Visceral leishmaniasis
Encyclopedia
Visceral leishmaniasis also known as kala-azar, black fever, and Dumdum fever, is the most severe form of leishmaniasis
. Leishmaniasis is a disease
caused by protozoan parasites of the Leishmania
genus. This disease is the second-largest parasitic killer in the world (after malaria
), responsible for an estimated 500,000 cases each year worldwide. The parasite migrates to the internal organs such as liver
, spleen
(hence 'visceral
') and bone marrow
, and, if left untreated, will almost always result in the death of the host. Signs and symptoms include fever
, weight loss
, mucosal ulcers, fatigue, anemia
and substantial swelling of the liver and spleen. Of particular concern, according to the World Health Organization
(WHO), is the emerging problem of HIV
/VL co-infection.
" (Africa, Asia, Europe) species are L. donovani
and L. infantum
and the "New World
" (South America) species is L. chagasi.
of the Phlebotomus genus
in the Old World and the Lutzomyia genus in the New World. Sandflies are tiny creatures, 3-6 millimeters long by 1.5-3 millimeters in diameter, and found in tropical or temperate regions throughout the world. Sandfly larvae grow in warm, moist organic matter, such as old trees, house walls or waste — making them hard to eradicate.
The adult female sand fly is a bloodsucker, usually feeding at night on sleeping prey. When the fly bites an animal infected with L. donovani, the pathogen is ingested along with the prey’s blood. At this point the protozoan is in the smaller of its two forms, called an amastigote
— round, non-motile, and only three to seven micrometers in diameter.
Taken into the stomach of the sandfly, the amastigotes quickly transform into a second L. donovani form, called the promastigote. This form is spindle-shaped, triple the size of the amastigote, and has a single flagellum
that allows for motility. The promastigotes live extracellularly in the sandfly’s alimentary canal, reproducing asexually, then migrate to the proximal end of the gut where they become poised for a regurgitational transmission. This is their means of transmission back into a mammalian host, as the fly injects its saliva into prey when it bites. The promastigotes are introduced locally at the bite site along with the fly’s saliva.
Once inside the new host, promastigotes invade macrophages. Once inside, they transform back into the smaller amastigote form. As an amastigote, L. donovani can only reproduce intracellularly — and the amastigotes replicate in the most hostile part of the macrophage cell, inside the phagolysosome
, whose normal defensive response they are able to prevent. After they have reproduced to a certain extent, the L. donovani lyse
their host cell by sheer pressure of mass, but there is some recent speculation that they are able to leave the cell by triggering the exocytosis
response of the macrophage. The daughter cell protozoans then migrate through the bloodstream to find new macrophage hosts. In time, L. donovani becomes a systemic infection, spreading to all the host’s organs, particularly the spleen and liver.
When a human patient does develop visceral leishmaniasis, the most typical symptoms are fever
and the enlargement of the spleen, or splenomegaly
, with enlargement of the liver — hepatomegaly
— sometimes being seen as well. The blackening of the skin that gave the disease its common name in India does not appear in most strains of the disease, and the other symptoms are very easy to mistake for those of malaria
. Mis-diagnosis is dangerous, as without proper treatment the mortality rate for kala-azar is close to 100%. L. donovani itself is not usually the direct cause of death in kala-azar sufferers, however. Pneumonia
, tuberculosis
and dysentery
are omnipresent in the depressed regions where leishmaniasis thrives, and, as with AIDS
, it is these opportunistic infection
s that are more likely to kill, flaring up in a host whose immune system has been weakened by the L. donovani infection. Progress of the disease is extremely variable, taking anywhere from one to twenty weeks, but a typical duration for the Sudanese strain of the disease is narrower, between twelve and sixteen weeks.
Even with recovery, kala-azar does not always leave its hosts unmarked. Some time after successful treatment—generally a few months with African kala-azar, or as much as several years with the Indian strain—a secondary form of the disease may set in, called post kala-azar dermal leishmaniasis, or PKDL. This condition manifests first as small, measle-like skin lesions on the face, which gradually increase in size and spread over the body. Eventually the lesions may coalesce to form disfiguring, swollen structures resembling leprosy
, and occasionally causing blindness if they spread to the eyes. (This disease is not the same as cutaneous leishmaniasis
, a milder disease caused by another protozoan of the Leishmania genus which also causes skin lesions.)
Serological
testing is much more frequently used in areas where leishmaniasis is endemic. The K39 dipstick test is easy to perform, and village health workers can be easily trained to use it. The kit may be stored at ambient temperature and no additional equipment needs to be carried to remote areas. The DAT
anti-leishmania antigen test is standard within MSF
is much more cumbersome to use and appears not to have any advantages over the K39 test.
There are a number of problems with serological testing: in highly endemic areas, not everyone who becomes infected will actually develop clinical disease or require treatment. Indeed, up to 32% of the healthy population may test positive, but not require treatment. Conversely, because serological tests look for an immune response and not for the organism itself, the test does not become negative after the patient is cured, it cannot be used as a check for cure, or to check for re-infection or relapse. Likewise, patients with abnormal immune systems (e.g., HIV infection) will have false-negative tests.
Other tests being developed include a latex agglutination test (KAtex
), which is currently being tested in Asia and Africa. Another potential test detects erythrosalicylic acid.
and malaria
) effective and affordable chemotherapy
is sorely lacking and parasites or insect vectors are becoming increasingly resistant to existing anti-parasite drugs. Presumably due to the lack of financial return, new drugs are slow to emerge and much of the basic research into potential drug targets takes place in universities, funded by charitable organisations. This may change as a result of infection of members of the armed forces from the developed nations that currently occupy nations such as Afghanistan
and Iraq
, where Leishmania is commonplace.
