The Yucatan Peninsula is considered an important endemic area of localized cutaneous leishmaniasis (LCL) caused by Leishmania (Leishmania) mexicana and mainly the states of Campeche and Quintana Roo where 41.5% of all new cases in Mexico were reported in 2015. People were affected due to the lack of the resources for early diagnosis and treatment and although many aspects of the disease are known, control of LCL is absent in this region. Thus, better case detection and epidemiological surveillance are required. The presence of emerging focus and changes in the clinical form suggest the importance of continuing the eco-epidemiological studies, which could lead to the implementation of a sustainable control on the disease. In this review, we focus on the results of our multi-disciplinary studies carried out in the southeastern Mexico, including LCL burden, clinical aspects, causal agents, vectors, reservoirs and the host immune response to Leishmania (L.) mexicana infection.
- immune response
- localized cutaneous leishmaniasis
- southeastern Mexico
American cutaneous leishmaniasis (ACL) is a vector-borne protozoan zoonotic disease widely spread in Latin America. At least 12 different
In south-eastern Mexico, the Yucatan Peninsula is an important endemic area of LCL, locally known as the “chiclero´s (gum collectors) ulcer”. The LCL was first described by Seidelin in 1912, who classified the agent as morphologically indistinguishable from
The purpose of this chapter is to review the most relevant studies performed in the last 30 years in the Laboratory of Immunology of the Autonomous University of Yucatan. This research has covered the characterization of the “chiclero´s ulcer”, its diagnosis and treatment, and the identification of risk factors as well as the
2. Epidemiology of LCL in southern Mexico
2.1. Incidence and prevalence
Leishmaniasis control is usually hampered by ignorance of the true incidence/prevalence of infection, thus underestimating human suffering and disability caused by the disease. After parasites are inoculated by a sand fly, the infection outcomes might be either an asymptomatic infection or a clinically manifested infection. Most studies done in Latin America with reference to ACL have been focused on incidence/prevalence of the disease (clinical infection).
In the first approach and after diagnostic tools were implemented, a total of 63 cases of LCL were recorded in the state of Campeche between 1982 and 1987. The most common clinical presentation was a chronic ulcerated lesion (with an evolution time longer than 10 years), located predominantly on the ear (39%). Single lesions were found in 49/63 (78%) cases affecting men working in the field .
Based on these data, a program for the study and surveillance of LCL in collaboration with health services from the state of Campeche was established. First of all, a study to determine the incidence of LCL was carried out in seven rural health communities of the state of Campeche from January to December, 1987. Montenegro skin test (MST) was carried out on a sample batch of 449 persons randomly selected from men aged 15–45 years. Risk factors including age (15–45 years old), sex (male) and exposure (working in the field) had been identified previously . MST-positive response ranged from 24 to 90% among the communities studied. These wide-range results could reflect differences in endemicity of LCL in the state of Campeche. A total of 56 new LCL cases with both a positive parasitological diagnosis (smear, isolation-culture and/or biopsy) and MST-positive response were recorded during 1987. In summary, an annual incidence rate of 0.5 per 1000 inhabitants was reported .
Asymptomatic infection is the term used to refer to those individuals living in endemic areas of LCL, exposed to sand fly bites, presenting a MST-positive response but without signs and symptoms of the disease. Based on the criteria given above, a study to determine the prevalence of asymptomatic infection was performed in four rural communities from Campeche. From January to December 1999, a total of 22/116 (18.9%) men of 15–45 years of age and working in the field showed a MST-positive response in the absence of signs and symptoms . Asymptomatic infection by
In the state of Yucatan, cases of LCL were restricted to villages located in the South, near to the characterized endemic areas from Campeche and Quintana Roo. Recently, a new outbreak of LCL was reported in the municipality of Tinum, Yucatán. This village is located in the West of the state and no cases had been reported before. In 2015, 17 new cases were recorded by the health services of the Yucatan State in comparison with the only case reported in 2014. From those cases, 11 were from Tinum. This increased incidence is alarming and suggests possible changes in the epidemiological patterns of leishmaniasis in the Yucatan Peninsula that need to be studied .
