Background
Visceral leishmaniasis is a parasitic disease caused by a protozoan parasite. In India specifically, this parasite is Leishmania donovani. This disease is transmitted and spread by female phlebotomine sandflies. These Phlebotomine sandflies are found primarily in warmer, intertropical climates, which is why the majority of cases of visceral leishmaniasis occur in countries such as India, Brazil, and Kenya (WHO 2020). This occurs through the sandflies biting an infected individual or animal, followed by a waiting period, after which the sand fly bites another individual or animal causing an infection. The infection can also be transmitted through blood contact with an infected individual. This is how this disease survives passage form one host to the next. It attaches to the host tissue by entering into PMNs and then being ingested by macrophages. This parasite is able to multiply within the body of their host, which assists them in being able to withstand the host’s defense system. This pathogen induces damages in the host as it causes ulcers, enlarged liver or spleen, decreased production of white blood cells to fight off the disease, weakening the immune system, and affects the bone marrow.
Worldwide, there are around 200,000 to 400,000 cases each year. Visceral leishmaniasis is considered the second deadliest parasitic illness, only behind malaria. The majority of the cases occur in areas in southeast Asia and Africa. In fact, the World Health Organization reported that 94% of new cases of visceral leishmaniasis were from India, Brazil, and countries the east Africa, such as Kenya, Somalia, and Sudan. (WHO 2020). In India, there are many issues in lowering the number of visceral leishmaniasis cases. One of these issues is the high poverty in certain areas, which limits the access that people have to healthcare and to treatment. Medication is also too expensive for most of the individuals in an area of poverty to be able to afford. In addition, there is a severe lack of education about the disease and methods of prevention. However, an initiative has begun, with the World Health Organization and the government of India, that aims to eliminate visceral leishmaniasis in India by increasing and improving treatment and testing, as well as educating the public about this disease.
Symptoms of visceral leishmaniasis can often take some time to appear. The incubation period for the disease is anywhere between 2 weeks and 18 months. However, sometimes symptoms can begin to appear years after the initial infection. Some of the most prominent symptoms include weight loss and weakness, enlarged liver and spleen, hair thinning, and greyish discoloration of skin, particularly in the hands, feet, abdomen, and face. The discoloration is the reason behind why visceral leishmaniasis can also be referred to as black fever. In an article by Ready, it is mentioned that infections that are symptomatic that do not receive treatment are typically fatal, with a mortality rate up to 95% (Ready 2014). Typically, when the disease is left untreated, death occurs in about two years.
Visceral leishmaniasis has been an issue globally for many years. The first cases of what was called “kala-azar”, otherwise known as visceral leishmaniasis, were reported in India and Africa in the 18th century. The name leishmaniasis itself came from a British medical officer, William Leishman. He studied the disease, and officially discovered it, in 1901. His work was then published in 1903. (Varma and Naseem 2010). In India specifically, this disease was almost completely eliminated in 1947 after a DDT spraying program in which the goal was to eradicate malaria. This program continued until 1963, and in between these years, there were no reported cases of visceral leishmaniasis. However, after 1963, the disease returned in massive endemic outbreaks across India, which it continues to have today. In this, visceral leishmaniasis is a re-emerging disease that continues to cause many deaths across India.
However, India is still considered as one of the countries with the highest amounts of cases of visceral leishmaniasis. From 2004 to 2008, 80% of the worldwide estimated cases of visceral leishmaniasis were reported from India. One specific state of India that reports the most cases of visceral leishmaniasis is Bihar. This state is located in the northern area of India. It accounts for nearly 80% of all reported visceral leishmaniasis cases in India. In this state, it is estimated that one to five people out of 10,000 per year become infected. This is much higher than the goal that India, and the World Health Organization have, with a current program running in order to help eliminate visceral leishmaniasis in southeast Asia.
Epidemiology
Visceral leishmaniasis, and especially cases of visceral leishmaniasis that usually end in death, tend to occur in rural, impoverished areas. This is often because there is little to no access to treatment, or a lack of funds in order to be able to afford the treatment. This is considered to be a primary factor as to why Bihar has the highest amount of visceral leishmaniasis cases in India, as it is a very poor, rural area of India. One of the main issues with determining who is most likely to become infected with visceral leishmaniasis is a lack of reporting or testing. It is estimated that only 20-45% of cases of this disease are reported. This is also due to a lack of access to medical care or testing.
