{{Short description|Human disease caused by protist parasites}} {{About|visceral leishmaniasis in humans|the disease in canids|canine leishmaniasis}} {{cs1 config|name-list-style=vanc}} {{Infobox medical condition | name = Visceral leishmaniasis <br /> ''kālā āzār'' | synonyms = '''Black fever''', and '''Dumdum fever'''<ref name="Andrews">{{cite book |author1=James, William D. |author2=Berger, Timothy G. |title=Andrews' Diseases of the Skin: clinical Dermatology |url=https://archive.org/details/andrewsdiseasess00mdwi_659 |url-access=limited |publisher=Saunders Elsevier |year=2006 |isbn=978-0-7216-2921-6 |display-authors=etal|page=[https://archive.org/details/andrewsdiseasess00mdwi_659/page/n436 426]}}</ref> | image = Amastigotes in a chorionic villus.jpg | width = 250px | caption = Amastigotes in a chorionic villus | pronounce = Kala-azar: ({{IPAc-en|UK|ˌ|k|ɑː|l|ə|_|ə|ˈ|z|ɑːr}}) | field = | symptoms = Rapid weight loss, fever, hepatoslepomegaly, diarrhea, anemia, non-stop vomiting, tachycardia, blackening of the skin | complications = Multiple Organ Dysfunction Syndrome (MODS) | onset = | duration = | types = | causes = | risks = | diagnosis = | differential = | prevention = | treatment = | medication = | prognosis = | frequency = | deaths = }}
'''Visceral leishmaniasis''' ('''VL'''), also known as '''kala-azar''' ({{langx|hi|काला आज़ार}}, "black sickness")<ref>{{cite web|title = WHO {{!}} Visceral leishmaniasis|url =https://www.who.int/leishmaniasis/visceral_leishmaniasis/en/|archive-url =https://web.archive.org/web/20130715110608/http://www.who.int/leishmaniasis/visceral_leishmaniasis/en/|archive-date =July 15, 2013|website = www.who.int|access-date = 2015-10-05}}</ref> or "'''black fever'''", is the most severe form of [[leishmaniasis]] and, without proper diagnosis and treatment, is associated with high fatality.<ref name=":0">{{cite journal |last1=Das |first1=Aritra |last2=Karthick |first2=Morchan |last3=Dwivedi |first3=Shweta |last4=Banerjee |first4=Indranath |last5=Mahapatra |first5=Tanmay |last6=Srikantiah |first6=Sridhar |last7=Chaudhuri |first7=Indrajit |date=2016-11-01 |title=Epidemiologic Correlates of Mortality among Symptomatic Visceral Leishmaniasis Cases: Findings from Situation Assessment in High Endemic Foci in India |journal=PLOS Neglected Tropical Diseases |volume=10 |issue=11 |article-number=e0005150 |doi=10.1371/journal.pntd.0005150 |issn=1935-2735 |pmc=5117587 |pmid=27870870 |doi-access=free }}</ref> Leishmaniasis is a [[disease]] caused by [[protozoan]] [[parasite]]s of the genus ''[[Leishmania]]''.
The parasite migrates to the internal organs such as the [[liver]], [[spleen]] (hence "[[Viscus|visceral]]"), and [[bone marrow]], and, if left untreated, will almost always result in the death of the host. Signs and symptoms include [[fever]], [[Cachexia|weight loss]], [[fatigue (medical)|fatigue]], [[anemia]], and substantial [[Hepatosplenomegaly|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.<ref>{{cite web |url=https://www.who.int/leishmaniasis/burden/hiv_coinfection/burden_hiv_coinfection/en/index.html |archive-url=https://web.archive.org/web/20070219135414/http://www.who.int/leishmaniasis/burden/hiv_coinfection/burden_hiv_coinfection/en/index.html |archive-date=February 19, 2007 |title= Leishmaniasis and HIV co-infection |work=WHO }}</ref>
VL is the second-largest parasitic killer in the world (after [[malaria]]), responsible for an estimated 20,000 to 30,000 deaths each year worldwide.<ref>{{cite web |title=Leishmaniasis|url=https://www.who.int/mediacentre/factsheets/fs375/en/ |website=WHO Fact sheet N°375 |publisher=World Health Organization |access-date=23 September 2014}}</ref><ref name="Desjeux2001">{{cite journal |author = Desjeux P. |year = 2001 |title = The increase of risk factors for leishmaniasis worldwide |journal = Transactions of the Royal Society of Tropical Medicine and Hygiene |volume = 95 |issue = 3 |pages = 239–43 |doi = 10.1016/S0035-9203(01)90223-8 |pmid = 11490989 |doi-access = free }}</ref>
[[Upendranath Brahmachari]] synthesised urea stibamine (carbostibamide) in 1922 and determined that it was an effective substitute for the other antimony-containing compounds in the treatment of VL caused by ''Leishmania donovani''.<ref>{{cite web |last=Hazra |first=Krishnakoli |date=July 7, 2023 |title=Upendranath Brahmachari—forgotten Bengali scientist behind kala-azar cure got 2 Nobel nods |url=https://theprint.in/theprint-profile/upendranath-brahmachari-forgotten-bengali-scientist-behind-kala-azar-cure-got-2-nobel-nods/1658329/ |access-date=July 8, 2023 |website=theprint.in}}</ref>
==Signs and symptoms== When people develop visceral leishmaniasis, the most typical symptoms are [[fever]] and the [[splenomegaly|enlargement of the spleen]], with [[hepatomegaly|enlargement of the liver]] sometimes being seen as well.<ref>{{Cite journal |last1=Poulaki |first1=Aikaterini |last2=Piperaki |first2=Evangelia-Theophano |last3=Voulgarelis |first3=Michael |date=2021-04-05 |title=Effects of Visceralising Leishmania on the Spleen, Liver, and Bone Marrow: A Pathophysiological Perspective |url= |journal=Microorganisms |volume=9 |issue=4 |page=759 |doi=10.3390/microorganisms9040759 |doi-access=free |issn=2076-2607 |pmc=8066032 |pmid=33916346}}</ref> The blackening of the skin that gave the disease its common name in India does not appear in most strains of the disease. The other symptoms are easily mistaken for those of [[malaria]]. Misdiagnosis is dangerous, as without proper treatment, the mortality rate for kala-azar is close to 100%.<ref>{{Cite journal |last1=Alemu |first1=Chekol |last2=Wudu |first2=Habitamu |last3=Dessie |first3=Getu |last4=Gashu |first4=Chalachew |date=2023-10-29 |title=Time to death and its determinant factors of visceral leishmaniasis with HIV co-infected patients during treatment period admitted at Metema hospital, Metema, Ethiopia: a hospital-based cross-sectional study design |url= |journal=Tropical Diseases, Travel Medicine and Vaccines |volume=9 |issue=1 |page=18 |doi=10.1186/s40794-023-00203-y |doi-access=free |issn=2055-0936 |pmc=10613359 |pmid=37898767}}</ref> ''L. donovani'' itself is not usually the direct cause of death in people with kala-azar, however. [[Pneumonia]], [[tuberculosis]], and [[dysentery]] are omnipresent in the immuno-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.<ref>{{Cite journal |last1=Mann |first1=Sarah |last2=Frasca |first2=Katherine |last3=Scherrer |first3=Sara |last4=Henao-Martínez |first4=Andrés F. |last5=Newman |first5=Sabrina |last6=Ramanan |first6=Poornima |last7=Suarez |first7=José A. |date=2021 |title=A Review of Leishmaniasis: Current Knowledge and Future Directions |url= |journal=Current Tropical Medicine Reports |volume=8 |issue=2 |pages=121–132 |doi=10.1007/s40475-021-00232-7 |issn=2196-3045 |pmc=7966913 |pmid=33747716}}</ref> 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.<ref>{{Cite journal |last1=Idris |first1=Muhammad |last2=Farid |first2=Jamila |last3=Gul |first3=Nasreen |last4=Anis-ur-Rehman |first4=null |date=2010 |title=Visceral leishmaniasis: adult population of Abbottabad at risk now |url= |journal=Journal of Ayub Medical College, Abbottabad |volume=22 |issue=2 |pages=214–215 |issn=1025-9589 |pmid=21702307}}</ref>
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, measles-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 cause 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.)<ref>{{cite journal|last1=Burza|first1=Sakib|last2=Croft|first2=Simon L.|last3=Boelaert|first3=Marleen|date=2018-09-15|title=Leishmaniasis|url=https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(18)31204-2/abstract|journal=The Lancet|language=en|volume=392|issue=10151|pages=951–970|doi=10.1016/S0140-6736(18)31204-2|issn=0140-6736|pmid=30126638|s2cid=208790410|url-access=subscription|hdl=10144/619264|hdl-access=free}}</ref>