2.2. Clinical picture
The clinical picture of LCL in the Yucatan Peninsula was characterized through a study performed between January 1990 and December 1995 . A total of 683 patients with cutaneous lesions suggestive of LCL were examined. Parasite demonstration by smear, biopsy and/or isolation-culture was positive in 445 cases (65.1%). From these samples,
The importance of the active surveillance program was highlighted by the observation of changes in the clinical form with time. The manifestation of LCL has evolved, during the last years, from the typical single, rounded, small and ulcerated lesion worldwide recognized as “benign” (Figure 1A–C), to nodular lesions with an increased diameter as well as the appearance of multiple lesions (Figure 1D–F). Those findings are suggestive of changes in pathogenicity of the parasite that need to be studied.
2.3. Histopathological picture
From the previous clinical study, 73 biopsies were taken to characterize the histopathology of LCL caused by
An investigation on the response of LCL to treatment with pentavalent antimonials (Sb5+) was carried out between January 1990 and December 1994 . This study was not designed to be a controlled clinical trial, but rather to evaluate the response of the chiclero´s ulcer to treatment with meglumine antimoniate. Patient eligibility for the study included a confirmed diagnosis of acute LCL (time of evolution lesser than 12 months) based on both clinical diagnosis and parasite visualization by smear, biopsy and/or isolation-culture, as well as no previous treatment with any antileishmanial drug, absence of any serious concomitant disease, and to be available for a 12-month follow-up. In all the 105 cases presented, at the end of the treatment, a complete re-epithelialization of all lesions occurred without both residual erythema and relapse during a 1-year monthly follow-up. The mean number of injections required for complete re-epithelialization of chiclero’s ulcer was 25.1 (range = 5–60), with a daily dose of one ampule. Since then LCL caused by
3. Ecology of the endemic area
The Yucatan Peninsula is a discrete biotic province of approximately 143,500 km2. The region is a broad, flat shelf of marine limestone of geologically recent formation (Paleocene to Recent). The peninsula includes the states of Yucatan, Campeche, Quintana Roo and a portion of Tabasco east of the Rio Usumacinta and north of the Sierra del Norte de Chiapas. The peninsula is surrounded on three sides by water and bounded on the south by highlands that isolate this region from the rest of Central America. An interesting observation is that because of its geographic isolation, the Yucatan Peninsula is an area of mammalian endemism with fauna that differs markedly from the rest of Mexico. The climate is subtropical with a relative humidity of 80%, an unpredictable rainy season (annual rainfall over 1401 mm) mostly during the summer, and an average temperature of 27 ± 5°C .
Epidemiological studies and molecular characterization of the New World leishmaniases have revealed that the genus
Based on both the clinical and epidemiological features of the disease, as well as on the biological characteristics of the parasite in laboratory animals [19–21],
Therefore, from January 1990 to July 1992, 153 patients with LCL determined by both clinical diagnosis and parasite visualization (smear, biopsy and/or isolation-culture) were studied. All of them were infected in the state of Campeche. Parasite isolation by needle aspirates taken from the edge of the lesions was positive in 49%. Isolates were characterized by isoenzyme markers (glucose phosphate isomerase, mannose phospate isomerase, nucleoside hydrolase, phosphoglucomutase, 6-phosphogluconate dehydrogenase and glucose-6-phosphate dehydrogenase). Seventy (93.3%) were identified as
Later on, a study to identify
Finally, to assure that
Phlebotomine sand flies (Diptera: Psychodidae: Phlebotominae) are insects of medical and veterinary importance since they are involved in the transmission of diverse pathogens . The blood-feeding females are usually considered as the only natural vectors of protozoan
To determine the transmission of leishmaniasis in south-eastern Mexico, vectors were captured near La Libertad, municipality of Escárcega, Campeche (<200 m) and in a medium-sized sub-perennial forest located 8 km southeast of this village. Near La Libertad, nine sand flies species were collected using CDC light traps, a Shannon trap and a mouth aspirator; the most abundant species were
Further entomological studies were carried out at 150 km, east of La Libertad in the village of La Guadalupe and the nearby village of Dos Naciones, municipality of Calakmul, Campeche. Using Shannon traps, Disney traps and CDC light traps, 15 sand fly species (
Although the abundance of sand fly vectors was determined in three foci, the species of
Leishmaniases is a complex of zoonotic diseases, which are infections transmitted from animals to humans. Identifying a reservoir of such zoonosis requires extensive ecological, entomological, mammalian, parasitological and epidemiological studies. The World Health Organization enumerated five criteria to incriminate a primary reservoir . Thus, a step-by-step method is needed to investigate a primary reservoir of a zoonosis.
