Complexities of assessing the disease burden attributable to leishmaniasis

Among parasitic diseases, morbidity and mortality caused by leishmaniasis are surpassed only by malaria and lymphatic filariasis. However, estimation of the leishmaniasis disease burden is challenging, due to clinical and epidemiological diversity, marked geographic clustering, and lack of reliable data on incidence, duration, and impact of the various disease syndromes. Non-health effects such as impoverishment, disfigurement, and stigma add to the burden, and introduce further complexities. Leishmaniasis occurs globally, but has disproportionate impact in the Horn of Africa, South Asia and Brazil (for visceral leishmaniasis), and Latin America, Central Asia, and southwestern Asia (for cutaneous leishmaniasis). Disease characteristics and challenges for control are reviewed for each of these foci. We recommend review of reliable secondary data sources and collection of baseline active survey data to improve current disease burden estimates, plus the improvement or establishment of effective surveillance systems to monitor the impact of control efforts.     

Zoonotic cutaneous leishmaniasis due to Leishmania (Viannia) braziliensis associated with domestic animals in Venezuela and Brazil

After outbreaks of cutaneous leishmaniasis in Solano State, Venezuela, 5% of the population had parasitized ulcers while after similar outbreaks in Mesquita, Rio de Janeiro State, Brazil, 9% had the disease. In these foci children, including some under six years of age, were affected. There was no significant difference in the occurrence of the disease according to sex or type of employment. In Solano, 3% of dogs and 28% of donkeys had parasitized lesions, while in Mesquita these indices were 19.8% and 30.8% respectively. The parasite from man, dogs and equines was identified as Leishmania (Viannia) braziliensis, by zymodeme and serodeme characterization. In these foci there is evidence suggesting that leishmaniasis is a zoonosis, possibly with equines and dogs as reservoirs, although both a wild enzootic cycle and the role of man as a source of infection can not be ruled out. Transmission is assumed to occur peridomestically by sandfly vectors such as Lutzomyia panamensis in Venezuela and Lutzomyia intermedia in Brazil. Information about the origin of these foci suggests that infected equines may be an important factor in the dissemination of the parasite in a peridomestic situation where these sandflies are abundant.     

The cutaneous leishmaniasis vulnerability index (CLVI)

South east of Morocco is one of the biggest cutaneous leishmaniasis disease foci. Despite its non-lethality, this disease causes several socioeconomic and psychological impacts. This disease has lots of risk factors. Some of these are related to the environmental change, and others are linked to the demographic and socio-economical system. The interactions between these risk factors create the need for a multidisciplinary approach to estimate the vulnerability risk to the cutaneous leishmaniasis. In this context, a new index was proposed and six provinces were selected, which are Zagora, Ouarzazate, Tinghir, Errachidia, Figuig, and Tata. The findings depict that in term of anthropogenic vulnerability, Tinghir is the most vulnerable to leishmaniasis followed by Errachidia and Ouarzazate. Geographically, Errachidia has the very high vulnerability score and Figuig have the high vulnerability. The results show also an important risk to leishmaniasis in all provinces regarding the socio-economical component, except for Tata. Regarding services category, Zagora is the most vulnerable. However, for the hygiene, Figuig, Ouarzazate, and Errachidia present the high scores of vulnerability, then the rest provinces. The total score of cutaneous leishmaniasis vulnerability of the selected provinces indicates that Tinghir is the most vulnerable regarding this disease followed respectively by Errachidia, Ouarzazate, Zagora, Figuig, and Tata.     

First molecular epidemiological study of cutaneous leishmaniasis in Libya

Background

Cutaneous leishmaniasis (CL) is a major public health problem in Libya. The objective of this study was to investigate, for the first time, epidemiological features of CL outbreaks in Libya including molecular identification of parasites, the geographical distribution of cases and possible scenarios of parasite transmission.