==Cause== Two species of ''Leishmania'' are known to give rise to the visceral form of the disease. The species commonly found in East Africa and the Indian subcontinent is ''[[Leishmania donovani|L. donovani]]'' and the species found in Europe, North Africa, and Latin America is ''[[Leishmania infantum|L. infantum]]'', also known as ''L. chagasi''.<ref>{{cite journal |vauthors=Chappuis F, et al | title = Visceral leishmaniasis: what are the needs for diagnosis, treatment and control? | url =https://www.who.int/leishmaniasis/resources/documents/VL_NMR_1107_ok.pdf | journal = Nature Reviews Microbiology | volume = 5 | issue = 11| pages = 873–82 | doi=10.1038/nrmicro1748| pmid = 17938629 | year = 2007 | s2cid = 6963295 | doi-access = free }}</ref>
The insect [[Vector (epidemiology)|vectors]] are species of [[Phlebotominae|sandfly]] of the [[genus]] ''[[Phlebotomus]]'' in the Old World, and of ''[[Lutzomyia]]'' in the New World. Sandflies are tiny flies, measuring 3–6 mm long by 1.5–3 mm in diameter, and are found in tropical or temperate regions throughout the world. The sandfly species ''[[Lutzomyia longipalpis]]'' is the primary vector of this disease.<ref>Alexander, Bruce; Lopes de Carvalho, Renata; McCallum, Hamish; Pereira, Marcos Horácio (December 2002). "Role of the Domestic Chicken (Gallus gallus)in the Epidemiology of Urban Visceral Leishmaniasis in Brazil". ''Emerging Infectious Diseases''. '''8''' (12): 1480–1485. [[Digital object identifier|doi]]:10.3201/eid0812.010485. [[PubMed Central|PMC]] 2738513. [[PubMed Identifier|PMID]] 12498667.</ref> The larvae grow in warm, moist organic matter around human habitations (such as old trees, house walls, or waste), making them hard to eradicate.<ref>{{Cite journal |last=Claborn |first=David M. |date=2010 |title=The biology and control of leishmaniasis vectors |url= |journal=Journal of Global Infectious Diseases |volume=2 |issue=2 |pages=127–134 |doi=10.4103/0974-777X.62866 |doi-access=free |issn=0974-8245 |pmc=2889652 |pmid=20606968}}</ref><ref>{{Cite journal |last=Feliciangeli |first=M. D. |date=2004 |title=Natural breeding places of phlebotomine sandflies |url= |journal=Medical and Veterinary Entomology |volume=18 |issue=1 |pages=71–80 |doi=10.1111/j.0269-283x.2004.0487.x |issn=0269-283X |pmid=15009450}}</ref><ref>{{Cite journal |last1=Alencar |first1=Ronildo Baiatone |last2=de Queiroz |first2=Raul Guerra |last3=Barrett |first3=Toby Vincent |date=2011-06-01 |title=Breeding sites of phlebotomine sand flies (Diptera: Psychodidae) and efficiency of extraction techniques for immature stages in terra-firme forest in Amazonas State, Brazil |journal=Acta Tropica |volume=118 |issue=3 |pages=204–208 |doi=10.1016/j.actatropica.2010.10.012 |pmid=21457701 |issn=0001-706X|doi-access=free }}</ref>
Visceral Leishmaniasis/kala-azar samples from India revealed the presence of not only the primary causative protozoan parasite, i.e., ''Leishmania donovani'' (LD), but also co-infection with another protozoan member called ''[[Leptomonas|Leptomonas seymouri]]'' (LS). The latter parasite (LS) further contained an RNA virus known as ''Leptomonas seymouri'' narna-like virus'' ''1 ([[Lepsey NLV1]]). So, it appears that a great majority of kala-azar patients in the Indian subcontinent are exposed to an RNA virus in LS, the co-infecting parasite with LD, i.e., the "LD-LS-Lepsey NLV1 triple pathogen" phenomenon.<ref>{{cite journal |last=Sukla|first=Soumi|author2=Roy, Syamal |author3=Sundar, Shyam|author4=Biswas, Subhajit | title=''Leptomonas seymouri'' narna-like virus 1 and not leishmaniaviruses detected in kala-azar samples from India | journal=Archives of Virology| volume=162 | issue=12 | pages=3827–35 | doi=10.1007/s00705-017-3559-y | year=2017 | pmid=28939968 |s2cid=31450182}}</ref><ref>{{cite journal |last=Sukla|first=Soumi|author2=Nath, Himadri |author3=Kamran, Mohd.|author4=Ejazi, Sarfaraz Ahmad |author5=Ali, Nahid |author6=Das, Pradeep |author7=Ravichandiran, V |author8=Roy, Syamal |author9=Biswas, Subhajit | title=Detection of Leptomonas seymouri narna-like virus in serum samples of visceral leishmaniasis patients and its possible role in disease pathogenesis | journal=Scientific Reports| volume=12 | issue=1 | page=14436 | doi=10.1038/s41598-022-18526-9 | year=2022 | pmid=36002553|pmc=9402534 |bibcode=2022NatSR..1214436S }}</ref>
===Life cycle=== The life cycle of ''Leishmania'' is completed in two hosts, humans and sandflies. The adult female sandfly is a bloodsucker, usually feeding at night on sleeping prey. When the fly bites an individual infected with ''Leishmania'', the pathogen is ingested along with the prey's blood. The [[protozoan]] is in the smaller of its two forms, called an [[amastigote]], which is round, non-motile, and only 3–7 micrometers in diameter. Inside the stomach of the sandfly, the amastigotes quickly transform into elongated and motile forms called the [[promastigote]]s. Promastigote is spindle-shaped, triple the size of the amastigote, and has a single [[flagellum]] that allows mobility. The promastigotes live extracellularly in the alimentary canal, reproducing asexually, then migrate to the proximal end of the gut where they become poised for regurgitative transmission. As the fly bites, the promastigotes are released from the proboscis and introduced locally at the bite site.<ref>{{cite journal|last=Sacks|first=DL|title=''Leishmania''-sand fly interactions controlling species-specific vector competence.|journal=Cellular Microbiology|year=2001|volume=3|issue=4|pages=189–96|pmid=11298643|doi=10.1046/j.1462-5822.2001.00115.x|s2cid=39033146|url=https://zenodo.org/record/1236490|doi-access=free}}</ref><ref>{{cite journal|last=Ilg|first=T|author2=Stierhof, YD |author3=Wiese, M |author4=McConville, MJ |author5= Overath, P |title=Characterization of phosphoglycan-containing secretory products of ''Leishmania''.|journal=Parasitology|year=1994|volume=108|issue=Suppl|pages=S63-71|pmid=8084657|doi=10.1017/s0031182000075739|s2cid=22659332}}</ref>
Once inside the human host, promastigotes invade [[macrophages]]. Inside the cells, they transform back into the smaller amastigote form. The amastigotes replicate in the most hostile part of the macrophage cell, inside the [[phagolysosome]], whose normal defensive response they can prevent. After repeated multiplication, they [[lysis|break down]] their host cell by sheer pressure of mass, but there is some recent speculation that they can leave the cell by triggering the [[exocytosis]] response of the macrophage.<ref>{{cite book|last=Lodge|first=R|author2=Descoteaux, A |title=Molecular Mechanisms of Parasite Invasion|chapter=Leishmania Invasion and Phagosome Biogenesis|year=2008|volume=47|pages=174–81|pmid=18512351|doi=10.1007/978-0-387-78267-6_14|series=Subcellular Biochemistry|isbn=978-0-387-78266-9}}</ref> The daughter cells protozoans then migrate to fresh cells or through the bloodstream to find new hosts. In this way, the infection is progressive, spreading to the host's [[mononuclear phagocyte system]], particularly the spleen and liver. The free amastigotes in peripheral tissues are then ingested by sandfly to enter another cycle.<ref name=chappuis>{{cite journal|last=Chappuis|first=François|author2=Sundar, Shyam |author3=Hailu, Asrat |author4=Ghalib, Hashim |author5=Rijal, Suman |author6=Peeling, Rosanna W. |author7=Alvar, Jorge |author8= Boelaert, Marleen |title=Visceral leishmaniasis: what are the needs for diagnosis, treatment and control?|journal=Nature Reviews Microbiology|year=2007|volume=5|issue=11|pages=S7–S16|doi=10.1038/nrmicro1748|pmid=17938629|s2cid=6963295|doi-access=free}}</ref><ref>{{cite journal|last=Pulvertaft|first=RJ|author2=Hoyle, GF |title=Stages in the life-cycle of ''Leishmania donovani''|journal=Transactions of the Royal Society of Tropical Medicine and Hygiene|year=1960|volume=54|issue=2|pages=191–6|doi=10.1016/0035-9203(60)90057-2|pmid=14435316}}</ref><ref name=chat>{{cite book|last=Chatterjee|first=K.D.|title=Parasitology (protozoology and helminthology) in relation to clinical medicine|year=2009|publisher=CBC Publishers|location=New Delhi|isbn=978-81-239-1810-5|pages=67–72|edition=13th}}</ref><ref>{{cite journal|last=Pulvertaft|first=R.J.V.|author2=Hoyle, G.F. |title=Stages in the life-cycle of ''Leishmania donovani''|journal=Transactions of the Royal Society of Tropical Medicine and Hygiene|year=1960|volume=54|issue=2|pages=191–196|doi=10.1016/0035-9203(60)90057-2|pmid=14435316}}</ref>