The traditional treatment is with pentavalent antimonial
s such as sodium stibogluconate
and meglumine antimoniate
. Resistance is now common in India, and rates of resistance have been shown to be as high as 60% in parts of Bihar, India.
The Indian medical practitioner, Upendra Nath Brahmachari
, was nominated for the Nobel Prize in Physiology or Medicine
in 1929 for his discovery of ureastibamine (an antimonial
compound
for the treatment of kala-azar) and a new disease, post kala-azar dermal leishmaniasis. Brahmachari's cure for visceral leishmaniasis was the urea salt of para-amino-phenyl stibnic acid which he called Urea Stibamine.
The treatment of choice for visceral leishmaniasis acquired in India is now Amphotericin B
in its various liposomal preparations (AmBisome, Abelcet, Amphocil)
A low dose (0.5–1 mg/kg) is given on the first day, increasing to 1–2 mg/kg on the second day, followed by 1.5–3 mg/kg on the third and subsequent days.
Miltefosine
Impavido is the first oral treatment for this disease. The cure rate of miltefosine in Phase III clinical trials is 95%; Studies in Ethiopia show that is also effective in Africa. In HIV immunosuppressed people which are coinfected with leishmaniasis it has shown that even in resistant cases 2/3 of the people responded to this new treatment.
Miltefosine has received approval by the Indian regulatory authorities in 2002 and in Germany in 2004.It is now registered in many countries.
The drug is generally better tolerated than other drugs. Main side effects are gastrointetinal disturbance in the first or second day of treatment (a course of treatment is 28 days) which does not affect the efficiency. Because it is available as an oral formulation, the expense and inconvenience of hospitalization is avoided, and outpatient distribution of the drug becomes an option, making Miltefosine a drug of choice.
The nonprofit Institute for OneWorld Health
has adopted the broad spectrum antibiotic paromomycin for use in treating VL; its antileishmanial properties were first identified in the 1980s. A treatment with paromomycin costs about $15 USD. The drug had originally been identified in the 1960s. The Indian government approved paromomycin for sale and use in August 2006.
In 2009, the Hebrew University of Jerusalem
Kuvin Center for the Study of Infectious and Tropical Diseases, in a collaborative effort with Addis Ababa University
, was awarded a grant by the Bill & Melinda Gates Foundation
for research into visceral leishmaniasis in Ethiopia
. The project will gather data to be analyzed to identify the weak links in the transmission cycle and devise methods for control of the disease.
Combination drug therapies are currently under investigation, particularly by the Drugs for Neglected Diseases initiative
(DNDi). Combination therapies allow for the use of existing drugs in combination, each in lower doses, which helps to decrease the incidence of severe side effects and drug toxicity, as well as the risk for development of resistance against the drugs; they have been shown to be cost-effective strategies strategies.
The drug development pipeline is lacking significantly, and no novel drug targets are expected for approval in the next 5 years. In the meantime, new combination therapies, and well as improvements to existing drugs targets, are under development. Single-dosage administrations of liposomal amphotericin B have been shown to be effective, and oral formulations are currently under development to increase access and facilitate distribution of the efficacious drug in the field.
Kala-azar first came to the attention of Western doctors in 1824 in Jessore, India (now Bangladesh
), where it was initially thought to be a form of malaria
. Assam
gave kala-azar one of its common names, Assam fever. Another common name, kala-azar, is derived from kala which means black in Sanskrit
, Assamese
, Hindi
and Urdu
and the Persian azar for disease, so called for the darkening of the skin on the extremities and abdomen that is a symptom of the Indian form of the disease. The agent of the disease was also first isolated in India by Scottish doctor William Leishman and Irish physician Charles Donovan
, working independently of each other. As they published their discovery almost simultaneously, the species was named for both of them — Leishmania donovani.
Today, the name kala-azar is used interchangeably with the scientific name visceral leishmaniasis for the most acute form of the disease caused by L. donovani. The disease is endemic in West Bengal
, where it was first discovered, but is seen at its most deadly in north and east Africa. It can also be found throughout the Arab
world and southern Europe (where the causative organism is L. infantum), and a slightly different strain of the pathogen, L. chagasi, is responsible for leishmaniasis in the new world. Several species of canines
serve as reservoir hosts of L. infantum (chagasi).
But, while the disease's geographical range is broad, it is not continuous. The disease clusters around areas of drought, famine, and high population density. In Africa, this has meant a knot of infection centers mostly in Sudan
, Kenya
, and Somalia
. Living conditions here have changed very little in the past century, and the people are not normally very mobile. Parts of the Sudan, in particular the Upper Nile region, are almost totally cut off from the rest of the country, and the people are as tied to the place of their birth as any peasant of Europe’s Dark Ages.
Contemporary life has made itself felt even here, however—not as "progress" but in the form of the many small wars of Africa's post-colonial era. In the Sudan
, where civil war has been continuous since 1983, the violence has been concentrated in the more populated south, and kala-azar was concentrated there too. But the wars have driven a steady stream of refugees out of the region, and these traveled either across the southern border or into the remoter western part of the country called the Upper Nile, where both war and the disease that went with it had not yet penetrated.
These refugees, moving at foot-speed, carried the disease with them, and when it arrived it hit the Upper Nile with a force comparable to smallpox
hitting the American Indians
. The isolated people of the Upper Nile had no access to medicine or education about the new disease among them. Worse, their immune system
s were defenseless against this new pathogen, foreign to them though it came only from another part of their own country. One village at the center of the epidemic, Duar
, was left with four survivors out of a population of a thousand, and from the late eighties to the mid-nineties a total of 100,000 succumbed to the sickness in that region alone. In the words of Jill Seaman
, the doctor who led relief efforts in the Upper Nile for the French organization Médecins Sans Frontières
, “Where else in the world could 50% of a population die without anyone knowing?”