Methodology/Principal Findings

We studied 450 patients that came from 49 areas distributed in 12 districts in north-west Libya. The patients'' ages ranged from 9 months to 87 years (median age 25 years); 54% of the cases were males. Skin scrapings spotted on glass slides were collected for molecular identification of causative agent. The ribosomal internal transcribed spacer 1 (ITS1) was amplified and subsequently characterized by restriction fragment length polymorphism (RFLP) analysis. In total, 195 samples were successfully identified of which 148 (75.9%) were Leishmania major, and 47 (24.1%) Leishmania tropica. CL cases infected with L. major were found in all CL areas whereas L. tropica cases came mainly from Al Jabal Al Gharbi (46.4%), Misrata (17.8%) and Tarhuna districts (10.7%). A trend of seasonality was noticed for the infections with L. major which showed a clear peak between November and January, but was less pronounced for infections by L. tropica.

Conclusion

The first molecular study on CL in Libya revealed that the disease is caused by L. major and L. tropica and the epidemiological patterns in the different foci were the same as in other Mediterranean foci of CL.     

Transmission patterns of Leishmania tropica around the Mediterranean basin: Could Morocco be impacted by a zoonotic spillover?

Cutaneous leishmaniasis (CL) due to Leishmania tropica is a neglected tropical disease characterized by a wide geographical distribution in the Mediterranean basin and is endemic in several of its countries. In addition, the vector Phlebotomus sergenti is abundantly present all around the basin. Its transmission cycle is still subject to debate. In some countries, the presence of an animal reservoir has been confirmed. In Morocco, CL due to L. tropica has risen since the 1980s and has spread widely to become the most abundant form of leishmaniasis in the territory. However, the anthroponotic transmission is so far the only recognized mode, despite recordings of L. tropica infection in animal hosts. In this review article, we assess the situation of CL due to L. tropica in the Mediterranean basin with a focus on Morocco and gather knowledge about any potential zoonotic transmission in the country. A concomitant zoonotic transmission could explain the persistence of the disease in areas where human protective measures combined with vector management did not help reduce the disease burden.     

A Cross-Sectional Survey of Knowledge,Attitude and Practices Related to Cutaneous Leishmaniasis and Sand Flies in Punjab,Pakistan

Background

Recent outbreaks of cutaneous leishmaniasis make the disease a public health concern in Punjab, Pakistan. The knowledge of how the population perceives the disease and its vector is essential in order to design an effective management strategy, but such studies are rare in Pakistan.

Methodology/Principal Findings

The present study was based on a cross-sectional self-administered survey comprising 250 household samples collected from five localities including Bhawalpur, Multan, Jhang, Faisalabad and Lahore. The results revealed that the respondents had a poor knowledge of the vector and disease. Few of the respondents were aware about the identification of sand flies, their breeding place, biting time, transmission of leishmaniasis and control measures. Skin infection and sandflies as the main disease symptom and vector of the disease, respectively, were known to some of the respondents. Some believed that summer was the main peak incidence of the disease and it could be transmitted from man to man via contact. However, most of the respondents believed that the disease could be cured. Admission to hospitals, cleanliness and use of bed nets were the treatment measures for the disease in suspected patients, whereas some thought that the use of bed nets could be helpful in preventing leishmaniasis infection.

Conclusions/Significance

Poor knowledge of the disease and its vector in the study population emphasize the need to initiate health education and awareness campaigns to minimize the risks of cutaneous leishmaniasis outbreaks in the future.     

Modelling the Effects of Seasonality and Socioeconomic Impact on the Transmission of Rift Valley Fever Virus

Rift Valley fever (RVF) is an important mosquito-borne viral zoonosis in Africa and the Middle East that causes human deaths and significant economic losses due to huge incidences of death and abortion among infected livestock. Outbreaks of RVF are sporadic and associated with both seasonal and socioeconomic effects. Here we propose an almost periodic three-patch model to investigate the transmission dynamics of RVF virus (RVFV) among ruminants with spatial movements. Our findings indicate that, in Northeastern Africa, human activities, including those associated with the Eid al Adha feast, along with a combination of climatic factors such as rainfall level and hydrological variations, contribute to the transmission and dispersal of the disease pathogen. Moreover, sporadic outbreaks may occur when the two events occur together: 1) abundant livestock are recruited into areas at risk from RVF due to the demand for the religious festival and 2) abundant numbers of mosquitoes emerge. These two factors have been shown to have impacts on the severity of RVF outbreaks. Our numerical results present the transmission dynamics of the disease pathogen over both short and long periods of time, particularly during the festival time. Further, we investigate the impact on patterns of disease outbreaks in each patch brought by festival- and seasonal-driven factors, such as the number of livestock imported daily, the animal transportation speed from patch to patch, and the death rate induced by ceremonial sacrifices. In addition, our simulations show that when the time for festival preparation starts earlier than usual, the risk of massive disease outbreaks rises, particularly in patch 3 (the place where the religious ceremony will be held).     

