Human leishmaniasis is a major public health problem with a wide clinical spectrum. Despite there is an epidemiological diversity of the disease, cases mostly occur in the developing countries around the subtropical region, and the incidence is significantly rising. The disease is usually classified into three groups: cutaneous leishmaniasis, mucosal leishmaniasis, and visceral leishmaniasis. But to ensure their survival in different conditions, Leishmania spp. have developed many adaptation mechanisms and can be seen in different clinical forms as well. Herein, an overview of the characteristics of the disease and the parasite, interactions with the host, clinical aspects, and latest developments in the diagnosis and treatment is presented.
- vector borne diseases
Human leishmaniasis is a sandfly-mediated parasitic disease that can lead to severe conditions in individuals especially with underdeveloped immune system. It usually affects people living in developing tropical countries and has high mortality rates . Transmission of the parasite starts with an infected sandfly bite. After getting bit by a female sandfly vector carrying the promastigote form of the
Leishmaniasis is considered to be an endemic disease effecting more than 98 countries with a global prevalence of 12 million people. Among different types of disease, CL makes up great percentage of the total amount of cases compared to other two. East Africa, Brazil, and Indian subcontinent are hot spots for VL cases, whereas CL cases are high in the Middle East, Mediterranean region, Central Asia, and Latin American countries . In European countries where leishmaniasis is not endemic, people traveling to endemic regions for various reasons such as military duty, tourism work, and vacation are the major cause of leishmaniasis occurrence .
There are more than 20
Leishmaniasis is ranked second in mortality right after malaria and ranked fourth in terms of morbidity among other communicable diseases . HIV outbreak in the 1990s resulting in HIV/VL coinfection and general global warming of the world increasing the possible habitat for the sandfly led to doubling the amount of cases from 1987 to 2014 despite developing medical technologies . It is estimated that each year around 400,000 people are having VL with a mortality rate of 10% going up to 20% in some areas [2, 3]. The Mediterranean region, Western Asia, and the Americas make up the 90% of 1 million CL cases, whereas ML is represented by 35,000 cases in these regions . Among the other common forms of the disease, CL has the highest amount of cases reported each year. On the other hand, VL is the most fatal one where death usually occurs 2 years after the first transmission.
There are 98 countries and territories with
Parasites can only reach infective stages in certain species of sandfly which as a result limits its transmission . In addition, parasite-vector contact is rare for great majority of the sandfly species . Epidemiological concerns about the leishmaniasis have increased greatly in the last 30 years. HIV/
Here, we aim to provide a general conceptualization of leishmaniasis by summarizing the historical development of the disease to provide a better understanding for possible future approaches.
2. History of the disease
In 1885, after observing
Despite being a neglected tropical disease, our knowledge about the disease has been increasing continuously. Case reports involving uncommon laryngeal leishmaniasis- and HIV-infected individuals showing leishmaniasis effects such as skin lesions and nodules have shown that leishmaniasis can occur again even after treatment hinting to the incubation period of parasite (Figure 1) [16, 17].
Treatment of leishmaniasis started with the use of pentavalent antimonials in the 1940s. Parasite gaining resistance and high level of toxicity for these drugs made it necessary to find an alternative. Amphotericin B is an alternative drug that has been in use since 1980. The main action mechanism of amphotericin B is to interfere with the membrane lipids and cause disruption. The length of the therapy changes between 15 and 45 days for different cases, whereas dosage can vary. Combinatorial use of this drug with some other drugs has shown great increase in the effectiveness of treatment.
Leishmaniasis is a globally common disease that affects more than 98 countries and territories. Even though its effects are mainly observed in underdeveloped or developing countries, this parasite has spread to Europe and the United States due to the traveling to these areas and immigration from these areas. Old World leishmaniasis is endemic in Asia, Africa, the Mediterranean, and the Middle East.
Poor process of record taking in underdeveloped and developing countries makes it difficult to determine its incidence and prevalence in certain areas. Syria is reported to have highest amount of incidence in the Middle East with 52,983 cases being reported in 2012 . In Iraq, leishmaniasis had a prevalence of 45.5 cases per 100,000 of population in 1992 due to the war and population migration which can give an estimate of current situation .