North Bihar
, India (including Araria
, Purnea and Kishanganj
) is the endemic zone of this disease.
Leishmaniasis
Leishmaniasis is a disease caused by protozoan parasites that belong to the genus Leishmania and is transmitted by the bite of certain species of sand fly...
. Leishmaniasis is a disease
Disease
A disease is an abnormal condition affecting the body of an organism. It is often construed to be a medical condition associated with specific symptoms and signs. It may be caused by external factors, such as infectious disease, or it may be caused by internal dysfunctions, such as autoimmune...
caused by protozoan parasites of the Leishmania
Leishmania
Leishmania is a genus of Trypanosomatid protozoa, and is the parasite responsible for the disease leishmaniasis. It is spread through sandflies of the genus Phlebotomus in the Old World, and of the genus Lutzomyia in the New World. Their primary hosts are vertebrates; Leishmania commonly infects...
genus. This disease is the second-largest parasitic killer in the world (after malaria
Malaria
Malaria is a mosquito-borne infectious disease of humans and other animals caused by eukaryotic protists of the genus Plasmodium. The disease results from the multiplication of Plasmodium parasites within red blood cells, causing symptoms that typically include fever and headache, in severe cases...
), responsible for an estimated 500,000 cases each year worldwide. The parasite migrates to the internal organs such as liver
Liver
The liver is a vital organ present in vertebrates and some other animals. It has a wide range of functions, including detoxification, protein synthesis, and production of biochemicals necessary for digestion...
, spleen
Spleen
The spleen is an organ found in virtually all vertebrate animals with important roles in regard to red blood cells and the immune system. In humans, it is located in the left upper quadrant of the abdomen. It removes old red blood cells and holds a reserve of blood in case of hemorrhagic shock...
(hence 'visceral
Viscus
In anatomy, a viscus is an internal organ, and viscera is the plural form. The viscera, when removed from a butchered animal, are known collectively as offal...
') and bone marrow
Bone marrow
Bone marrow is the flexible tissue found in the interior of bones. In humans, bone marrow in large bones produces new blood cells. On average, bone marrow constitutes 4% of the total body mass of humans; in adults weighing 65 kg , bone marrow accounts for approximately 2.6 kg...
, and, if left untreated, will almost always result in the death of the host. Signs and symptoms include fever
Fever
Fever is a common medical sign characterized by an elevation of temperature above the normal range of due to an increase in the body temperature regulatory set-point. This increase in set-point triggers increased muscle tone and shivering.As a person's temperature increases, there is, in...
, weight loss
Cachexia
Cachexia or wasting syndrome is loss of weight, muscle atrophy, fatigue, weakness, and significant loss of appetite in someone who is not actively trying to lose weight...
, mucosal ulcers, fatigue, anemia
Anemia
Anemia is a decrease in number of red blood cells or less than the normal quantity of hemoglobin in the blood. However, it can include decreased oxygen-binding ability of each hemoglobin molecule due to deformity or lack in numerical development as in some other types of hemoglobin...
and substantial swelling of the liver and spleen. Of particular concern, according to the World Health Organization
World Health Organization
The World Health Organization is a specialized agency of the United Nations that acts as a coordinating authority on international public health. Established on 7 April 1948, with headquarters in Geneva, Switzerland, the agency inherited the mandate and resources of its predecessor, the Health...
(WHO), is the emerging problem of HIV
HIV
Human immunodeficiency virus is a lentivirus that causes acquired immunodeficiency syndrome , a condition in humans in which progressive failure of the immune system allows life-threatening opportunistic infections and cancers to thrive...
/VL co-infection.
Species that give rise to VL
Several species of Leishmania are known to give rise to the visceral form of the disease. The "Old WorldOld World
The Old World consists of those parts of the world known to classical antiquity and the European Middle Ages. It is used in the context of, and contrast with, the "New World" ....
" (Africa, Asia, Europe) species are L. donovani
Leishmania donovani
Leishmania donovani is a species of Leishmania. It is an important cause of visceral leishmaniasis. The reference genome of L. donovani extracted in the south eastern Nepal was published in 2011...
and L. infantum
Leishmania infantum
Leishmania infantum is the causative agent of infantile visceral leishmaniasis in the Mediterranean region of the Old World and in Latin America, where it has been called Leishmania chagasi. It is also an unusual cause of cutaneous leishmaniasis. Wild canids and domestic dogs are the natural...
and the "New World
New World
The New World is one of the names used for the Western Hemisphere, specifically America and sometimes Oceania . The term originated in the late 15th century, when America had been recently discovered by European explorers, expanding the geographical horizon of the people of the European middle...
" (South America) species is L. chagasi.
Life-cycle of the parasite
Visceral leishmaniasis (Kala-azar) is spread through an insect vector, the sandflyPhlebotominae
Members of the subfamily Phlebotominae are known outside of the United States by the name sand fly. This subfamily includes numerous genera of blood-feeding flies, including the primary vectors of leishmaniasis, bartonellosis and pappataci fever...
of the Phlebotomus genus
Genus
In biology, a genus is a low-level taxonomic rank used in the biological classification of living and fossil organisms, which is an example of definition by genus and differentia...
in the Old World and the Lutzomyia genus in the New World. Sandflies are tiny creatures, 3-6 millimeters long by 1.5-3 millimeters in diameter, and found in tropical or temperate regions throughout the world. Sandfly larvae grow in warm, moist organic matter, such as old trees, house walls or waste — making them hard to eradicate.