IL-22 Protects against Tissue Damage during Cutaneous Leishmaniasis

Cutaneous leishmaniasis is a disease characterized by ulcerating skin lesions, the resolution of which requires an effective, but regulated, immune response that limits parasite growth without causing permanent tissue damage. While mechanisms that control the parasites have been well studied, the factors regulating immunopathologic responses are less well understood. IL-22, a member of the IL-10 family of cytokines, can contribute to wound healing, but in other instances promotes pathology. Here we investigated the role of IL-22 during leishmania infection, and found that IL-22 limits leishmania-induced pathology when a certain threshold of damage is induced by a high dose of parasites. Il22 ^-/- mice developed more severe disease than wild-type mice, with significantly more pathology at the site of infection, and in some cases permanent loss of tissue. The increased inflammation was not due to an increased parasite burden, but rather was associated with the loss of a wound healing phenotype in keratinocytes. Taken together, these studies demonstrate that during cutaneous leishmaniasis, IL-22 can play a previously unappreciated role in controlling leishmania-induced immunopathology.     

Visceral Leishmaniasis in Ethiopia: An Evolving Disease

Visceral leishmaniasis (also known as kala-azar) is classified as one of the most neglected tropical diseases. It is becoming a growing health problem in Ethiopia, with endemic areas that are continually spreading. The annual burden of visceral leishmaniasis (VL) in Ethiopia is estimated to be between 4,500 and 5,000 cases, and the population at risk is more than 3.2 million. There has been a change in the epidemiology of VL in Ethiopia. Over the last decades, almost all cases and outbreaks of VL were reported from arid and semi-arid parts of the country; however, recent reports indicated the introduction of this disease into the highlands. Migration of labourers to and from endemic areas, climatic and environmental changes, and impaired immunity due to HIV/AIDS and malnutrition resulted in the change of VL epidemiology. HIV spurs the spread of VL by increasing the risk of progression from asymptomatic infection towards full VL. Conversely, VL accelerates the onset of AIDS. In Ethiopia, VL epidemiology remains complex because of the diversity of risk factors involved, and its control is becoming an increasing challenge. This paper reviews the changes in epidemiology of VL in Ethiopia and discusses some of the possible explanations for these changes. The prospects for novel approaches to VL control are discussed, as are the current and future challenges facing Ethiopia''s public health development program.     

Resource allocation for epidemic control in metapopulations

Deployment of limited resources is an issue of major importance for decision-making in crisis events. This is especially true for large-scale outbreaks of infectious diseases. Little is known when it comes to identifying the most efficient way of deploying scarce resources for control when disease outbreaks occur in different but interconnected regions. The policy maker is frequently faced with the challenge of optimizing efficiency (e.g. minimizing the burden of infection) while accounting for social equity (e.g. equal opportunity for infected individuals to access treatment). For a large range of diseases described by a simple SIRS model, we consider strategies that should be used to minimize the discounted number of infected individuals during the course of an epidemic. We show that when faced with the dilemma of choosing between socially equitable and purely efficient strategies, the choice of the control strategy should be informed by key measurable epidemiological factors such as the basic reproductive number and the efficiency of the treatment measure. Our model provides new insights for policy makers in the optimal deployment of limited resources for control in the event of epidemic outbreaks at the landscape scale.     