==Regulatory T and B cells== The cell-mediated immunity (CMI) that kills ''Leishmania'' also produces inflammation. If the inflammation is excessive, it can cause tissue damage. The role of regulatory T and [[regulatory B cells]] is to suppress CMI enough to prevent tissue damage.<ref name = "belkaid">{{cite journal | vauthors=Belkaid Y | title=Regulatory T Cells and Infection: a Dangerous Necessity | url=http://cnc.cj.uc.pt/BEB/private/pdfs/2007-2008/Immunology/B/Rev_paper_B3.pdf | journal=Nature Reviews Immunology | year=2007 | volume=7 | issue=11 | pages=875–88 | pmid=17948021 | doi=10.1038/nri2189 | s2cid=28127648 | access-date=2018-10-17 | archive-date=2018-10-18 | archive-url=https://web.archive.org/web/20181018043342/http://cnc.cj.uc.pt/BEB/private/pdfs/2007-2008/Immunology/B/Rev_paper_B3.pdf }}</ref><ref name = "rosser">{{cite journal |vauthors= Rosser E, Mauri C |title=Regulatory B Cells: Origin, Phenotype, and Function |journal= Immunity |year=2015 | volume=42 | issue=4 | pages=607–12 | pmid =25902480 | doi= 10.1016/j.immuni.2015.04.005 | doi-access=free }}</ref> However, an excessive regulatory response can prevent clearance of ''Leishmania'' and could explain the anergy of VL, poor response to drug treatment, development of PKDL, and relapses. A role for regulatory cells in VL has long been suspected.<ref>{{cite journal | vauthors = Carvalho E, Bacellar O, Barral A, et al |title= Antigen-specific Immunosuppression in Visceral Leishmaniasis Is Cell Mediated | journal=J. Clin. Invest. |year=1989 | volume=83 | issue=3 | pages=860–4 | pmid =2522103 | doi=10.1172/JCI113969| pmc=303759}}</ref> A variety of regulatory T and B cells have been implicated in VL, including Type 1 T helper cells that secrete IL-10 in addition to IFN-γ, natural T reg, Tr1, CD8+ T reg, and B reg. All of these lymphocytes act, at least in part, by secreting IL-10 and other suppressive cytokines.<ref>{{Cite journal |last1=Rodrigues |first1=Vasco |last2=Cordeiro-da-Silva |first2=Anabela |last3=Laforge |first3=Mireille |last4=Silvestre |first4=Ricardo |last5=Estaquier |first5=Jérôme |date=2016-03-01 |title=Regulation of immunity during visceral Leishmania infection |journal=Parasites & Vectors |volume=9 |article-number=118 |doi=10.1186/s13071-016-1412-x |doi-access=free |issn=1756-3305 |pmc=4774109 |pmid=26932389}}</ref><ref>{{Cite journal |last1=Faleiro |first1=Rebecca J. |last2=Kumar |first2=Rajiv |last3=Hafner |first3=Louise M. |last4=Engwerda |first4=Christian R. |date=2014 |title=Immune regulation during chronic visceral leishmaniasis |url= |journal=PLOS Neglected Tropical Diseases |volume=8 |issue=7 |article-number=e2914 |doi=10.1371/journal.pntd.0002914 |doi-access=free |issn=1935-2735 |pmc=4091888 |pmid=25010815}}</ref>
CD4+ T regs are present at increased frequency in the bone marrow of VL patients, are one source of IL-10, and proliferate in response to ''Leishmania'' antigen.<ref name = "rai"/> Levels of [[FoxP3]] mRNA were also up-regulated in lesional tissue from PKDL patients.<ref name = "ganguly"/> However, T regs are not elevated in spleen cells from VL patients nor does depletion of T regs increase ''Leishmania'' antigen specific IFN-γ secretion<ref>{{cite journal | vauthors = Nylen S, Maurya R, Eidsmo L, et al |title=Splenic Accumulation of IL-10 mRNA T Cells Distinct from CD4+ CD25+ (FoxP3+) Regulatory T Cells in Human Visceral Leishmaniasis |journal=J Exp Med |year=2007 | volume=204 | issue=4 | pages=805–17 | pmid =17389235 | doi=10.1084/jem.20061141 | pmc=2118563}}</ref> The highest levels of IL-10 mRNA in spleen cells is in CD8+ and other non-FoxP3+ T cells.<ref name="gautam"/> White blood cell CD8+ T cells from VL patients have elevated IL-10 levels.<ref name = "peruhype06">{{cite journal | vauthors = Peruhype-Magalhaes V, Martins-Filho O, Prata A, et al | title = Mixed Inflammatory/Regulatory Cytokine Profile Marked by Simultaneous Raise of Interferon-g and Interleukin-10 and Low Frequency of Tumor Necrosis Factor-a Monocytes Are Hallmarks of Active Human Visceral Leishmaniasis Due to ''Leishmania chagasi'' Infection | journal = Clin. Exp. Immunol. | year = 2006 | volume = 146 | issue = 1 | pages = 124–32 | pmid = 16968407| doi = 10.1111/j.1365-2249.2006.03171.x | pmc = 1809731}}</ref> There is a 9.6 fold increase in IL-10 expressing CD8+ T cells among PBMC lymphocytes from PKDL patients.<ref name = "ganguly"/> In the one study of T cell clones from VL patients, the clones isolated from VL PBMC were 100% CD8+.<ref name = "holaday93b"/> When mixed with self PBMC one or three years after successful treatment the CD8+ T cells decreased ''Leishmania'' antigen specific proliferation and IFN-γ secretion and increased IL-10 secretion. Depletion of CD8+ T cells from VL PBMC stopped endogenous IL-10 secretion but increased ''Leishmania'' antigen-specific IL-10 secretion, suggesting that CD8+ regulatory T cells are responsible for endogenous IL-10 secretion.<ref name = "holaday00"/> CD4+ clones could only be isolated from VL PBMC after CD8+ T cell depletion. The CD4+ clones had little effect on IL-10 secretion but decreased IFN-γ secretion when mixed with self PBMC collected after successful treatment.<ref>{{Cite journal |last1=Kumar |first1=Rajiv |last2=Singh |first2=Neetu |last3=Gautam |first3=Shalini |last4=Singh |first4=Om Prakash |last5=Gidwani |first5=Kamlesh |last6=Rai |first6=Madhukar |last7=Sacks |first7=David |last8=Sundar |first8=Shyam |last9=Nylén |first9=Susanne |date=2014 |title=Leishmania specific CD4 T cells release IFNγ that limits parasite replication in patients with visceral leishmaniasis |url= |journal=PLOS Neglected Tropical Diseases |volume=8 |issue=10 |article-number=e3198 |doi=10.1371/journal.pntd.0003198 |doi-access=free |issn=1935-2735 |pmc=4183461 |pmid=25275531}}</ref>