The adult female sand fly is a bloodsucker, usually feeding at night on sleeping prey. When the fly bites an animal infected with L. donovani, the pathogen is ingested along with the prey’s blood. At this point the protozoan is in the smaller of its two forms, called an amastigote
Amastigote
An amastigote is a cell that does not have a visible external flagella or cilia. The term is used mainly to describe a certain phase in the life-cycle of trypanosome protozoans. It is also called the leishmanial stage, since in Leishmania it is the form the parasite takes in the vertebrate host,...
— round, non-motile, and only three to seven micrometers in diameter.
Taken into the stomach of the sandfly, the amastigotes quickly transform into a second L. donovani form, called the promastigote. This form is spindle-shaped, triple the size of the amastigote, and has a single flagellum
Flagellum
A flagellum is a tail-like projection that protrudes from the cell body of certain prokaryotic and eukaryotic cells, and plays the dual role of locomotion and sense organ, being sensitive to chemicals and temperatures outside the cell. There are some notable differences between prokaryotic and...
that allows for motility. The promastigotes live extracellularly in the sandfly’s alimentary canal, reproducing asexually, then migrate to the proximal end of the gut where they become poised for a regurgitational transmission. This is their means of transmission back into a mammalian host, as the fly injects its saliva into prey when it bites. The promastigotes are introduced locally at the bite site along with the fly’s saliva.
Once inside the new host, promastigotes invade macrophages. Once inside, they transform back into the smaller amastigote form. As an amastigote, L. donovani can only reproduce intracellularly — and the amastigotes replicate in the most hostile part of the macrophage cell, inside the phagolysosome
Phagolysosome
A phagolysosome is the membrane-enclosed organelle which forms when a phagosome fuses with a lysosome. After fusion, the food particles or pathogens contained within the phagosome are usually digested by the enzymes contained within the lysosome. Phagolysosome formation follows phagocytosis...
, whose normal defensive response they are able to prevent. After they have reproduced to a certain extent, the L. donovani lyse
Lysis
Lysis refers to the breaking down of a cell, often by viral, enzymic, or osmotic mechanisms that compromise its integrity. A fluid containing the contents of lysed cells is called a "lysate"....
their host cell by sheer pressure of mass, but there is some recent speculation that they are able to leave the cell by triggering the exocytosis
Exocytosis
Exocytosis , also known as 'The peni-cytosis', is the durable process by which a cell directs the contents of secretory vesicles out of the cell membrane...
response of the macrophage. The daughter cell protozoans then migrate through the bloodstream to find new macrophage hosts. In time, L. donovani becomes a systemic infection, spreading to all the host’s organs, particularly the spleen and liver.
Disease progression
In human hosts, response to infection by L. donovani varies a great deal, not only by the strength but also by the type of the patient’s immune reaction. People with a history of infection by strains of leishmania that cause visceral leishmaniasis show a continuum of immune responses from protective to non-protective. Those who acquired protective immunity (skin test positive) without ever having visceral leishmaniasis have a strong type 1 CD4+ response to leishmania antigens. Antigen specific interferon-gamma and proliferation, as well as the ability to kill intracellular leishmania, are hallmarks of protective immunity.[4,5] Because visceral leishmaniasis patients lack these responses to leishmania and other antigens, they usually die of secondary infections unless treated. In addition, increased interleukin-10 secretion is characteristic of the disease[6-8]. Addition of interleukin-12, anti-interleukin-10, or anti-interleukin-4 to peripheral blood mononuclear cells from acute patients sometimes increases interferon-gamma secretion and proliferation.[9-11] Acute patient peripheral blood mononuclear cells include CD8+ T regulatory cells that decrease interferon-gamma secretion and proliferation responses to leishmania and other antigens and increase interleukin-10 secretion when added to autologous peripheral blood mononuclear cells harvested after successful treatment.[8,12] Thus, the CD8+ T regulatory cells reproduce the immune response characteristic of visceral leishmaniasis. CD8+ T regulatory cells are also associated with post kala azar dermal leishmaniasis.[13] Addition of interleukin-12 or interferon-gamma does not prevent CD8+ T regulatory activity. The dominance of type 1 CD4+ T cells in skin test positive adults maybe explained by their secretion of factors that inhibit and kill CD8+ T regulatory cells.[11,12] Successfully treated patients rarely develop visceral leishmaniasis a second time. Their peripheral blood mononuclear cells show a mixed T1/T2 CD4+ and CD8+ T suppressor response but do have the ability to kill intracellular leishmania.[4,12,14]When a human patient does develop visceral leishmaniasis, the most typical symptoms are fever
Fever
Fever is a common medical sign characterized by an elevation of temperature above the normal range of due to an increase in the body temperature regulatory set-point. This increase in set-point triggers increased muscle tone and shivering.As a person's temperature increases, there is, in...
and the enlargement of the spleen, or splenomegaly
Splenomegaly
Splenomegaly is an enlargement of the spleen. The spleen usually lies in the left upper quadrant of the human abdomen. It is one of the four cardinal signs of hypersplenism, some reduction in the number of circulating blood cells affecting granulocytes, erythrocytes or platelets in any...
, with enlargement of the liver — hepatomegaly
Hepatomegaly
Hepatomegaly is the condition of having an enlarged liver. It is a nonspecific medical sign having many causes, which can broadly be broken down into infection, direct toxicity, hepatic tumours, or metabolic disorder. Often, hepatomegaly will present as an abdominal mass...
— sometimes being seen as well. The blackening of the skin that gave the disease its common name in India does not appear in most strains of the disease, and the other symptoms are very easy to mistake for those of malaria
Malaria
Malaria is a mosquito-borne infectious disease of humans and other animals caused by eukaryotic protists of the genus Plasmodium. The disease results from the multiplication of Plasmodium parasites within red blood cells, causing symptoms that typically include fever and headache, in severe cases...