Candidate gene case-control and functional study shows macrophage inhibitory factor (MIF) polymorphism is associated with cutaneous leishmaniasis

American tegumentary leishmaniasis (ATL) is an infectious disease caused mostly by Leishmania (Viannia) braziliensis in Southeast Brazil. The clinical manifestations are vast, ranging from asymptomatic to severe mucosal leishmaniasis (ML). It has been suggested that variation of the pathogen does not fully explain the response spectrum and the variability of clinical manifestations. Previous data have shown that host genetics also play a role in disease outcome. Herein, we have tested the association of TNF, IL10, IL12 and MIF single nucleotide polymorphisms (SNPs) using a case-control study design including 110 cutaneous leishmaniasis (CL) patients and 682 healthy subjects. The genotype–phenotype correlation was also assessed using leishmania antigens to stimulate peripheral blood mononuclear cells obtained from cured CL patients. Results demonstrated that the MIF ?173C allele is associated with leishmaniasis outcome and also with lower levels of MIF in culture supernatants. Also, the TNF ?308AA genotype was statistically increased among leishmaniasis patients. The results showed here suggest that the lower levels of MIF produced by MIF ?173C carriers could influence the host–Leishmania interaction, favoring infection and disease progression. On the other hand, high TNF levels can contribute to tissue damage, consequently leading to skin lesions.     

Leishmania species and zymodemes isolated from endemic areas of cutaneous leishmaniasis in Jordan

Background  

Cutaneous leishmaniasis (CL) is endemic in the Middle Eastern countries. New cases are emerging in areas previously free of the disease. In Jordan, the diagnosis of cases during the 1960s and 1970s was mainly reported in military hospitals in Amman. Endemicity of the disease was ascertained after reporting a total of 524 cases during 1973–1978.     

Cytokine gene polymorphisms and susceptibility to cutaneous leishmaniasis in Iranian patients

Cutaneous Leishmaniasis (CL) is one of the most prevalent clinical forms of leishmaniasis. Preliminary data suggest that cytokine gene polymorphisms can contribute to resistance or susceptibility to CL. Therefore, we investigated the association of functional polymorphisms in four cytokine genes with susceptibility to, and clinical outcome of CL. A total of 201 patients with self-healing cutaneous leishmaniasis (SCL) and 92 asymptomatic infected controls (AIC) from Fars province as well as 58 patients with chronic cutaneous leishmaniasis (CCL) and their 688 normal controls (normal Iranian population or NIP) who were collected from the different areas of Iran were included in the study. The allele-specific oligonucleotide polymerase chain reaction (ASO-PCR) or PCR-RFLP (restriction fragment length polymorphism) methods were used for genotyping. The frequency of TNF-alpha -308 G-->A and TNF-beta +252 G-->A gene polymorphisms were not different between studied groups. Distribution of IFN-gamma +874 A-->T and IL-4 -590 C-->T polymorphism were also compared between SCl or CCL patients and their controls. IFN-gamma +874 A-->T polymorphism was less common in CCL patients compared to the NIP (chi(2)=12.53, p=0.0019). Significant differences in frequency of IL-4 -590 C -->T polymorphism were also found between the SCL and AIC (chi(2)=8.64, p=0.003). In conclusion, our results suggest that functional genetic variants in the IL-4 promoter could influence the risk of developing CL while the polymorphism in the first intron of the IFN-gamma gene might influence the progression of disease towards CCL.     

Leishmaniasis and poverty

Leishmaniasis, a neglected tropical disease, has strong but complex links with poverty. The burden of leishmaniasis falls disproportionately on the poorest segments of the global population. Within endemic areas, increased infection risk is mediated through poor housing conditions and environmental sanitation, lack of personal protective measures and economically driven migration and employment that bring nonimmune hosts into contact with infected sand flies. Poverty is associated with poor nutrition and other infectious diseases, which increase the risk that a person (once infected) will progress to the clinically manifested disease. Lack of healthcare access causes delays in appropriate diagnosis and treatment and accentuates leishmaniasis morbidity and mortality, particularly in women. Leishmaniasis diagnosis and treatment are expensive and families must sell assets and take loans to pay for care, leading to further impoverishment and reinforcement of the vicious cycle of disease and poverty. Public investment in treatment and control would decrease the leishmaniasis disease burden and help to alleviate poverty.     