Regulatory B cells are known to favor development of regulatory T cells and suppress development of Type 1 T helper cells by producing IL-10 and other down-regulatory cytokines.<ref name = "rosser"/> IL-10 levels are elevated in B cells from VL PBMC.<ref name = "peruhype06"/> A study of dogs with naturally acquired VL showed that the percentage of regulatory B cells increased three-fold during VL.<ref>{{cite journal | vauthors= Schaut R, Lamb I, Toepp A, et al |title= Regulatory IgDhi B Cells Suppress T Cell Function Via IL-10 and PD-L1 during Progressive Visceral Leishmaniasis |journal=J Immunol |year=2016 | volume=196 | issue=10 | pages=4100–9 | pmid =27076677 | doi=10.4049/jimmunol.1502678 | pmc=4868652}}</ref> Depletion of B cells increased CD4+ T cell proliferation and IFN-γ secretion but decreased IL-10 secretion. Blocking IL-10 or [[programmed cell death protein 1|programmed cell death]] receptors on B cells increased ''Leishmania'' antigen-specific T cell proliferation and IFN-γ secretion. Co-culture of T cells with B cells decreased the percentage of CD4+ T cell proliferation and IFN-γ secretion four-fold.<ref>{{Cite journal |last1=Schaut |first1=Robert G. |last2=Lamb |first2=Ian M. |last3=Toepp |first3=Angela J. |last4=Scott |first4=Benjamin |last5=Mendes-Aguiar |first5=Carolina O. |last6=Coutinho |first6=Jose F. V. |last7=Jeronimo |first7=Selma M. B. |last8=Wilson |first8=Mary E. |last9=Harty |first9=John T. |last10=Waldschmidt |first10=Thomas J. |last11=Petersen |first11=Christine A. |date=2016-05-15 |title=Regulatory IgDhi B Cells Suppress T Cell Function via IL-10 and PD-L1 during Progressive Visceral Leishmaniasis |url= |journal=Journal of Immunology |volume=196 |issue=10 |pages=4100–4109 |doi=10.4049/jimmunol.1502678 |issn=1550-6606 |pmc=4868652 |pmid=27076677}}</ref>
==Diagnosis== The gold standard for diagnosis is visualization of the [[amastigotes]] in [[splenic aspirate]] or [[Bone marrow aspiration|bone marrow aspirate]].<ref>{{cite web |date=2022-03-16 |title=Leishmaniasis - Diagnosis |url=https://www.cdc.gov/parasites/leishmaniasis/diagnosis.html |access-date=2022-04-20 |website=www.cdc.gov |language=en-us}}</ref> However, the technique is associated with discomfort, high risk of tissue damage, while being expensive and difficult.<ref>{{Cite journal |last1=Thakur |first1=Shivani |last2=Joshi |first2=Jyoti |last3=Kaur |first3=Sukhbir |date=2020 |title=Leishmaniasis diagnosis: an update on the use of parasitological, immunological and molecular methods |url= |journal=Journal of Parasitic Diseases|volume=44 |issue=2 |pages=253–272 |doi=10.1007/s12639-020-01212-w |issn=0971-7196 |pmc=7223249 |pmid=32419743}}</ref> The detection is also unreliable as it gives high false negative results, while the true positives are often having very low infection.<ref>{{Cite journal |last1=El-Amin |first1=Lana M. |last2=Khalid |first2=K. E. |last3=El-Badry |first3=Ayman A. |date=2020 |title=Risk-free point-of-care visceral leishmaniasis diagnostics: combining buffy coat microscopy and immunoassay in tertiary rural hospitals in Sudan |url= |journal=Acta Tropica |volume=211 |article-number=105599 |doi=10.1016/j.actatropica.2020.105599 |issn=1873-6254 |pmid=32592684}}</ref>
[[Serology|Serological]] testing is much more frequently used in areas where leishmaniasis is endemic. A 2014 [[Cochrane review]] evaluated different rapid diagnostic tests. One of them (the rK39 [[immunochromatographic]] test) gave correct, positive results in 92% of the people with visceral leishmaniasis, and it gave correct, negative results in 92% of the people who did not have the disease. A second rapid test (called [[latex agglutination test]]) gave correct, positive results in 64% of the people with the disease, and it gave correct, negative results in 93% of the people without the disease. Other types of tests have not been studied thoroughly enough to ascertain their efficacy.<ref>{{cite journal |vauthors=Boelaert M, Verdonck K, Menten J, etal |title=Rapid tests for the diagnosis of visceral leishmaniasis in patients with suspected disease |journal=Cochrane Database Syst Rev |volume=2014 |issue= 6|article-number=CD009135 |date=June 2014 |pmid=24947503 |doi=10.1002/14651858.CD009135.pub2|pmc=4468926}}</ref>
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 [[Direct agglutination test|DAT]] anti-leishmania antigen test, standard within [[Médecins Sans Frontières|MSF]], is much more cumbersome to use and appears not to have any advantages over the K39 test.<ref>{{cite journal |vauthors=Chappuis F, Rijal S, Soto A, Menten J, Boelaert M | title=A meta-analysis of the diagnostic performance of the direct agglutination test and rK39 dipstick for visceral leishmaniasis | journal=Br Med J | volume=333 | issue=7571 | pages=723–6 | doi=10.1136/bmj.38917.503056.7C | year=2006 | pmid=16882683 | pmc=1592383 }}</ref>
There are many 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.<ref>{{cite journal |vauthors=Sundar S, Singh RK, Maurya R, etal |title=Serological diagnosis of Indian visceral leishmaniasis: direct agglutination test versus rK39 strip test |journal=Trans. R. Soc. Trop. Med. Hyg. |volume=100 |issue=6 |pages=533–7 |date=June 2006 |pmid=16325874 |doi=10.1016/j.trstmh.2005.08.018 }}</ref><ref>{{cite journal |vauthors=Sundar S, Maurya R, Singh RK, etal |title=Rapid, noninvasive diagnosis of visceral leishmaniasis in India: comparison of two immunochromatographic strip tests for detection of anti-K39 antibody |journal=J. Clin. Microbiol. |volume=44 |issue=1 |pages=251–3 |date=January 2006 |pmid=16390983 |pmc=1351954 |doi=10.1128/JCM.44.1.251-253.2006 }}</ref> 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.<ref name="Lockwood">{{cite journal |vauthors=Lockwood DN, Sundar S |title=Serological tests for visceral leishmaniasis |journal=BMJ |volume=333 |issue=7571 |pages=711–2 |date=October 2006 |pmid=17023436 |pmc=1592372 |doi=10.1136/bmj.38989.567083.BE }}</ref> Likewise, patients with abnormal immune systems (e.g., HIV infection) will have false-negative tests.<ref>{{cite journal |vauthors=Pasquau F, Ena J, Sanchez R, etal |title=Leishmaniasis as an opportunistic infection in HIV-infected patients: determinants of relapse and mortality in a collaborative study of 228 episodes in a Mediterranean region |journal=Eur. J. Clin. Microbiol. Infect. Dis. |volume=24 |issue=6 |pages=411–8 |date=June 2005 |pmid=15928908 |doi=10.1007/s10096-005-1342-6|s2cid=26991291 }}</ref>
Other tests being developed include detects [[erythrosalicylic acid]].<ref name="Lockwood"/>
==Prevention== As of 2018, there are no vaccines or preventive drugs for visceral leishmaniasis. However, vaccines are in development.<ref name=":1">{{cite web |date=January 10, 2013 |title=Parasites-Leishmaniasis Prevention and Control |url=https://www.cdc.gov/parasites/leishmaniasis/prevent.html |access-date=April 29, 2014}}</ref><ref>{{cite journal|last1=Gillespie|first1=Portia M.|last2=Beaumier|first2=Coreen M.|last3=Strych|first3=Ulrich|last4=Hayward|first4=Tara|last5=Hotez|first5=Peter J.|last6=Bottazzi|first6=Maria Elena|date=2016-06-03|title=Status of vaccine research and development of vaccines for leishmaniasis|journal=Vaccine|volume=34|issue=26|pages=2992–2995|doi=10.1016/j.vaccine.2015.12.071|issn=1873-2518|pmid=26973063|doi-access=free}}</ref> The most effective method to prevent infection is to protect from sand fly bites. To decrease the risk of being bitten, these precautionary measures are suggested:<ref>{{Cite web |last=CDC |date=2024-03-11 |title=Preventing Leishmaniasis |url=https://www.cdc.gov/leishmaniasis/prevention/index.html |access-date=2024-06-06 |website=Leishmaniasis |language=en-us}}</ref><ref>{{Cite web |date=2024-05-09 |title=Leishmaniasis: Types, symptoms, treatment, and prevention |url=https://www.medicalnewstoday.com/articles/leishmaniasis |access-date=2024-06-06 |website=www.medicalnewstoday.com |language=en}}</ref><ref>{{Cite journal |last1=Davies |first1=Clive R. |last2=Kaye |first2=Paul |last3=Croft |first3=Simon L. |last4=Sundar |first4=Shyam |date=2003-02-15 |title=Leishmaniasis: new approaches to disease control |journal=BMJ (Clinical Research Ed.) |volume=326 |issue=7385 |pages=377–382 |doi=10.1136/bmj.326.7385.377 |issn=1756-1833 |pmc=1125241 |pmid=12586674}}</ref> * Outdoors: 1. Avoid outdoor activities, especially from dusk to dawn, when sand flies are generally the most active.