. Mis-diagnosis is dangerous, as without proper treatment the mortality rate for kala-azar is close to 100%. L. donovani itself is not usually the direct cause of death in kala-azar sufferers, however. Pneumonia
Pneumonia
Pneumonia is an inflammatory condition of the lung—especially affecting the microscopic air sacs —associated with fever, chest symptoms, and a lack of air space on a chest X-ray. Pneumonia is typically caused by an infection but there are a number of other causes...
, tuberculosis
Tuberculosis
Tuberculosis, MTB, or TB is a common, and in many cases lethal, infectious disease caused by various strains of mycobacteria, usually Mycobacterium tuberculosis. Tuberculosis usually attacks the lungs but can also affect other parts of the body...
and dysentery
Dysentery
Dysentery is an inflammatory disorder of the intestine, especially of the colon, that results in severe diarrhea containing mucus and/or blood in the faeces with fever and abdominal pain. If left untreated, dysentery can be fatal.There are differences between dysentery and normal bloody diarrhoea...
are omnipresent in the depressed regions where leishmaniasis thrives, and, as with AIDS
AIDS
Acquired immune deficiency syndrome or acquired immunodeficiency syndrome is a disease of the human immune system caused by the human immunodeficiency virus...
, it is these opportunistic infection
Opportunistic infection
An opportunistic infection is an infection caused by pathogens, particularly opportunistic pathogens—those that take advantage of certain situations—such as bacterial, viral, fungal or protozoan infections that usually do not cause disease in a healthy host, one with a healthy immune system...
s that are more likely to kill, flaring up in a host whose immune system has been weakened by the L. donovani infection. Progress of the disease is extremely variable, taking anywhere from one to twenty weeks, but a typical duration for the Sudanese strain of the disease is narrower, between twelve and sixteen weeks.
Even with recovery, kala-azar does not always leave its hosts unmarked. Some time after successful treatment—generally a few months with African kala-azar, or as much as several years with the Indian strain—a secondary form of the disease may set in, called post kala-azar dermal leishmaniasis, or PKDL. This condition manifests first as small, measle-like skin lesions on the face, which gradually increase in size and spread over the body. Eventually the lesions may coalesce to form disfiguring, swollen structures resembling leprosy
Leprosy
Leprosy or Hansen's disease is a chronic disease caused by the bacteria Mycobacterium leprae and Mycobacterium lepromatosis. Named after physician Gerhard Armauer Hansen, leprosy is primarily a granulomatous disease of the peripheral nerves and mucosa of the upper respiratory tract; skin lesions...
, and occasionally causing blindness if they spread to the eyes. (This disease is not the same as cutaneous leishmaniasis
Cutaneous leishmaniasis
Cutaneous leishmaniasis is the most common form of leishmaniasis. It is a skin infection caused by a single-celled parasite that is transmitted by sandfly bites...
, a milder disease caused by another protozoan of the Leishmania genus which also causes skin lesions.)
Diagnosis
The gold standard for diagnosis is visualization of the amastigotes in splenic aspirate or bone marrow aspirate. This is a technically challenging procedure that is frequently unavailable in areas of the world where visceral leishmaniasis is endemic.Serological
Serology
Serology is the scientific study of blood serum and other bodily fluids. In practice, the term usually refers to the diagnostic identification of antibodies in the serum...
testing is much more frequently used in areas where leishmaniasis is endemic. The K39 dipstick test is easy to perform, and village health workers can be easily trained to use it. The kit may be stored at ambient temperature and no additional equipment needs to be carried to remote areas. The DAT
Direct agglutination test
A direct agglutination test is any test that uses whole organisms as a means of looking for serum antibodies. The abbreviation, DAT, is most frequently used for the serological test for visceral leishmaniasis....
anti-leishmania antigen test is standard within MSF
Médecins Sans Frontières
' , or Doctors Without Borders, is a secular humanitarian-aid non-governmental organization best known for its projects in war-torn regions and developing countries facing endemic diseases. Its headquarters are in Geneva, Switzerland...
is much more cumbersome to use and appears not to have any advantages over the K39 test.
There are a number of problems with serological testing: in highly endemic areas, not everyone who becomes infected will actually develop clinical disease or require treatment. Indeed, up to 32% of the healthy population may test positive, but not require treatment. Conversely, because serological tests look for an immune response and not for the organism itself, the test does not become negative after the patient is cured, it cannot be used as a check for cure, or to check for re-infection or relapse. Likewise, patients with abnormal immune systems (e.g., HIV infection) will have false-negative tests.
Other tests being developed include a latex agglutination test (KAtex
Katex
Katex is a village and the most populous municipality, except for the capital Balakən, in the Balakan Rayon of Azerbaijan. It has a population of 7,432. The municipality consists of the villages of Katex and Beretbinə....
), which is currently being tested in Asia and Africa. Another potential test detects erythrosalicylic acid.
Treatments
As with many diseases in developing nations, (including trypanosomiasisTrypanosomiasis
Trypanosomiasis or trypanosomosis is the name of several diseases in vertebrates caused by parasitic protozoan trypanosomes of the genus Trypanosoma. Approximately 500,000 men, women and children in 36 countries of sub-Saharan Africa suffer from human African trypanosomiasis which is caused by...
and malaria
Malaria
Malaria is a mosquito-borne infectious disease of humans and other animals caused by eukaryotic protists of the genus Plasmodium. The disease results from the multiplication of Plasmodium parasites within red blood cells, causing symptoms that typically include fever and headache, in severe cases...
