary tremendously. Summatively, sodium stibogluconate is used in East Africa but has high failure rates in India. Liposomal amphotericin B is available primarily in resource-rich countries, and other formulations of amphotericin B are used in India. Paromomycin has good cure rates in India but is not as efficacious in Africa. It is used as a combination therapy in Africa with sodium stibogluconate. Pentamidine is used in South America for primary treatment and as secondary prevention of disease in patients with AIDS in Europe. [13]

• Differential Diagnosis

Cutaneous ulcers in tropical regions include [4] :

• Furuncular myiasis 
• Staphylococcal infection
• Lepromatous leprosy (leonine facies)
• Tuberculoid leprosy (hypopigmented patches and plaques)
• Yaws (primary stage of ulcerative or nodular lesions on lower extremities)

Limited cutaneous disease often is spontaneously cleared, depending on the host's innate immune system.

Mortality seen among patients with visceral disease varies when examining hospital-based populations as opposed to community-based mortality records. Overall, the WHO tentatively established a case-fatality of 10%. [14]

If treated, a cure is frequently achieved and rates are discussed above in their respective sections. Among patients with HIV, however, mortality is significantly increased as exemplified by a mortality rate of 33.6% in Ethiopian HIV-positive individuals compared with 3.6% in Ethiopian HIV-negative individuals. Despite good treatment, adverse effects of medications are common and often severe. [12] [14] [13]

• Pearls and Other Issues

CL is the most common manifestation of leishmaniasis, and often laboratory testing is not available due to the setting in which disease occurs. CL can be suspected by the epidemiologic setting of an endemic tropical rural area. Signs and symptoms include crusted ulcerative lesions with or without satellite lesions, lymphangitic spread, or mucosal involvement.

Visceral involvement is usually manifested as fever, pallor, and weakness, or anorexia. Objective findings include splenomegaly, hepatomegaly, anemia, thrombocytopenia, and less commonly, leukopenia.

• Enhancing Healthcare Team Outcomes

Leishmaniasis is a global disease, and efforts to provide education, diagnostic tools, and treatment to endemic areas is needed. Coordination through the WHO and literature from countries all over the world has provided insight into treatment, drug resistance, and transmission.

Evaluation of individual treatments has occurred worldwide. The efficacy of amphotericin in the treatment of VL is well established. [15] (Level II) Miltefosine is the only oral agent approved for VL, and similar efficacy has been demonstrated in comparison with amphotericin in Asian Indian populations. [16]  (Level III) Another agent frequently employed with good results is the pentavalent antimonial compound sodium stibogluconate. [17]  (Level III)

Additional global epidemics including the HIV/AIDS population has been relevantly studied with one retrospective cohort showing anti-retroviral treatment significantly decreased relapse among patients with VL. [18]  (Level III)

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Leishmaniasis Tables Contributed by Dr. Luke Maxfield

Disclosure: Luke Maxfield declares no relevant financial relationships with ineligible companies.

Disclosure: Jonathan Crane declares no relevant financial relationships with ineligible companies.

This book is distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0) ( http://creativecommons.org/licenses/by-nc-nd/4.0/ ), which permits others to distribute the work, provided that the article is not altered or used commercially. You are not required to obtain permission to distribute this article, provided that you credit the author and journal.

• Cite this Page Maxfield L, Crane JS. Leishmaniasis. [Updated 2023 Jun 28]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan-.