In Asia, Afghanistan, Iran, and Syria are the three Middle Eastern countries where CL is endemic and reported most. Syria having the most amount of CL cases also named the disease as Aleppo boil . Moving toward Eastern Asia, Pakistan holds great number of CL cases, whereas India and Bangladesh can be considered as the sole reservoir for VL . In China, there are three defined VL types: anthroponotic VL, which is caused by
In Africa, three
Realizing the importance of leishmaniasis in most of the African countries is a challenge compared to other countries because of the low quality healthcare services, poor data management, and absent reports. East Africa and sub-Saharan Africa are the geographical regions where leishmaniasis was the least common until 2012 . Considering leishmaniasis is endemic in these regions, it is safe to say that observed value will be much different than the real outcome once enough data are gathered.
When it comes to Europe, countries in the Mediterranean region such as Italy, Greece, Turkey, and Albania have highest prevalence of VL cases . In addition, few number of VL cases were observed in France, Spain, Portugal, and Croatia . In terms of CL cases, Turkey holds great percentage of reports compared to others. In the Netherlands, 185 CL, 8 VL, and 2 MCL cases were observed between 2005 and 2012 . In general, traveling to endemic regions such as Afghanistan or Morocco is shown as a significant risk factor of
American region has low VL and high amount of CL cases reported in general with a 1–20 difference. Brazil has the highest amount of reported cases both in VL and CL. Colombia, Peru, Nicaragua, and Venezuela are other areas where CL cases happen frequently .
Mexico, the United States, and Canada have relatively low amount of reported cases in terms of global occurrence. A total of 811 CL and 7 VL cases were reported in Mexico between 2004 and 2008. The US Army Forces going to endemic regions such as Afghanistan for military duty resulted in few reported
Australia and Antarctica are the two continents where leishmaniasis is not considered to be endemic . Between the years 2008 and 2014, 52 CL and 3 VL cases were reported in Australia . Traveling to
4. Transmission and prevention
Only vector responsible for transmitting leishmaniasis is the female sandfly, belonging to the genera
Transmission can be zoonotic or anthroponotic depending on the reservoir. Domestic dogs are considered to be the major reservoir for zoonotic transmission. In the Americas and Central Asia, interaction between wild animals and humans also causes zoonotic transmission. Humans with VL or post kala-azar dermal leishmaniasis serve as the only reservoir in anthroponotic transmission.
Attenuated parasite vaccines that will provide long-term immunity and prevent transmission are in development. Zoonotic transmission occurs with dogs, and treatment methods targeting infected dogs are not preferred due to the fact that it may result with increased resistance for parasite or there is a high chance of infection in the nature even after the treatment . Deltamethrin-treated collars were tested for the control of the disease and a significant reduction in infection levels in dogs was observed . Avoiding outdoor areas in endemic areas, using protective clothing, using insect repellents, covering around the bed with a net, sleeping above the ground level, and avoiding night time activities are some of the useful methods in order to prevent transmission in humans.
5. Host-parasite interactions
Protective immune response to leishmaniasis mainly depends on the T-cell subset response accompanied with the specific cytokines, transcription factors, presenting of antigen, and production of various interleukins having direct or indirect effect on the main immune system. However, it is important to note that susceptibility or resistance to leishmaniasis is possible in individuals with altered genetics or depending on the environmental conditions as well as parasite strain starting the infection .
Immune response starts with the cells of innate immune system. Neutrophils are the first immune system cells responding to the sandfly bite starting the leishmaniasis infection . Neutrophils are capable of producing microbicidal factors effective against
IFN-γ is another important immune system molecule produced by parasite-dependent Th1 CD4+ lymphocytes and is related to intracellular control of parasites upon infection. On the other hand, Th2 CD4+ cells are responsible from the progression of the disease. This difference in Th1 and Th2 cell line responses was further confirmed by Holaday et al.’s study done on mouse models carrying specific mutations. The study showed that in the presence of antigen, Th1-like cell line response was to produce IL-2 and IFN-γ, whereas Th2-like cell line response was to produce IL-4 and IL-5 upon stimulation .
In another study, Th1, Th2, and Th17 CD4+ T-cell subsets were found to induce production of IL-10 despite having different signaling pathways and transcription route. ERK1 and ERK2 transcriptional activation was common in all these Th cell subsets. c-Maf is an important transcription factor in macrophages for the process of IL-10 expression and was also found to be common for the previously mentioned three different T-cell subsets. c-Maf expression was also found to be dependent on ERK activation in Th1 and Th17 cells .
6. Clinical characteristics of the disease in humans
Cutaneous leishmaniasis is the milder form of leishmaniasis and usually leads to formation of skin lesions or nodules around the exposed bite sites such as face, neck, or limbs [8, 24]. Lesions can heal spontaneously in few months, or in some extreme cases, it can take few years to resolve . Although CL is self-curing and nonlife-threatening, accumulation of CL often leads to disfigured formations on skin. Lesion number can vary between 1 and 20, and upon healing, distinct scars are left on the skin. Various treatment methods are used in order to speed up the healing process for CL.