2. When outdoors (or in unprotected quarters), minimize the amount of exposed (uncovered) skin to the extent that is tolerable in the climate. Wear long-sleeved shirts, long pants, and socks, and tuck your shirt into your pants.
3. Apply insect repellent to exposed skin and under the ends of sleeves and pant legs. Follow the instructions on the label of the repellent. The most effective repellents generally are those that contain the chemical DEET (N, N-diethylmetatoluamide). * Indoors: 1. Stay in well-screened or air-conditioned areas.
2. Keep in mind that sand flies are much smaller than mosquitoes and therefore can get through smaller holes.
3. Spray living/sleeping areas with an insecticide to kill insects.
4. If you are not sleeping in a well-screened or air-conditioned area, use a bed net and tuck it under your mattress. If possible, use a bed net that has been soaked in or sprayed with a pyrethroid-containing insecticide. The same treatment can be applied to screens, curtains, sheets, and clothing (clothing should be retreated after five washings).
==Treatments== As with many diseases in developing nations (including [[trypanosomiasis]] and [[malaria]]), effective and affordable [[chemotherapy]] is sorely lacking, and parasites or insect vectors are becoming increasingly resistant to existing anti-parasite drugs. Possibly 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 organizations. Product Development Partnership, Drugs for Neglected Diseases ''initiative'' works on the development of new treatments (combination treatments and new chemical entities) for visceral leishmaniasis.<ref>{{cite web|title=DNDi Annual Report 2015|url=http://www.dndi.org/wp-content/uploads/2016/08/DNDi_AR_2015.pdf|publisher= Drugs for Neglected Diseases initiatives|access-date=2016-09-19}}</ref>
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 are as high as 60% in parts of Bihar, India.<ref name="Sundar2000">{{cite journal |vauthors=Sundar S, More DK, Singh MK, etal |title=Failure of pentavalent antimony in visceral leishmaniasis in India: report from the center of the Indian epidemic |journal=Clin. Infect. Dis. |volume=31 |issue=4 |pages=1104–7 |date=October 2000 |pmid=11049798 |doi=10.1086/318121 |doi-access=free }}</ref><ref name="Thakur2004">{{cite journal |vauthors=Thakur CP, Narayan S, Ranjan A |title=Epidemiological, clinical & pharmacological study of antimony-resistant visceral leishmaniasis in Bihar, India |journal=Indian J. Med. Res. |volume=120 |issue=3 |pages=166–72 |date=September 2004 |pmid=15489554 |url=http://www.icmr.nic.in/ijmr/2004/0904.pdf}}</ref>
The treatment of choice for visceral leishmaniasis acquired in India is now [[amphotericin B]]<ref name="Thakur1999">{{cite journal |vauthors=Thakur CP, Singh RK, Hassan SM, Kumar R, Narain S, Kumar A |title=Amphotericin B deoxycholate treatment of visceral leishmaniasis with newer modes of administration and precautions: a study of 938 cases |journal=Trans. R. Soc. Trop. Med. Hyg. |volume=93 |issue=3 |pages=319–23 |year=1999 |pmid=10492770 |doi=10.1016/S0035-9203(99)90037-8 }}</ref> in its various liposomal preparations.<ref name="Thakur1996">{{cite journal |vauthors=Thakur CP, Pandey AK, Sinha GP, Roy S, Behbehani K, Olliaro P |title=Comparison of three treatment regimens with liposomal amphotericin B (AmBisome) for visceral leishmaniasis in India: a randomized dose-finding study |journal=Trans. R. Soc. Trop. Med. Hyg. |volume=90 |issue=3 |pages=319–22 |year=1996 |pmid=8758093 |doi=10.1016/S0035-9203(96)90271-0 }}</ref><ref name="Sundar2006">{{cite journal |vauthors=Sundar S, Mehta H, Chhabra A, etal |title=Amphotericin B colloidal dispersion for the treatment of Indian visceral leishmaniasis |journal=Clin. Infect. Dis. |volume=42 |issue=5 |pages=608–13 |date=March 2006 |pmid=16447104 |doi=10.1086/500138 |doi-access=free }}</ref> In East Africa, the WHO recommended treatment is SSG&PM (sodium stibogluconate and paromomycin) developed by Drugs for Neglected Diseases ''initiative'' (DNDi) in 2010.<ref>New treatment for kala azar, the most deadly parasitic disease after malaria. ScienceDaily, 23 September 2011</ref>
[[Miltefosine]] 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 it is also effective in Africa. In HIV immunosuppressed people who are coinfected with leishmaniasis, it has been shown that even in resistant cases, 2/3 of the people responded to this new treatment. Miltefosine received approval from the Indian regulatory authorities in 2002, in Germany in 2004, and in the U.S.A. in 2014.<ref>{{cite web|url=https://www.fda.gov/newsevents/newsroom/pressannouncements/ucm389671.htm|archive-url=https://web.archive.org/web/20140322022750/http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm389671.htm|archive-date=March 22, 2014|title=FDA approves Impavido to treat tropical disease leishmaniasis|author=FDA News Release|publisher=FDA|date=19 March 2014}}</ref> It is now registered in other countries such as Nepal, Argentina, Bangladesh, Bolivia, Colombia, Ecuador, Guatemala, Honduras, Mexico, Pakistan, Paraguay, Peru, and Israel.<ref>{{Cite journal |last1=Sunyoto |first1=Temmy |last2=Potet |first2=Julien |last3=Boelaert |first3=Marleen |date=2018 |title=Why miltefosine-a life-saving drug for leishmaniasis-is unavailable to people who need it the most |journal=BMJ Global Health |volume=3 |issue=3 |article-number=e000709 |doi=10.1136/bmjgh-2018-000709 |issn=2059-7908 |pmc=5935166 |pmid=29736277}}</ref>
The drug is generally better tolerated than other drugs. Main side effects are gastrointestinal disturbance in the first or second day of treatment (a course of treatment is 28 days), which does not affect the efficacy. 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. However, there are some important disadvantages: 1) there is evidence of reduced efficacy after a decade of use<ref>{{cite journal|last1=Rijal|first1=Suman|last2=Ostyn|first2=Bart|last3=Uranw|first3=Surendra|last4=Rai|first4=Keshav|last5=Bhattarai|first5=Narayan Raj|last6=Dorlo|first6=Thomas P. C.|last7=Beijnen|first7=Jos H.|last8=Vanaerschot|first8=Manu|last9=Decuypere|first9=Saskia|last10=Dhakal|first10=Subodh S.