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• Xenodiagnosis to evaluate the infectiousness of humans to sandflies in an area endemic for visceral leishmaniasis in Bihar, India: a transmission-dynamics study. [Lancet Microbe. 2021] Xenodiagnosis to evaluate the infectiousness of humans to sandflies in an area endemic for visceral leishmaniasis in Bihar, India: a transmission-dynamics study. Singh OP, Tiwary P, Kushwaha AK, Singh SK, Singh DK, Lawyer P, Rowton E, Chaubey R, Singh AK, Rai TK, et al. Lancet Microbe. 2021 Jan; 2(1):e23-e31.
• Review Leishmaniasis. [Lancet. 1999] Review Leishmaniasis. Herwaldt BL. Lancet. 1999 Oct 2; 354(9185):1191-9.
• Leishmania donovani hybridisation and introgression in nature: a comparative genomic investigation. [Lancet Microbe. 2021] Leishmania donovani hybridisation and introgression in nature: a comparative genomic investigation. Lypaczewski P, Matlashewski G. Lancet Microbe. 2021 Jun; 2(6):e250-e258. Epub 2021 Mar 23.
• Genome wide comparison of Leishmania donovani strains from Indian visceral leishmaniasis and para-kala-azar dermal leishmaniasis patients. [Acta Trop. 2021] Genome wide comparison of Leishmania donovani strains from Indian visceral leishmaniasis and para-kala-azar dermal leishmaniasis patients. Sarraf NR, Mukhopadhyay S, Banerjee A, Das AK, Roy S, Chakrabarti S, Manna M, Saha P. Acta Trop. 2021 Nov; 223:106086. Epub 2021 Aug 10.
• Review Cutaneous leishmaniasis in Pakistan. [Dermatol Online J. 2005] Review Cutaneous leishmaniasis in Pakistan. Khan SJ, Muneeb S. Dermatol Online J. 2005 Mar 1; 11(1):4. Epub 2005 Mar 1.

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‘Forever chemicals’ found to rain down on all five Great Lakes

FOR IMMEDIATE RELEASE

“The Ins and Outs of Per- and Polyfluoroalkyl Substances in the Great Lakes: The Role of Atmospheric Deposition” Environmental Science & Technology

Perfluoroalkyl and polyfluoroalkyl substances, also known as PFAS or “forever chemicals,” have become persistent pollutants in the air, water and soil. Because they are so stable, they can be transported throughout the water cycle, making their way into drinking water sources and precipitation. According to findings published in ACS’ Environmental Science & Technology , precipitation introduces similar amounts of PFAS into each of the Great Lakes; however, the lakes eliminate the chemicals at different rates.

Consuming PFAS has been linked to negative health outcomes. And in April 2024, the U.S. Environmental Protection Agency (EPA) designated two forever chemicals — PFOS and PFOA — as hazardous substances, placing limits on their concentrations in drinking water. The Great Lakes are a major freshwater source for both the U.S. and Canada, and the EPA reports that the surrounding basin area is home to roughly 10% and 30% of each country’s population, respectively. Previous studies demonstrated that these lakes contain PFAS. But Marta Venier at Indiana University and colleagues from the U.S. and Canada wanted to understand where the compounds come from and where they go.

Between 2021 and 2022, 207 precipitation samples and 60 air samples were taken from five sites surrounding the Great Lakes in the U.S.: Chicago; Cleveland; Sturgeon Point, N.Y.; Eagle Harbor, Mich.; and Sleeping Bear Dunes, Mich. During the same period, 87 different water samples were collected from the five Great Lakes. The team analyzed all the samples for 41 types of PFAS and found:

• ·In precipitation samples, PFAS concentrations largely remained the same across sites, suggesting that the compounds are present at similar levels regardless of population density.
• In air samples, Cleveland had the highest median concentration of PFAS and Sleeping Bear Dunes the lowest, suggesting a strong connection between population density and airborne PFAS.
• In the lake water samples, the highest concentration of PFAS were in Lake Ontario, followed by Lake Michigan, Lake Erie, Lake Huron and Lake Superior.
• ·The concentration of PFOS and PFOA in lake water decreased compared to data from previous studies as far back as 2005, but the concentration of a replacement PFAS known as PFBA remained high, suggesting that further regulation efforts may be needed.

The team calculated that airborne deposition from precipitation is primarily how PFAS get into the lakes, while they’re removed by sedimentation, attaching to particles as they settle to the lakebed or flowing out through connecting channels. Overall, their calculations showed that the northernmost lakes (Superior, Michigan and Huron) are generally accumulating PFAS. Further south, Lake Ontario is generally eliminating the compounds and levels in Lake Erie remain at a steady state. The researchers say that this work could help inform future actions and policies aimed at mitigating PFAS’ presence in the Great Lakes. 