In a study by Jervis et al., the proportion of visceral leishmaniasis patients was examined by age, sex, district and season. In Figure 2a from this study, the seasonality is examined by onset of symptoms. On average in this figure, highest number of patients had an onset of symptoms between January and March. This tends to be because of the development of the vector, that the female sand fly, which is the vector for this disease, needs blood in order for the eggs to develop. It is also visible in this figure that the number of cases per year, from 2012 to 2013, decreased. (Jervis 2017). In Figure 5b of this study examined the number of reported visceral leishmaniasis cases in men and women by age. In this figure, the proportion of cases of visceral leishmaniasis is about the same for men and women up until about age fifteen. In every age group after this, men had a significantly higher proportion of cases than women. At ages 75-79, for example, men had a proportion of about 1.1, while women had zero reported cases. (Jervis 2017). This is thought to be because women often do not have the same means as men do to access the healthcare system without their parents taking them. This reduced amount access usually leads to a lack of diagnosis for women, and therefore, a lower number of reported cases. Children and young adults also have a higher risk for this disease, as age 10-14 is seen in Figure 5a as the maximum number of cases reported (Jervis 2017)
The socioeconomic background of the patient also is seen to have a role in the number of reported cases of visceral leishmaniasis. One study that examined this was by Bulstra et al. Specifically Figure 6 of this study examined the number of cases of visceral leishmaniasis in hotspot areas, such as Bihar, as well as households that are not in hotspot areas, and the percentage of poor households. Specifically, households in the lowest two asset quintiles. In this figure, it was found that a significantly higher number of poor households were in the areas that are considered a hotspot for visceral leishmaniasis (Bulstra et al. 2018). In addition to this, even with households that were not in the hotspot areas, there was a higher incidence of visceral leishmaniasis as the percentage of households that were in the lower two quintiles increased. This is often because those who live in areas with that are impoverished tend to have very limited, if not no access to medical treatment. Also, many people who live under the poverty line cannot afford the medication that is needed to treat visceral leishmaniasis. Age also is examined in this study.
Drug and Vaccine Development
Currently, treatment for visceral leishmaniasis relies heavily on four different drugs. These include paromomycin, amphotericin B, pentavalent antimonials, and miltefosine, with miltefosine being the most commonly used and the only drug that is orally effective (Gupta 2014). However, these current drugs and their administrations have many drawbacks and limitations. In an article by Singh et al. the advantages and limitations for each of these drugs, as well as their effectiveness is listed in Table 1. For example, pentavalent antimonials are the most easily available, however in India there tends to be a lot of resistance to this drug. For example, it is only 50% effective in Bihar, which has the highest prevalence of visceral leishmaniasis. Amphotericin B is a very effective drug used against visceral leishmaniasis; however, it must be administered in a hospital. Since visceral leishmaniasis is most common in poor areas, there is a lack of access to the healthcare system, and thus this drug is difficult to receive. Miltefosine, while having an advantage in that it is an oral drug, and thus does not need to be administered in a hospital, it is also very expensive and there has been a developing resistance to this drug (Singh et al. 2016).
One movement that has begun to occur is the development and discovery of new drugs that are effective against this disease. One of the classes of compounds that were looked at when searching for new drugs was Nitroimidazoles. Nitroimidazoles are known to have antimicrobial activity against many parasites. In this class of compounds, one in particular, DNDI-VL-2098, has been studied to be a candidate for a new oral drug to treat visceral leishmaniasis. In this study, figure 1 describes that in the hamsters treated with DNDI-VL-2098, the immune protective response is much higher than in those treated with miltefosine, the only current oral drug. In addition, Figure 2 demonstrates that the nitric oxide generation is higher in hamsters treated with DNDI-VL-2098 than in untreated hamsters. (Gupta et al. 2015). Nitric oxide is crucial in the effective clearance of parasites, making this increase very important.
In addition to new drugs being created, another alternative that has been considered because of the drawbacks of the current drugs is a vaccine. In particular the rLdSir2RP, or Leishmania donovani NAD-dependent Silent information regulator protein-2, has been studied to determine if it could be used as a vaccine. This is primarily because it modulates and increases the Th 1 type immune response, which is crucial in preventing and curing visceral leishmaniasis. One study, from Baharia et al. that was conducted in determining whether this rLdSir2RP could be used as a vaccine, conducted experiments on naïve and infected hamsters to determine the effectiveness of rLdSir2RP compared to no treatment and to the currently studied routes of treatment. Figure 2 in this study describes how the cells responded to rLdSir2RP in hamsters infected with, L. donovani, which causes visceral leishmaniasis a higher nitric concentration than in hamsters with SLD, which is another antigen that is associated with L. donovani. In addition to this figure, the study also considered nitric oxide production in hamsters with rLdSir2RP, and how these amounts are higher in hamsters that were immunized with rLdSir2RP in Figure 6 (Baharia et al). Through this, it was determined that rLdSir2RP is a very effective T-cell stimulatory antigen, and in accordance with this, could be considered to be a new vaccine candidate against visceral leishmaniasis.