|last11=Das|first11=Murari Lal|date=2013-06-01|title=Increasing Failure of Miltefosine in the Treatment of Kala-azar in Nepal and the Potential Role of Parasite Drug Resistance, Reinfection, or Noncompliance|url=https://academic.oup.com/cid/article/56/11/1530/302997|journal=Clinical Infectious Diseases|language=en|volume=56|issue=11|pages=1530–1538|doi=10.1093/cid/cit102|pmid=23425958|issn=1058-4838|doi-access=free}}</ref> 2) it is potentially embryotoxic, fetotoxic and [[teratology|teratogenic]], and thus cannot be used without anticonception in women of child-bearing age for three months (in some cases, five months<ref>{{Cite journal |last1=Kämink |first1=Suzette |last2=Masih |first2=Boota |last3=Ali |first3=Noor |last4=Ullah |first4=Aman |last5=Khan |first5=Syed Juma |last6=Ashraf |first6=Shakil |last7=Pylypenko |first7=Tetyana |last8=Grobusch |first8=Martin P. |last9=Fernhout |first9=Jena |last10=den Boer |first10=Margriet |last11=Ritmeijer |first11=Koert |date=January 2021 |title=Effectiveness of miltefosine in cutaneous leishmaniasis caused by Leishmania tropica in Pakistan after antimonial treatment failure or contraindications to first line therapy-A retrospective analysis |url= |journal=PLOS Neglected Tropical Diseases |volume=15 |issue=1 |article-number=e0008988 |doi=10.1371/journal.pntd.0008988 |doi-access=free |issn=1935-2735 |pmc=7872246 |pmid=33507944}}</ref><ref>{{Cite journal |last1=Pijpers |first1=Joyce |last2=den Boer |first2=Margriet L. |last3=Essink |first3=Dirk R. |last4=Ritmeijer |first4=Koert |date=2019 |title=The safety and efficacy of miltefosine in the long-term treatment of post-kala-azar dermal leishmaniasis in South Asia - A review and meta-analysis |url= |journal=PLOS Neglected Tropical Diseases |volume=13 |issue=2 |article-number=e0007173 |doi=10.1371/journal.pntd.0007173 |doi-access=free |issn=1935-2735 |pmc=6386412 |pmid=30742620}}</ref>) after treatment.<ref>{{Cite journal |last1=Monge-Maillo |first1=Begoña |last2=López-Vélez |first2=Rogelio |date=2015-05-01 |title=Miltefosine for visceral and cutaneous leishmaniasis: drug characteristics and evidence-based treatment recommendations |url=https://academic.oup.com/cid/article/60/9/1398/404258 |journal=Clinical Infectious Diseases|volume=60 |issue=9 |pages=1398–1404 |doi=10.1093/cid/civ004 |issn=1537-6591 |pmid=25601455}}</ref><ref>{{Cite journal |last1=Sindermann |first1=H. |last2=Engel |first2=J. |date=2006 |title=Development of miltefosine as an oral treatment for leishmaniasis |journal=Transactions of the Royal Society of Tropical Medicine and Hygiene |volume=100 |issue=Suppl 1 |pages=S17–20 |doi=10.1016/j.trstmh.2006.02.010 |issn=0035-9203 |pmid=16730362}}</ref>
Incomplete treatment has been cited as a major reason for death from visceral leishmaniasis.<ref name=":0" />
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 US$15. The drug had originally been identified in the 1960s.<ref name="nytimes.com">[https://www.nytimes.com/2006/07/31/health/31charity.html A Small Charity Takes the Reins in Fighting a Neglected Disease], ''[[New York Times]]'', July 31, 2006.</ref> The Indian government approved paromomycin for sale and use in August 2006.<ref>{{usurped|1=[https://web.archive.org/web/20070706200451/http://www.oneworldhealth.org/media/details.php?prID=154 NEW CURE FOR DEADLY VISCERAL LEISHMANIASIS (KALA-AZAR) APPROVED BY GOVERNMENT OF INDIA]}}, ''Institute for OneWorld Health'' Press Release, September 8, 2006.</ref>
==Prognosis== ===Protective immunity=== Immunity to ''Leishmania'' is determined by the interplay of [[white blood cells]], [[cytokines]], [[immune complexes]], and genetic and environmental factors.<ref>{{cite journal | vauthors = Saha S, Mondal S, Banerjee, et al | title = Immune Responses in Kala-azar | journal = Indian J Med Res | year = 2006 | volume = 123 | issue = 3 | pages = 245–66 | pmid = 16778308 }}</ref> Protective immunity develops either after successful treatment of VL (cured) or after asymptomatic infections that resolve without development of VL (asymptomatic).<ref>{{cite journal | vauthors = Manson-Bahr P | title = Immunity in Kala-azar | journal= Trans. R. Soc. Trop. Med. Hyg. | year = 1961 | volume = 55 | issue = 6 | pages = 550–55 | doi = 10.1016/0035-9203(61)90078-5| pmid = 14469435 }}</ref><ref>{{cite journal | vauthors = Manson-Bahr P | title= Cryptic Infections of Humans in an Endemic Kala-azar Area | url = https://www.cabdirect.org/cabdirect/abstract/19672902412 | journal = E. African Med. J. | year = 1967 | volume = 44 | issue = 4 | pages = 177–82 | issn=0012-835X }}</ref> Both types of immunity are characterized by [[cell-mediated immunity]] (CMI), including [[type IV hypersensitivity|skin test positivity]], [[cell division|proliferation]], and [[interleukin 2]] (IL-2), [[interferon gamma]] (IFN-γ), and [[interleukin 12]] (IL-12) secretion by peripheral blood [[agranulocytes|mononuclear cells]] (PBMC) in response to ''Leishmania'' [[antigens]].<ref name = "carvalho81">{{cite journal | vauthors = Carvalho E, Teixeira R, Johnson W Jr | title =Cell Mediated Immunity in American Visceral Leishmaniasis: Reversible Immunosuppression during Acute Infection | journal = Infect. Immun. | year = 1981 | volume = 33 | issue = 2 | pages = 498–502 | pmid = 7275314 | doi=10.1128/IAI.33.2.498-500.1981| pmc = 350726 }}</ref><ref name="carvalho85">{{cite journal | vauthors = Carvalho E, Badaro R, Reed S, et al| title = Absence of gamma interferon and interleukin 2 production during active visceral leishmaniasis |journal = J. Clin. Invest. |year = 1985 | volume = 76 | issue = 6 | pages = 2066–2069| pmid = 3935667 | doi = 10.1172/JCI112209 | pmc = 424308}}</ref><ref>{{cite journal | vauthors = Carvalho E, Barral A, Pedral-Sampaio D, et al | title = Immunologic Markers of Clinical Evolution in Children Recently Infected with ''Leishmania donovani chagasi'' | journal = J. Infect. Dis. | year = 1992 | volume = 165 | issue = 3 | pages = 535–40 | pmid = 1347057 | doi=10.1093/infdis/165.3.535}}</ref><ref name = "carvalho94">{{cite journal | vauthors = Carvalho E, Bacellar O, Brownell C, et al |title = Restoration of IFN-gamma Production and Lymphocyte Proliferation in Visceral Leishmaniasis | journal = J. Immunol. | year = 1994 | volume = 15 | issue = 12 | pages = 5949–56 |doi = 10.4049/jimmunol.152.12.5949 | pmid = 8207220 |s2cid = 31372945 | doi-access = free }}</ref><ref name = "ghalib">{{cite journal | vauthors = Ghalib H, Whittle J, Kubin M, et al | title = IL-12 Enhances Th-1 Type Responses in Human ''Leishmania donovani'' Infections | journal = J. Immunol. | year = 1995 | volume = 154 | issue = 9 | pages = 4623–9 | doi = 10.4049/jimmunol.154.9.4623 | pmid = 7722314 | s2cid = 37383454 | doi-access = free }}</ref> T cells isolated from both cured and asymptomatic PBMC activate autologous macrophages to kill intracellular amastigotes.<ref name = "holaday93a">{{cite journal | vauthors = Holaday B, Pompeu M, Evans T, et al | title = Correlates of ''Leishmania''-specific Immunity in the Clinical Spectrum of Infection with ''Leishmania chagasi'' | journal = J. Infect. Dis. | year = 1993 | volume = 167 | issue = 2 | pages = 411–17 | pmid = 8421174 | doi= 10.1093/infdis/167.2.411 }}</ref> IFN-γ activates macrophages to kill intracellular parasites so its role in VL has been studied extensively and IFN-γ production is often used as a marker of protective immunity. Cured PBMC generally secrete less IFN-γ and more [[interleukin 10]] (IL-10) in response to ''Leishmania'' antigens than asymptomatic PBMC.