Arginase Activity in the Blood of Patients with Visceral Leishmaniasis and HIV Infection

Background

Visceral leishmaniasis is a parasitic disease associated with high mortality. The most important foci of visceral leishmaniasis in Ethiopia are in the Northwest and are predominantly associated with high rates of HIV co-infection. Co-infection of visceral leishmaniasis patients with HIV results in higher mortality, treatment failure and relapse. We have previously shown that arginase, an enzyme associated with immunosuppression, was increased in patients with visceral leishmaniasis and in HIV seropositive patients; further our results showed that high arginase activity is a marker of disease severity. Here, we tested the hypothesis that increased arginase activities associated with visceral leishmaniasis and HIV infections synergize in patients co-infected with both pathogens.

Methodology/Principal Findings

We recruited a cohort of patients with visceral leishmaniasis and a cohort of patients with visceral leishmaniasis and HIV infection from Gondar, Northwest Ethiopia, and recorded and compared their clinical data. Further, we measured the levels of arginase activity in the blood of these patients and identified the phenotype of arginase-expressing cells. Our results show that CD4⁺ T cell counts were significantly lower and the parasite load in the spleen was significantly higher in co-infected patients. Moreover, our results demonstrate that arginase activity was significantly higher in peripheral blood mononuclear cells and plasma of co-infected patients. Finally, we identified the cells-expressing arginase in the PBMCs as low-density granulocytes.

Conclusion

Our results suggest that increased arginase might contribute to the poor disease outcome characteristic of patients with visceral leishmaniasis and HIV co-infection.     

Cell mediated immunity in American cutaneous and mucosal leishmaniasis

Cellular immune responses were studied in 35 Brazilian patients with either active cutaneous leishmaniasis (CL), active mucosal leishmaniasis (ML), or healed cutaneous leishmaniasis. The mean age and duration of illness in the two groups were as follows: 14 CL patients, age 28 +/- 13 yr, disease 5 +/- mo; and 16 ML patients, age 34 +/- 15 yr, disease 86 +/- 117 mo. Patients with CL and ML responded well to leishmania antigen in blastogenesis assays. However, the response of ML patients was over three times greater than the response of CL patients. There was a significant correlation between the magnitude of the lymphoproliferative response and the duration of disease activity. There were no significant differences between CL and ML patients in terms of the following parameters: lymphoproliferative responsiveness to mitogens (phytohemagglutinin, concanavalin A, and pokeweed mitogen) and peripheral blood lymphocyte subpopulations (T and B cells, oKT8+ and OKT4+ cells, OKT4:OKT8 ratio). Peripheral blood mononuclear cells from ML patients also generated interferon-gamma containing lymphokine in response to stimulation with leishmania antigen. This lymphokine was capable of inducing macrophages from ML patients to inhibit the intracellular multiplication of leishmania in vitro. These studies have determined that the parameters of lymphocyte and macrophage functions evaluated in ML and CL patients are comparable, except for an enhanced lymphoproliferative response, with leishmania antigen in ML patients. This later finding may be a function of the long duration of active disease in this population and unrelated to the pathogenesis of their mucosal lesions.     

Monitoring of canine leishmaniasis in northern Italy: an update from a scientific network