The first step is to identify animals that harbour the parasite. The first attempt to find leishmanial hosts close to the Yucatan Peninsula was carried out in Belize in the early 1960s [29–31]. However, the south of Belize has to be considered as a different endemic area of the disease since this area is not part of the Biotic Province of the Peninsula of Yucatán . In the Yucatan Peninsula,
The second step to identify a primary reservoir is that the species, which is relatively abundant in the focus to provide a food source for sand flies. In southern Campeche,
In the Yucatan Peninsula, a well-defined transmission season has been demonstrated, which is limited to the coolest months of the year, from November to March . Thus, an important step to demonstrate a primary reservoir in an area of seasonal transmission is that the individuals of the reservoir species survive the infection and keep the parasite until the next transmission season, which is more than 7 months. In the field,
The next step to implicate a primary reservoir is that the proportion of animals infected is high enough (20%) to infect the vector during the transmission season (OMS 1984). In the state of Campeche, the seasonal prevalence of infection of
The last step to identify the primary reservoir is that the species of parasite is identical in all hosts (reservoir, vector and human) thus, the geographic and temporal distributions of humans and the transient micro-habitat of reservoir and vector need to overlap. Leishmaniasis existed first among wild animals and sand flies and the forest was not very populated by humans. However, with the human displacements due to overpopulation of some areas, new settlements appear constantly deep in the forest. A deforested ring around village limits the contact with the reservoir species and vectors. However, due to the Mayan slash-and-burn agriculture human enters deep into the forest exposing themselves to the bites of infected sand flies. Moreover, subsistence hunting takes place during the night mainly when the agricultural season is over . Moreover, with the ecological protection of large forests, such as the Calakmul Biosphere Reserve in the State of Campeche, the incidence of wild zoonotic diseases might increase.
3.4. Seasonal transmission
To know the timing of the transmission cycle in each focus of leishmaniasis is very important because high-risk seasons might be restricted. Thus, intervention measures such as prevention through medical education could be conducted before the high-risk period. Moreover, epidemiological and ecological studies could be limited to that season and consequently the cost of research could be diminished.
Based on this rationale, all the results of previous research were analysed focusing on the timing of transmission of
In summary, the median-size humid forests of the Yucatan Peninsula have ideal ecological conditions for
4. Immune response to
L. (L.) mexicana
The skin is the first immune barrier against
Based on this rationale, the characterization of the cytokine expression profile was studied in 13 LCL lesions caused by
Another study of 20 LCL patients was carried out to analyse the role of IL-12 in the protective immune response to
Epidemiological studies detected many individuals from the endemic area of LCL without suggestive signs of the disease but with a delayed hypersensitivity skin test (DHT) positive to
Special thanks to all researchers and students that collaborate to carry out all these studies. We are grateful to the personnel of the Social Security Mexican Institute (IMSS) and the Ministry of Health Services (SS) from the state of Campeche, for their valuable collaboration through these 30 years of study. We thank IQ Silvia Andrade Canto for photography technical assistance.
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