<ref name="holaday93b">{{cite journal | vauthors = Holaday B, Pompeu M, Jeronimo S, et al | title = Potential Role for Interleukin-10 in the Immunosuppression Associated with Kala-azar | journal = J. Clin. Invest. | year = 1993 | volume = 92 | issue = 6 | pages = 2626–32 | pmid = 8254019 | doi = 10.1172/JCI116878| pmc = 288459}}</ref> IL-12 is important in the development and maintenance of Type 1 [[T helper cell]] responses and protective immunity so its role in VL has also been studied. Addition of IL-12 to some VL PBMC increases proliferation and IFN-γ secretion in response to ''Leishmania'' antigens, and anti-IL-12 inhibits proliferation and IFN-γ secretion by some cured PBMC.<ref name = "ghalib"/><ref>{{cite journal | vauthors = Bacellar O, Brodskyn C, Guerreiro J, et al | title = Interleukin-12 Restores Interferon-γ Production and Cytotoxic Responses in Visceral Leishmaniasis | url = https://academic.oup.com/jid/article-pdf/173/6/1515/3285816/173-6-1515.pdf | journal = J. Infect. Dis. | year = 1996 | volume = 173 | issue = 6 | pages = 1515–8 | pmid = 8648233 | doi= 10.1093/infdis/173.6.1515| doi-access = free }}</ref><ref name="holaday99">{{cite journal | vauthors = Holaday B | title = Immunotherapy for Visceral Leishmaniasis: Ability of Factors Produced during Anti-''Leishmania'' Responses of Skin Test Positive Adults to Inhibit Peripheral Blood Mononuclear Cell Activities Associated with Visceral Leishmaniasis | journal = Mem. Inst. Oswaldo Cruz | year = 1999 | volume = 94 | issue = 1 | pages = 55–66 | pmid = 10029912 | doi= 10.1590/S0074-02761999000100013| doi-access = free }}</ref><ref>{{ cite journal | vauthors = Bacellar O, D'oliveira A Jr, Jerônimo S, et al | title = IL-10 and IL-12 Are the Main Regulatory Cytokines in Visceral Leishmaniasis. | journal = Cytokine | year = 2000 | volume = 12 |issue = 8 | pages = 1228–31 | pmid = 10930301 | doi = 10.1006/cyto.2000.0694 | url = http://www.repositorio.ufba.br/ri/handle/ri/7814 }}</ref> Other cytokines also appear to be important in immunity to ''Leishmania'' but their roles are not as well characterized.<ref>{{Cite journal |last1=Almeida |first1=Fernanda Silva |last2=Vanderley |first2=Shayenne Eduarda Ramos |last3=Comberlang |first3=Fernando Cézar |last4=Andrade |first4=Arthur Gomes de |last5=Cavalcante-Silva |first5=Luiz Henrique Agra |last6=Silva |first6=Edson Dos Santos |last7=Palmeira |first7=Pedro Henrique de Sousa |last8=Amaral |first8=Ian P. G. do |last9=Keesen |first9=Tatjana S. L. |date=2023-05-15 |title=Leishmaniasis: Immune Cells Crosstalk in Macrophage Polarization |journal=Tropical Medicine and Infectious Disease |volume=8 |issue=5 |page=276 |doi=10.3390/tropicalmed8050276 |doi-access=free |issn=2414-6366 |pmc=10222886 |pmid=37235324}}</ref><ref>{{Cite journal |last1=Alimohmmadian |first1=Mohammad Hossein |last2=Ajdary |first2=Soheila |last3=Bahrami |first3=Fariborz |date=2022-03-01 |title=A Historic Review of the Role of CD4+ T-Cell Subsets in Development of the Immune Responses against Cutaneous and Visceral Leishmaniases |journal=Iranian Biomedical Journal |volume=26 |issue=2 |pages=99–109 |doi=10.52547/ibj.26.2.99 |doi-broken-date=12 July 2025 |issn=2008-823X |pmc=8987415 |pmid=35090305}}</ref>
''Leishmania'' antigen stimulation of PBMC from cured patients shows a mixed T helper cell and [[regulatory T cell]] response.<ref>{{cite journal | vauthors = Kemp K, Kemp M, Kharazmi A, et al | title = ''Leishmania''-specific T Cells Expressing Interferon-gamma (IFN-γ) and IL-10 upon Activation Are Expanded in Individuals Cured of Visceral Leishmaniasis | journal = Clin. Exp. Immunol. | year = 1999 | volume = 116 | issue = 3 | pages = 500–4 | pmid = 10361241| doi = 10.1046/j.1365-2249.1999.00918.x | pmc = 1905302}}</ref> Both [[CD4+]] and [[CD8+]] T cells contributed to IFN-γ production.<ref name = "gautam">{{cite journal | vauthors = Gautam S, Kumar R, Singh N, et al | title = CD8 T Cell Exhaustion in Human Visceral Leishmaniasis | journal = J. Infect. Dis. | year = 2014 | volume = 209 | issue = 2 | pages = 290–99 | pmid = 23922369 | doi = 10.1093/infdis/jit401 | pmc = 3873784}}</ref><ref name = "saha07">{{cite journal | vauthors = Saha S, Mondal S, Ravindran R, et al |title = IL-10- and TGF-B-Mediated Susceptibility in Kala-azar and Post-kala-azar Dermal Leishmaniasis: The Significance of Amphotericin B in the Control of ''Leishmania donovani'' Infection in India | journal = J. Immunol. | year = 2007 | volume = 179 | issue = 8 | pages = 5592–5603 | pmid = 17911647| doi = 10.4049/jimmunol.179.8.5592 | doi-access = free }}</ref> Studies of ''Leishmania'' antigen specific T cell clones from cured patient PBMC confirm that cured patients have a mixed T cell response that involves both CD4+ helper T cells and CD4+ and CD8+ regulatory T cells.<ref name = "holaday00">{{cite journal | author=Holaday B |title=Role of CD8+ T Cells in Endogenous Interleukin-10 Secretion Associated with Visceral Leishmaniasis | journal=Mem. Inst. Oswaldo Cruz | year = 2000 | volume = 95 | issue = 2 | pages=217–20 | pmid = 10733741 | doi=10.1590/s0074-02762000000200013 | doi-access=free }}</ref><ref name = "kemp93">{{cite journal | vauthors = Kemp M, Kurtzhals J, Bendtzen K, et al | title = ''Leishmania donovani''-reactive TH1-like T Cell Clones from Individuals Who Have Recovered from Visceral Leishmaniasis | journal = Infect. Immun. | year = 1993 | volume = 61 | issue = 3 | pages = 1069–73 | pmid = 8432588| doi=10.1128/IAI.61.3.1069-1073.1993| pmc = 302840 }}</ref><ref name = "mary">{{cite journal | vauthors = Mary C, Auriault V, Faugere B, et al | title = Control of ''Leishmania infantum'' Infection Is Associated with CD8+ and Gamma-interferon and Interleukin-5 Producing CD4+ Antigen-specific T Cells | journal = Infect. Immun. | year = 1999 | volume = 67 | issue = 11 | pages = 5559–66 | pmid = 10531200 | doi=10.1128/IAI.67.11.5559-5566.1999| pmc = 96926}}</ref> Two studies of asymptomatic T cell clones show that most have Type 1 profiles and secrete more IFN-γ than T cell clones from cured patients. Neither study revealed the presence of [[T helper cell|Type 2]] or regulatory T cells.<ref name = "holaday93b"/><ref name = "mary"/> Some clones secreted soluble factors that caused the death of CD8+ regulatory T cells but not CD4+ T cells from VL patients, which might explain the strong protective immunity of asymptomatic patients.<ref name = "holaday99"/>