Vector
The vector for visceral leishmaniasis is the female sand fly, also known as Phlebotomus argentipes. These sand flies transmit this disease by biting an infected individual or animal, followed by a waiting period of around 20 days, after which the sand fly bites another individual or animal causing an infection. There have been many attempts to control and decrease the number of sandflies in India, and many different methods have been used. In a study by Mondal et al., the efficacy of three of the major methods of vector control were examined. The first of these methods is EM, or environmental management, which involves covering sand fly breeding areas with bleach and washing the walls of a household with lime. The second was durable wall lining, or DWL. This involves the proper installation of durable wall lining that contains deltamethrin. Finally, the third method of vector control that was examined was impregnated bed nets, or ITN. These are bed nets that have slow-release insecticide tablets in them. All three of these methods were studied for density of sand fly and mortality.
The results of this study were examined every three months for a year. In Figure 2, this study shows that environmental management has a very low sand fly mortality rate, starting at 43.87% and decreasing to less than 21.72% over the year. (Mondal et al. 2016). In this graph, it was determined that the method with the highest sand fly mortality was the durable wall lining. The mortality of sand flies using this method began at 83.65% and decreased over a year to 74.39%. It was also determined that impregnated bed nets also had a high efficacy rate, beginning at 74.77% and decreasing to 49.02% over twelve months (Mondal et al. 2016). However, the cost effectiveness of these two methods is important in suggesting policy using one of these forms of vector control. The durable wall lining has a high cost, especially for areas where visceral leishmaniasis is most common, as these areas tend to have a high degree of poverty. Therefore, although the impregnated bed nets tend to have a lower degree of efficacy, especially over time, they would be better to use because they are more cost effective.
The current method of vector control is indoor residual spraying, or IRS. This method was first used in India from 1953-1962 to prevent malaria. During this, the number of visceral leishmaniasis cases greatly decreased. This practice has continued over time as part many different Indian visceral leishmaniasis elimination program as a way to control the vector, Phlebotomus argentipes, of the disease. Currently, DDT is used as the insecticide for the indoor residual spraying, though many have an issue with its use as it harms the environment. However, in a recent form of the elimination program in 2010, the efficacy of this insecticide was greatly decrease from past results. One study that examined this was by Coleman et al., in which a quality assurance of the indoor residual spraying was conducted and samples of walls that indoor residue spraying were used on were tested for DDT residue concentration, both pre-spray, as well as post-spray. In addition, sand fly mortality and abundance were measured in order to determined resistance.
In the study conducted by Coleman et al., Figure 3 uses data to measure the mortality of the sand flies over time from 1978 to 2014. In this figure the mortality of the sand flies decreased from 100% in 1978 to about 40% in 2014 in Bihar, India, which tend to have a high number of cases of visceral leishmaniasis (Coleman et al. 2015). This demonstrates a decrease in the susceptibility of the sand flies to DDT. In addition, this study found that in the eight endemic districts of Bihar, India that were studied, 84.9% of walls were under sprayed, 7.6% were over sprayed, and only 7.4% were sprayed in the correct range (Coleman et al. 2015). These results could have contributed to the decrease in susceptibility of the sand flies to the DDT because since the majority of walls were over sprayed, the sand flies would be able to gain resistance to the DDT and thus, have a lower mortality rate.
Migration
Another issue that affects the morbidity of visceral leishmaniasis in India is migration. In certain villages in Bihar, for example, residents migrate seasonally from their home in the southern hamlet to the northern part of India in order to get work (Kumar et al. 2020). This migration occurs from October to the return of the villagers in May. This migration period takes place primarily because of the high rate of poverty. In a study by Kumar et al., a recent endemic in a typically low endemic to non-endemic area of Bihar was studied and data was collected from the individuals in the affected villages.
In this study, Figure 5 uses data to represent the number of cases of visceral leishmaniasis per month over time by month of diagnosis and by month of developing fever. Through this, there is a large number of cases that developed a fever sometime between November 2016 to May 2017. However, there was not a large increase in number of cases diagnosed until March 2017, when the number of cases diagnosed increased from one to 17 in a one-month span. (Kumar et al. 2020). This is largely due to the early return of migrant workers to their villages because of the developed fever. This return would allow these villagers to seek medical care in their villages. The number of cases decreased after June 2017, from 13 cases to one. (Kumar et al. 2020). This was largely due to the outbreak response that occurred in order to combat the increase in cases. Overall, although the migration itself was not considered a reason for the disease, factors that occurred because of the migration, such as malnutrition, and stress, most likely caused the villagers to become more likely to contract this disease. In addition, this migration decreased the access to healthcare, which delayed the diagnosis of cases of visceral leishmaniasis, and also delayed treatment for this disease.