) effective and affordable chemotherapy
Chemotherapy
Chemotherapy is the treatment of cancer with an antineoplastic drug or with a combination of such drugs into a standardized treatment regimen....
is sorely lacking and parasites or insect vectors are becoming increasingly resistant to existing anti-parasite drugs. Presumably due to the lack of financial return, new drugs are slow to emerge and much of the basic research into potential drug targets takes place in universities, funded by charitable organisations. This may change as a result of infection of members of the armed forces from the developed nations that currently occupy nations such as Afghanistan
Afghanistan
Afghanistan , officially the Islamic Republic of Afghanistan, is a landlocked country located in the centre of Asia, forming South Asia, Central Asia and the Middle East. With a population of about 29 million, it has an area of , making it the 42nd most populous and 41st largest nation in the world...
and Iraq
Iraq
Iraq ; officially the Republic of Iraq is a country in Western Asia spanning most of the northwestern end of the Zagros mountain range, the eastern part of the Syrian Desert and the northern part of the Arabian Desert....
, where Leishmania is commonplace.
The traditional treatment is with pentavalent antimonial
Pentavalent antimonial
Pentavalent antimonials are a group of compounds used for the treatment of leishmaniasis. They are also called pentavalent antimony compounds.-Types:...
s such as sodium stibogluconate
Sodium stibogluconate
Sodium stibogluconate is a medicine used to treat leishmaniasis and is only available for administration by injection. It belongs to the class of medicines known as the pentavalent antimonials. Sodium stibogluconate is sold in the United Kingdom as Pentostam...
and meglumine antimoniate
Meglumine antimoniate
Meglumine antimoniate is a medicine used for treating leishmaniasis. It is manufactured by Aventis and sold as Glucantime in France, and Glucantim in Italy. It belongs to a group of compounds known as the pentavalent antimonials. It is administered by intramuscular injection....
. Resistance is now common in India, and rates of resistance have been shown to be as high as 60% in parts of Bihar, India.
The Indian medical practitioner, Upendra Nath Brahmachari
Upendranath Brahmachari
Sir Upendranath Brahmachari, KIH was a noted Indian scientist and a leading medical practitioner of his time...
, was nominated for the Nobel Prize in Physiology or Medicine
Nobel Prize in Physiology or Medicine
The Nobel Prize in Physiology or Medicine administered by the Nobel Foundation, is awarded once a year for outstanding discoveries in the field of life science and medicine. It is one of five Nobel Prizes established in 1895 by Swedish chemist Alfred Nobel, the inventor of dynamite, in his will...
in 1929 for his discovery of ureastibamine (an antimonial
Antimony
Antimony is a toxic chemical element with the symbol Sb and an atomic number of 51. A lustrous grey metalloid, it is found in nature mainly as the sulfide mineral stibnite...
compound
Chemical compound
A chemical compound is a pure chemical substance consisting of two or more different chemical elements that can be separated into simpler substances by chemical reactions. Chemical compounds have a unique and defined chemical structure; they consist of a fixed ratio of atoms that are held together...
for the treatment of kala-azar) and a new disease, post kala-azar dermal leishmaniasis. Brahmachari's cure for visceral leishmaniasis was the urea salt of para-amino-phenyl stibnic acid which he called Urea Stibamine.
The treatment of choice for visceral leishmaniasis acquired in India is now Amphotericin B
Amphotericin B
Amphotericin B is a polyene antifungal drug, often used intravenously for systemic fungal infections...
in its various liposomal preparations (AmBisome, Abelcet, Amphocil)
- AmBisome dose: total dose 21 mg/kg (Mediterranean/Brazilian VL); total dose 7.5 mg/kg over 6 days (Indian VL)
- Amphocil dose: total dose 7.5 mg/kg over 6 days (Indian VL)
A low dose (0.5–1 mg/kg) is given on the first day, increasing to 1–2 mg/kg on the second day, followed by 1.5–3 mg/kg on the third and subsequent days.
Miltefosine
Miltefosine
Miltefosine is a phospholipid drug.Originally developed as an antineoplastic , it is finding use as an antiprotozoal drug...
Impavido is the first oral treatment for this disease. The cure rate of miltefosine in Phase III clinical trials is 95%; Studies in Ethiopia show that is also effective in Africa. In HIV immunosuppressed people which are coinfected with leishmaniasis it has shown that even in resistant cases 2/3 of the people responded to this new treatment.
Miltefosine has received approval by the Indian regulatory authorities in 2002 and in Germany in 2004.It is now registered in many countries.
The drug is generally better tolerated than other drugs. Main side effects are gastrointetinal disturbance in the first or second day of treatment (a course of treatment is 28 days) which does not affect the efficiency. Because it is available as an oral formulation, the expense and inconvenience of hospitalization is avoided, and outpatient distribution of the drug becomes an option, making Miltefosine a drug of choice.
The nonprofit Institute for OneWorld Health
Institute for OneWorld Health
OneWorld Health is a 501 nonprofit drug development organization founded in 2000. Its mission is to discover, develop, and deliver safe, effective and affordable new treatments and interventions for people with neglected infectious diseases in the developing countries, with an emphasis on diseases...
has adopted the broad spectrum antibiotic paromomycin for use in treating VL; its antileishmanial properties were first identified in the 1980s. A treatment with paromomycin costs about $15 USD. The drug had originally been identified in the 1960s. The Indian government approved paromomycin for sale and use in August 2006.
In 2009, the Hebrew University of Jerusalem
Hebrew University of Jerusalem
The Hebrew University of Jerusalem ; ; abbreviated HUJI) is Israel's second-oldest university, after the Technion – Israel Institute of Technology. The Hebrew University has three campuses in Jerusalem and one in Rehovot. The world's largest Jewish studies library is located on its Edmond J...