Canine leishmaniasis (CanL) due to Leishmania infantum is a disease of great veterinary importance and a serious public health problem. In humans, L. infantum causes visceral (VL) and cutaneous leishmaniasis (CL) and the distribution of VL overlaps that of CanL. Currently, VL is considered by WHO as an emerging zoonosis in southern Europe. The dog is the only domestic reservoir of the infection and phlebotomine sandflies are the only proven vectors of leishmaniasis for dogs and humans. CanL is endemic in Italy, particularly in central and southern regions, including islands. Until 1983, all regions of northern Italy but Liguria and some territories of Emilia Romagna were considered free from CanL. From early '90s new stable foci of CanL have appeared, most of them located within classical endemic areas including territories of Emilia Romagna, Tuscany, Umbria, Marche, and Abruzzi regions. But the most relevant aspect, from an epidemiological point of view, has been the appearance of stable CanL foci in northern Italy, namely in Veneto and Piedmont regions. In these two foci, entomological surveys showed the presence of P. perniciosus and of a second phlebotomine vector, P. neglectus, which may have played a role in the CanL diffusion in some parts of northern Italy. Furthermore, in these areas, autochthonous human VL cases have occurred. There is therefore a realistic risk that CanL infection could rapidly spread through northern latitudes and a surveillance activity is strongly needed. For this reason, in October 2002, thanks to the collaboration and support of Intervet Italia, the network "LeishMap" was created, with the main purpose of monitoring the spread of CanL and vectors in northern Italy. LeishMap consists of scientific and sanitary institutions with proven experience both in field surveys and diagnostic methodologies on CanL and phlebotomine vector. It is organised in 4 Operational Units (OU), represented by researchers of the Veterinary Faculties of the University of Bologna, Padua, Milan and Turin, under the scientific coordination of the MIPI Department, ISS of Rome and with the collaboration of private and public veterinarians operating in the regions under study. During the first year of activity, each OU was involved in the serological and entomological surveillance of several territories in the respective regions, where recent autochthonous CanL cases were registered. The studies have involved five regions, namely Valle D'Aosta, Piedmont, Lombardia, Veneto, Trentino-Alto Adige and Emilia Romagna. In the Symposium 6 of this Congress we report detailed results of a retrospective analysis of data concerning CanL and vectors in northern Italy till 2002 and the preliminary results of 2003 on the seroprevalence rates observed in foci studied and on the entomological surveys carried out. In summary, the results outlined that already known foci of CanL are expanding from the original sites. Several new foci have been identified and many others are at high risk of evolving toward a stable endemicity. P. perniciosus has been found in all but one the suspected new foci. In Emilia Romagna region P. perfiliewi was identified in 2 areas and in one was the only species present. The occurrence of P. neglectus was confirmed in three regions, Veneto, Lombardia and Piedmont. In conclusion, from the 2002-2003 LeishMap activities it appears that further monitoring activities are necessary to identify new endemic foci of CanL, this representing the prerequisite for the implementation of programs for leishmaniasis control in northern Italy.     

Determination of the trend of incidence of cutaneous leishmaniasis in Kerman province 2014-2020 and forecasting until 2023. A time series study

IntroductionCutaneous leishmaniasis (CL) is currently a health problem in several parts of Iran, particularly Kerman. This study was conducted to determine the incidence and trend of CL in Kerman during 2014–2020 and its forecast up to 2023. The effects of meteorological variables on incidence was also evaluated.Materials and methods4993 definite cases of CL recorded from January 2014 to December 2020 by the Vice-Chancellor for Health at Kerman University of Medical Sciences were entered. Meteorological variables were obtained from the national meteorological site. The time series SARIMA methods were used to evaluate the effects of meteorological variables on CL.ResultsMonthly rainfall at the lag 0 (β = -0.507, 95% confidence interval:-0.955,-0.058) and monthly sunny hours at the lag 0 (β = -0.214, 95% confidence interval:-0.308,-0.119) negatively associated with the incidence of CL. Based on the Akaike information criterion (AIC) the multivariable model (AIC = 613) was more suitable than univariable model (AIC = 690.66) to estimate the trend and forecast the incidence up to 36 months.ConclusionThe decreasing pattern of CL in Kerman province highlights the success of preventive, diagnostic and therapeutic interventions during the recent years. However, due to endemicity of disease, extension and continuation of such interventions especially before and during the time periods with higher incidence is essential.     

Decreased Temperature Facilitates Short-Term Sea Star Wasting Disease Survival in the Keystone Intertidal Sea Star Pisaster ochraceus

An extensive 2013 mass mortality event along the West Coast of North America due to Sea Star Wasting Disease (SSWD) has affected at least 20 species of sea stars. Among environmental factors potentially contributing to the timing of the current outbreak, increased coastal water temperatures are hypothesized to have contributed to previous and current outbreaks of SSWD. With a laboratory experiment, we tested whether cooler temperatures, similar to average winter temperatures, compared to average summer temperatures could slow the progression of morbidity or prevent SSWD mortality entirely in Pisaster ochraceus. Sea stars housed in cooler water progressed through SSWD states more slowly than sea stars housed at summer temperatures. However, the cooler temperature did not prevent SSWD mortality, and all stars died of the disease. Our data are consistent with experimental studies and field observations during previous and current outbreaks, and support the hypothesis that changes in coastal water temperatures have influenced one of the largest disease related mass mortality events in our oceans.