Knowledge and Attitude
One of the main issues in dealing with visceral leishmaniasis globally in general is a lack of knowledge about the disease. This lack of knowledge is common among visceral leishmaniasis patients as these individuals tend to come from areas with high rates of poverty that often do not have adequate education systems or did not attend school for a long period of time. One study that examined this lack of knowledge by individuals on visceral leishmaniasis was conducted by Bhowmick and Khanum. This study analyzed 215 individuals and 45 professionals on their knowledge of aspects of visceral leishmaniasis, as well as on their living situations and knowledge of medications and treatments used to combat the disease. This study was conducted in Mymensingh, which is located in Bangladesh, near the border of India.
Using the professionals in this study, Figure 4 uses data to determine their knowledge of visceral leishmaniasis. In this, 35.29% of professionals were correct in that the reservoir for visceral leishmaniasis was humans, and 27.06% believed the reservoir to be mosquitoes (Bhowmick and Khanum). This highlights the lack of knowledge of the disease, even by those who are professionals in the field. In addition to this, Table 7 uses data to examine the knowledge of the inhabitants used in this study. While the inhabitants knew the name of the disease, only 53.02% knew it was curable. Also, and perhaps even more importantly, 99.07% of inhabitants had not heard of a sand fly (Bhowmick and Khanum). As the sand fly is the vector of this disease, the major lack of knowledge of it is an issue for prevention. Since the inhabitants had no knowledge of the sand fly, these people would not have taken protective measures against it, and therefore, would not have been able to prevent the disease.
However, work has begun to increase communication and the spread of knowledge about this disease in India. This is done primarily through behavior change communication programs that take place in endemic areas in India. The goal of these programs is to improve knowledge and practices of both visceral leishmaniasis and the indoor residue spraying, or IRS. The program aimed to increase knowledge of symptoms and treatment of visceral leishmaniasis and when to seek medical care. This was mostly done in order to increase the number of individuals that allowed IRS to take place in their homes, in addition to overall safety, in order to decrease the number of cases of the disease.
In a study by Srinivasan et al. the effectiveness of this program is determined through assessing the knowledge of visceral leishmaniasis to a group that did have events with behavior communication change information, called intervention, and a control group that did not attend any events or receive any information from these groups. This is shown in Table 8, in which questions about visceral leishmaniasis and its causes and treatment to both an intervention and a control group. Of knowledge of the vector, 68.4% of individuals of the intervention group knew that the sand fly was the vector for visceral leishmaniasis, while only 7.4% of the control group had this knowledge (Srinivasan et al. 2018). In addition to this, 68.1% of the control group did not know symptoms of visceral leishmaniasis and 52.0% did not know the effective treatment for this disease. This is in contrast to the group that did engage in the behavior communication change, or intervention, in which 64.7% knew the effective treatment of visceral leishmaniasis (Srinivasan et al. 2018).
This data demonstrates an increase in knowledge of individuals who were in intervention villages from those that were in control villages. This information allows the villagers to make better choices and take more preventative measures against the disease, as well as allows the villagers to know when to go see a healthcare professional. This is most evident in the fact that 25% of control villages refused IRS, while only 5% of intervention villages did (Srinivasan et al. 2018). This is because those in the intervention villages had more knowledge as to why IRS was needed and how it was used to prevent visceral leishmaniasis.
Future Challenges/Goals
The future still holds many challenges for research in visceral leishmaniasis. One of the main challenges is the continuing resistance to the medication used to treat this disease. Most importantly, miltefosine, as this is the only drug for this disease that can be taken orally. In a study by Srivastava et al. This growing resistance was researched, with Figure 3 demonstrating the cell viability at different concentrations this drug, as well as others, for two cases of visceral leishmaniasis as well as the standard strain. It is shown on the graph that the percent cell viability for the two actual cases were both at and above 50% at 100 micromoles, unlike the stand strain, which decrease to 0% at 100 micromoles (Srivastava et al. 2017).
In addition to this, another challenge of research in this disease in the future is the continuance of the poverty levels and the need to expand healthcare. One of the main issues currently behind this disease is delayed diagnosis or treatment that tends to occur because of a lack of access to the healthcare system. This lack of access to the healthcare system occurs primarily because of living in poverty. In addition to this, many medications for this disease are very expensive, thus the individuals who get sick most cannot afford them. Another challenge will be resistance of the sand fly to the insecticides used for vector control for this disease.
One future goal of the research in this area is be continued efforts to educate the public, especially those in poor areas, on the treatment and prevention for this disease. In addition to this, another goal is finding a new medication that can be taken orally and that is inexpensive, as resistance grows to the current medications. Another goal of research in visceral leishmaniasis is to increase access to healthcare and medication for those who are sick, and to use indoor residual spraying, or IRS, in every house in endemic areas in order to attempt to control the vector of this disease. Finally, a goal of research in this area is to continue awareness for this disease and to lower the cost of the medications used to combat visceral leishmaniasis.
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