Kuvin Center for the Study of Infectious and Tropical Diseases, in a collaborative effort with Addis Ababa University
Addis Ababa University
Addis Ababa University is a university in Ethiopia. It was originally named "University College of Addis Ababa" at its founding, then renamed for the former Ethiopian emperor Haile Selassie I in 1962, receiving its current name in 1975.Although the university has six of its seven campuses within...
, was awarded a grant by the Bill & Melinda Gates Foundation
Bill & Melinda Gates Foundation
The Bill & Melinda Gates Foundation is the largest transparently operated private foundation in the world, founded by Bill and Melinda Gates. It is "driven by the interests and passions of the Gates family"...
for research into visceral leishmaniasis in Ethiopia
Ethiopia
Ethiopia , officially known as the Federal Democratic Republic of Ethiopia, is a country located in the Horn of Africa. It is the second-most populous nation in Africa, with over 82 million inhabitants, and the tenth-largest by area, occupying 1,100,000 km2...
. The project will gather data to be analyzed to identify the weak links in the transmission cycle and devise methods for control of the disease.
Combination drug therapies are currently under investigation, particularly by the Drugs for Neglected Diseases initiative
Drugs for Neglected Diseases Initiative
The Drugs for Neglected Diseases Initiative 501 is a non-profit drug research and development organization that is developing new treatments for neglected diseases....
(DNDi). Combination therapies allow for the use of existing drugs in combination, each in lower doses, which helps to decrease the incidence of severe side effects and drug toxicity, as well as the risk for development of resistance against the drugs; they have been shown to be cost-effective strategies strategies.
The drug development pipeline is lacking significantly, and no novel drug targets are expected for approval in the next 5 years. In the meantime, new combination therapies, and well as improvements to existing drugs targets, are under development. Single-dosage administrations of liposomal amphotericin B have been shown to be effective, and oral formulations are currently under development to increase access and facilitate distribution of the efficacious drug in the field.
History and epidemiology
See also History of leishmaniasisKala-azar first came to the attention of Western doctors in 1824 in Jessore, India (now Bangladesh
Bangladesh
Bangladesh , officially the People's Republic of Bangladesh is a sovereign state located in South Asia. It is bordered by India on all sides except for a small border with Burma to the far southeast and by the Bay of Bengal to the south...
), where it was initially thought to be a form of malaria
Malaria
Malaria is a mosquito-borne infectious disease of humans and other animals caused by eukaryotic protists of the genus Plasmodium. The disease results from the multiplication of Plasmodium parasites within red blood cells, causing symptoms that typically include fever and headache, in severe cases...
. Assam
Assam
Assam , also, rarely, Assam Valley and formerly the Assam Province , is a northeastern state of India and is one of the most culturally and geographically distinct regions of the country...
gave kala-azar one of its common names, Assam fever. Another common name, kala-azar, is derived from kala which means black in Sanskrit
Sanskrit
Sanskrit , is a historical Indo-Aryan language and the primary liturgical language of Hinduism, Jainism and Buddhism.Buddhism: besides Pali, see Buddhist Hybrid Sanskrit Today, it is listed as one of the 22 scheduled languages of India and is an official language of the state of Uttarakhand...
, Assamese
Assamese language
Assamese is the easternmost Indo-Aryan language. It is used mainly in the state of Assam in North-East India. It is also the official language of Assam. It is also spoken in parts of Arunachal Pradesh and other northeast Indian states. Nagamese, an Assamese-based Creole language is widely used in...
, Hindi
Hindi
Standard Hindi, or more precisely Modern Standard Hindi, also known as Manak Hindi , High Hindi, Nagari Hindi, and Literary Hindi, is a standardized and sanskritized register of the Hindustani language derived from the Khariboli dialect of Delhi...
and Urdu
Urdu
Urdu is a register of the Hindustani language that is identified with Muslims in South Asia. It belongs to the Indo-European family. Urdu is the national language and lingua franca of Pakistan. It is also widely spoken in some regions of India, where it is one of the 22 scheduled languages and an...
and the Persian azar for disease, so called for the darkening of the skin on the extremities and abdomen that is a symptom of the Indian form of the disease. The agent of the disease was also first isolated in India by Scottish doctor William Leishman and Irish physician Charles Donovan
Charles Donovan
Colonel Charles Donovan MD was born in Calcutta. At the age of thirteen he was sent to Cork City to live with his grandfather to advance his secondary and university education. He studied at Queen's College, Cork and Trinity College, Dublin Colonel Charles Donovan MD (1863–1951) was born in...
, working independently of each other. As they published their discovery almost simultaneously, the species was named for both of them — Leishmania donovani.
Today, the name kala-azar is used interchangeably with the scientific name visceral leishmaniasis for the most acute form of the disease caused by L. donovani. The disease is endemic in West Bengal
West Bengal
West Bengal is a state in the eastern region of India and is the nation's fourth-most populous. It is also the seventh-most populous sub-national entity in the world, with over 91 million inhabitants. A major agricultural producer, West Bengal is the sixth-largest contributor to India's GDP...
, where it was first discovered, but is seen at its most deadly in north and east Africa. It can also be found throughout the Arab
Arab
Arab people, also known as Arabs , are a panethnicity primarily living in the Arab world, which is located in Western Asia and North Africa. They are identified as such on one or more of genealogical, linguistic, or cultural grounds, with tribal affiliations, and intra-tribal relationships playing...
world and southern Europe (where the causative organism is L. infantum), and a slightly different strain of the pathogen, L. chagasi, is responsible for leishmaniasis in the new world. Several species of canines
Canidae
Canidae is the biological family of carnivorous and omnivorous mammals that includes wolves, foxes, jackals, coyotes, and domestic dogs. A member of this family is called a canid . The Canidae family is divided into two tribes: Canini and Vulpini...
serve as reservoir hosts of L. infantum (chagasi).