Depending on the disease forms observed clinically such as uncomplicated form, chronic recurrent form, and diffuse form, there are four causative pathogens in the Old World and five causative pathogens in the New World .
VL also known as kala-azar is the fatal form of leishmaniasis with a mortality rate of 75–95%. Macrophages affected by the parasite spread the infection throughout the body, and patients develop pancytopenia and immunosuppression [6, 43, 44]. VL is often discussed together with HIV as they both affect immune system heavily making patients susceptible to other infections. Incubation period is between 2 weeks and 2 years. Liver- and spleen-related problems are common in patients with VL.
Parasite spreading around the initial bite site using the lymphatic way and infecting the nose or mouth mucosa leads to ML (Figure 1) . Immune system reacting to parasite at the tip of the nose effects airway walls causing lumen obstruction which is related to necrosis of the cartilage in the nose. Unlike CL, ML is not a self-healing disease and can cause permanent skin problems. Destruction of the tip of the nose is a severe condition that may affect patients in their social life. Breathing problems are common result of ML in patients due to the blocked airways .
Another form of the disease, post kala-azar dermal leishmaniasis is a complication of VL in which patients cured of VL develops nodular, macular, or maculopapular rash on skin as a result of immune suppression following VL. It is mainly observed in Sudan and India where majority of the VL cases progress into post kala-azar dermal leishmaniasis .
7. Treatment and resistance in humans
There are various treatment methods depending on the host immune system effectiveness and the type of
Pentavalent antimonials, sodium stibogluconate and N-methylglucamine, liposomal amphotericin B, miltefosine, and paramycin are some of the widely used drugs in routine treatment [6, 48]. Compared to liposomal amphotericin B which is a less toxic form, conventional amphotericin B has complicated application procedure and harmful side effects making liposomal amphotericin B a better choice in treatment of both CL and VL which is also an antifungal agent. Still in some underdeveloped or developing countries that cannot afford liposomal amphotericin B treatment, pentavalent antimonials are used. Despite their toxic effects on the liver and kidneys, pentavalent antimonials are still highly effective . On the other hand, emerging resistance limits the therapy frequently. Miltefosine is another drug with known effect of inducing parasite resistance if not used properly.
Global antibiotic resistance problem has emerged in the treatment of leishmaniasis too, and a number of papers reporting treatment failures are increasing . Anthroponotic transmission is the main cause of drug resistance in
8. Latest developments in the diagnosis, prevention, and treatment
Permanent solution for the leishmaniasis in terms of successful human vaccination is still a major challenge. However, there are different vaccinations currently being tested in mouse model. One of them uses “killed but metabolically active” parasites to induce host immune system reaction. Mice infected by “killed but metabolically active”
Using salivary peptides of the sandfly holds potential to be used as a vaccine component; however, complex immune response makes it a challenge. Novel drug combinations have been tested in some endemic regions in order to lower the treatment cost and toxicity and preventing resistance gain by the parasite. Nitroquinolines were found to show leishmanicidal activity. Antimicrobial peptides including dermaseptin, andropin, and cecropin have been found effective against CL. Edelfosine is an oral drug with greatly increased activity compared to miltefosine. There are also compounds isolated from plants which are tested and observed to have antileishmanial activity. For example, a polyphenolic flavanoid, quercetin, has shown antileishmanial activity in treatment of VL . Four plant species named
Macrophage targeted drug delivery system is another novel approach to directly effect
9. Conclusion and future perspectives
Leishmaniasis still remains as a big public health challenge in some parts of the world. Despite developments in scientific knowledge and medical technology, there is still a need for quick and cheap detection of
In terms of treatment of leishmaniasis, emerging resistance is a big threat for infectious disease specialists like in other microbial diseases. There are two arms of fight. One is the development of a successful vaccine, and the other is the progress of finding new compounds to cure the infection. If applicable early treatment should be applied in order to further prevent the spreading of the parasite. Having no effective human vaccines puts the disease at this critical point. That is why studies focusing on the development of vaccine will be pathfinder in the future decade. On the other hand, studies evaluating the antileishmanial activity of various natural products or chemically modified compounds are needed to find new opportunities in successful treatment of
The author wants to express his special thanks to Namık Refik Kerküklü for his kind help during the preperation of this chapter.
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