The authors acknowledge funding from the Great Lakes Restoration Initiative from the U.S. Environmental Protection Agency’s Great Lakes National Program Office.

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Recent advances and new strategies on leishmaniasis treatment

• Mini-Review
• Published: 02 September 2020
• Volume 104 , pages 8965–8977, ( 2020 )

Cite this article

• Bruno Mendes Roatt 1 , 2 , 3 ,
• Jamille Mirelle de Oliveira Cardoso 1 ,
• Rory Cristiane Fortes De Brito 1 ,
• Wendel Coura-Vital 1 , 4 ,
• Rodrigo Dian de Oliveira Aguiar-Soares 1 , 4 &
• Alexandre Barbosa Reis   ORCID: orcid.org/0000-0001-8123-4164 1 , 3 , 4  

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Leishmaniasis is one of the most important tropical neglected diseases according to the World Health Organization. Even after more than a century, we still have few drugs for the disease therapy and their great toxicity and side effects put in check the treatment control program around the world. Moreover, the emergence of strains resistant to conventional drugs, co-infections such as HIV/ Leishmania spp., the small therapeutic arsenal (pentavalent antimonials, amphotericin B and formulations, and miltefosine), and the low investment for the discovery/development of new drugs force researchers and world health agencies to seek new strategies to combat and control this important neglected disease. In this context, the aim of this review is to summarize new advances and new strategies used on leishmaniasis therapy addressing alternative and innovative treatment paths such as physical and local/topical therapies, combination or multi-drug uses, immunomodulation, drug repurposing, and the nanotechnology-based drug delivery systems.

• The treatment of leishmaniasis is a challenge for global health agencies.

• Toxicity, side effects, reduced therapeutic arsenal, and drug resistance are the main problems.

• New strategies and recent advances on leishmaniasis treatment are urgent.

• Immunomodulators, nanotechnology, and drug repurposing are the future of leishmaniasis treatment.

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This work was financially supported by the Brazilian agencies, CNPq (grant number 435224/2018-2), FAPEMIG (grant number APQ-03505-13 - PROGRAMA DE PESQUISA PARA O SUS–PPSUS, APQ-01373-14 – PRONEX, APQ 02577-18 and APQ-02556-18), CAPES (this study was financed in part by the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior-Brasil (CAPES) - Finance Code 001), and Universidade Federal de Ouro Preto – UFOP for funding (TO 072018020, TO 222019019). R.C.F.B. are grateful for CAPES fellowship, and A.B.R. and B.M.R. are also grateful to CNPq for fellowships.

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Bruno Mendes Roatt, Jamille Mirelle de Oliveira Cardoso, Rory Cristiane Fortes De Brito, Wendel Coura-Vital, Rodrigo Dian de Oliveira Aguiar-Soares & Alexandre Barbosa Reis

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All the authors participated with suggestions during the development of this manuscript; B.M.R and J.M.O.C. performed all the literature search and participated in drafting the manuscript. All the authors participated in the critical revising process for important intellectual content and created the tables. The authors B.M.R., J.M.O.C., R.D.O.A.-S, R.C.F.B., W.C-V., and A.B.R. participated in the study conception and critical revision of the article. B.M.R and A.B.R. contributed to the supervision.

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Roatt, B.M., de Oliveira Cardoso, J.M., De Brito, R.C.F. et al. Recent advances and new strategies on leishmaniasis treatment. Appl Microbiol Biotechnol 104 , 8965–8977 (2020). https://doi.org/10.1007/s00253-020-10856-w

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Received : 21 May 2020

Revised : 13 August 2020

Accepted : 23 August 2020

Published : 02 September 2020

Issue Date : November 2020

DOI : https://doi.org/10.1007/s00253-020-10856-w

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