But, while the disease's geographical range is broad, it is not continuous. The disease clusters around areas of drought, famine, and high population density. In Africa, this has meant a knot of infection centers mostly in Sudan
Sudan
Sudan , officially the Republic of the Sudan , is a country in North Africa, sometimes considered part of the Middle East politically. It is bordered by Egypt to the north, the Red Sea to the northeast, Eritrea and Ethiopia to the east, South Sudan to the south, the Central African Republic to the...
, Kenya
Kenya
Kenya , officially known as the Republic of Kenya, is a country in East Africa that lies on the equator, with the Indian Ocean to its south-east...
, and Somalia
Somalia
Somalia , officially the Somali Republic and formerly known as the Somali Democratic Republic under Socialist rule, is a country located in the Horn of Africa. Since the outbreak of the Somali Civil War in 1991 there has been no central government control over most of the country's territory...
. Living conditions here have changed very little in the past century, and the people are not normally very mobile. Parts of the Sudan, in particular the Upper Nile region, are almost totally cut off from the rest of the country, and the people are as tied to the place of their birth as any peasant of Europe’s Dark Ages.
Contemporary life has made itself felt even here, however—not as "progress" but in the form of the many small wars of Africa's post-colonial era. In the Sudan
Sudan
Sudan , officially the Republic of the Sudan , is a country in North Africa, sometimes considered part of the Middle East politically. It is bordered by Egypt to the north, the Red Sea to the northeast, Eritrea and Ethiopia to the east, South Sudan to the south, the Central African Republic to the...
, where civil war has been continuous since 1983, the violence has been concentrated in the more populated south, and kala-azar was concentrated there too. But the wars have driven a steady stream of refugees out of the region, and these traveled either across the southern border or into the remoter western part of the country called the Upper Nile, where both war and the disease that went with it had not yet penetrated.
These refugees, moving at foot-speed, carried the disease with them, and when it arrived it hit the Upper Nile with a force comparable to smallpox
Smallpox
Smallpox was an infectious disease unique to humans, caused by either of two virus variants, Variola major and Variola minor. The disease is also known by the Latin names Variola or Variola vera, which is a derivative of the Latin varius, meaning "spotted", or varus, meaning "pimple"...
hitting the American Indians
Indigenous peoples of the Americas
The indigenous peoples of the Americas are the pre-Columbian inhabitants of North and South America, their descendants and other ethnic groups who are identified with those peoples. Indigenous peoples are known in Canada as Aboriginal peoples, and in the United States as Native Americans...
. The isolated people of the Upper Nile had no access to medicine or education about the new disease among them. Worse, their immune system
Immune system
An immune system is a system of biological structures and processes within an organism that protects against disease by identifying and killing pathogens and tumor cells. It detects a wide variety of agents, from viruses to parasitic worms, and needs to distinguish them from the organism's own...
s were defenseless against this new pathogen, foreign to them though it came only from another part of their own country. One village at the center of the epidemic, Duar
Duar
Duar is a large village in Koch County, Unity State, South Sudan. It is on the main oil road leading south from Bentiu, and is close to the Thar Jath Central Processing Facility in the Block 5A oil concession.The village is in a Jagei Nuer region....
, was left with four survivors out of a population of a thousand, and from the late eighties to the mid-nineties a total of 100,000 succumbed to the sickness in that region alone. In the words of Jill Seaman
Jill Seaman
Jill Seaman is an American doctor with Médecins Sans Frontières . She is a native of Moscow, Idaho and a graduate of Middlebury College and the University of Washington School of Medicine....
, the doctor who led relief efforts in the Upper Nile for the French organization Médecins Sans Frontières
Médecins Sans Frontières
' , or Doctors Without Borders, is a secular humanitarian-aid non-governmental organization best known for its projects in war-torn regions and developing countries facing endemic diseases. Its headquarters are in Geneva, Switzerland...
, “Where else in the world could 50% of a population die without anyone knowing?”
North Bihar
Bihar
Bihar is a state in eastern India. It is the 12th largest state in terms of geographical size at and 3rd largest by population. Almost 58% of Biharis are below the age of 25, which is the highest proportion in India....
, India (including Araria
Araria
Araria is a town and a municipality that is headquarters of Araria district in the state of Bihar, India.-Geography:Araria is located at . It has an average elevation of 47 metres . Araria is situated at the northern part of Purnia and Madhepura in Bihar...
, Purnea and Kishanganj
Kishanganj
Kishanganj is headquarters of Kishanganj district in the Indian state of Bihar.-Geography:Kishanganj is a town and district headquarter of Kishangnj district in Purnea division of Bihar state, but gographically and culturally it is part of the north Bengal.It is part of the chicken neck of Indian...
) is the endemic zone of this disease.
See also
- LeishmaniasisLeishmaniasisLeishmaniasis is a disease caused by protozoan parasites that belong to the genus Leishmania and is transmitted by the bite of certain species of sand fly...
- LeishmaniaLeishmaniaLeishmania is a genus of Trypanosomatid protozoa, and is the parasite responsible for the disease leishmaniasis. It is spread through sandflies of the genus Phlebotomus in the Old World, and of the genus Lutzomyia in the New World. Their primary hosts are vertebrates; Leishmania commonly infects...
- Cutaneous leishmaniasisCutaneous leishmaniasisCutaneous leishmaniasis is the most common form of leishmaniasis. It is a skin infection caused by a single-celled parasite that is transmitted by sandfly bites...
- MalariaMalariaMalaria is a mosquito-borne infectious disease of humans and other animals caused by eukaryotic protists of the genus Plasmodium. The disease results from the multiplication of Plasmodium parasites within red blood cells, causing symptoms that typically include fever and headache, in severe cases...
- List of cutaneous conditions