===Non-protective immunity=== VL patients are unable to clear their infections because they lack CMI. This anergy may be limited to ''Leishmania'' antigens or extend to [[mitogens]] and other antigens as the disease progresses.<ref>{{cite journal | vauthors = Ho M, Koech D, Iha D, et al | title = Immune Suppression in Kenyan Visceral Leishmaniasis | journal = Clin. Exp. Immunol. | year = 1983 | volume = 51 | issue = 2 | pages = 207–14 | pmid = 6839538 | pmc = 1536899}}</ref> In addition to skin test negativity, VL patient PBMC do not proliferate or secrete IL-2 or IFN-γ in response to ''Leishmania'' antigens.<ref name = "carvalho81"/><ref name="carvalho85"/><ref>{{cite journal | vauthors = Haldar J, Ghose S, Saha K, et al | title = Cell-mediated Immune Response in Indian Kala-azar and Post-kala-azar Dermal Leishmaniasis | journal = Infect. Immun. | year = 1983 | volume = 42 | issue = 2 | pages = 702–7 | pmid = 6642649 | doi=10.1128/IAI.42.2.702-707.1983| pmc = 264486}}</ref> [[Memory T cells]] may be depleted in VL patient PBMC.<ref name = "cilliari">{{cite journal | vauthors = Cillari E, Vitale G, Arcoleo F, et al | title = In Vivo and In Vitro Cytokine and Mononuclear Cell Subsets in Sicilian Patients with Visceral Leishmaniasis | journal = Cytokine | year = 1995 | volume = 7 | issue = 7 | pages = 740–5 | pmid = 8580385 | doi= 10.1006/cyto.1995.0088 }}</ref><ref>{{cite journal | vauthors = Hailu A, van Baarle D, Knol G, et al |title= T Cell and Cytokine Profiles in Human Visceral Leishmaniasis during Active and Asymptomatic or Sub-clinical Infection with ''Leishmania donovani'' | journal = Clin. Immunol. | year = 2005 | volume = 117 | issue = 2 | pages = 182–91 | pmid = 16125466 | doi= 10.1016/j.clim.2005.06.015 |hdl= 1874/380043 |s2cid= 3186886 | hdl-access = free }}</ref> Since IL-10 is known to suppress [[innate immune system|innate]] and [[adaptive immune system|acquired]] immunity and prevent IFN-γ from activating macrophages, its role in VL has been studied extensively and elevated IL-10 production is often used as a marker of non-protective immunity in VL. Elevated levels of IL-10 in the plasma, infected tissues, and PBMC of VL patients accompany the anergy of VL.<ref name="holaday93b"/><ref name = "cilliari"/><ref>{{cite journal | vauthors = Karp C, el-Safi S, Wynn T, et al | title = In vivo Cytokine Profiles in Patients with Kala-azar. Marked Elevation of Both Interleukin-10 and Interferon-gamma | journal = J. Clin. Invest. | year = 1993 | volume = 91 | issue = 4 | pages = 1664–8 | pmid = 8097208 | doi = 10.1172/JCI116372 | pmc = 288142}}</ref><ref>{{cite journal | vauthors = Ghalib H, Piuvezam M, Skeiky Y, et al | title = Interleukin-10 Production Correlates with Pathology in Human ''Leishmania donovani'' Infections | journal = J Clin Invest | year = 1993 | volume = 92 | issue = 1 | pages = 324–9 | pmid = 8326000 | doi = 10.1172/JCI116570| pmc = 293600}}</ref><ref>{{cite journal | vauthors = Medeiros I, Castelo A, Salomão R | title = Presence of Circulating Levels of Interferon-gamma, Interleukin-10 and Tumor Necrosis Factor-alpha in Patients with Visceral Leishmaniasis. | journal = Rev Inst Med Trop Sao Paulo | year = 1998 | volume = 40 | issue = 1 | pages = 31–4 | pmid = 9713135 | doi = 10.1590/S0036-46651998000100007| doi-access = free }}</ref><ref name="peruhype05">{{cite journal | vauthors = Peruhype-Magalhaes V, Martins-Filho O, Prata A, et al | title = Immune Response in Human Visceral Leishmaniasis: Analysis of the Correlation between Innate Immunity Cytokine Profile and Disease Outcome |journal = Scand. J. Immunol. | year = 2005 | volume = 62 | issue = 5 | pages = 487–495 | pmid = 16305646 | doi = 10.1111/j.1365-3083.2005.01686.x | s2cid = 25506998 | doi-access = free }}</ref> PKDL patients also have elevated IL-10 levels.<ref name = "ganguly">{{cite journal | vauthors = Ganguly S, Mukhopadhyay D, Das N, et al | title = Enhanced Lesional FoxP3 Expression and Peripheral Anergic Lymphocytes Indicate a Role for Regulatory T Cells in Indian Post-Kala-azar Dermal Leishmaniasis | url = https://www.jidonline.org/article/S0022-202X(15)34778-3/fulltext#s0050| journal = J. Invest. Dermatol. | year = 2010 | volume = 130 | issue = 4 | pages = 1013–22 | pmid = 20032994 | doi= 10.1038/jid.2009.393 | doi-access = free }}</ref> VL patients with the highest IL-10 levels are more likely to be unresponsive to treatment and progress to PKDL.<ref name = "rai">{{cite journal | vauthors = Rai A, Chandreshwar P, Singh A, et al | title = Regulatory T Cells Suppress T Cell Activation at the Pathologic Site in Human Visceral Leishmaniasis | journal = PLOS ONE |year = 2012 | volume = 7 | issue = 2 | article-number = e31551 | pmid = 22347492 | doi = 10.1371/journal.pone.0031551 | pmc = 3275558| bibcode = 2012PLoSO...731551R | doi-access = free }}</ref><ref>{{cite journal | vauthors = Gasim S, Elhassan A, Khalil E, et al | title = High Levels of Plasma IL-10 and Expression of IL-10 by Keratinocytes during Visceral Leishmaniasis Predict Subsequent Development of Post-kala-azar Dermal Leishmanniasis | journal = Clin. Exp. Immunol. | year = 1998 | volume = 111 | issue = 1 | pages = 64–9 | pmid = 9472662 | doi=10.1046/j.1365-2249.1998.00468.x| pmc = 1904865}}</ref> PBMC secretion of IL-10 without the addition of ''Leishmania'' antigen (endogenous) is inversely correlated with antigen specific IFN-γ secretion but ''Leishmania'' antigen specific IL-10 and IFN-γ secretion are not correlated, suggesting that endogenous secretion is more important in pathology.<ref name = "holaday00"/> Addition of anti-IL-10 increases proliferation and IFN-γ secretion by PBMC from some patients.<ref name = "carvalho94"/><ref name="holaday99"/> Both CD4+ and CD8+ T cells have been shown to contribute to IL-10 secretion by VL PBMC.<ref name = "peruhype06"/><ref name="saha07"/> The high level of immune complexes characteristic of VL have also been shown to increase IL-10 levels.<ref>{{cite journal | vauthors = Elshafie A, Ahlin E, Mathsson L, et al | title = Circulating Immune Complexes (IC) and IC-induced Levels of GM-CSF Are Increased in Sudanese Patients with Acute Visceral ''Leishmania donovani'' Infection Undergoing Sodium Stibogluconate Treatment: Implications for Disease Pathogenesis |journal = J. Immunol. | year = 2007 | volume = 178 | issue = 8 | pages = 5383–89 | pmid = 17404324| doi = 10.4049/jimmunol.178.8.5383| doi-access = free }}</ref>
==Epidemiology== {{See also|Kala azar in India}} More than 90% of the global burden of visceral leishmaniasis (VL) was contributed by seven countries in 2015: Brazil, Ethiopia, India, Kenya, Somalia, South Sudan and Sudan.<ref name=":0" /> In India, more than 70% of VL cases are reported from the state of Bihar.<ref name=":0" /> North [[Bihar]], India (including [[Araria]], [[Purnea Airport|Purnea]], and [[Kishanganj]]) is the endemic zone of this disease. The disease is endemic in more than 70 countries.<ref>{{Cite journal |last1=Scarpini |first1=Sara |last2=Dondi |first2=Arianna |last3=Totaro |first3=Camilla |last4=Biagi |first4=Carlotta |last5=Melchionda |first5=Fraia |last6=Zama |first6=Daniele |last7=Pierantoni |first7=Luca |last8=Gennari |first8=Monia |last9=Campagna |first9=Cinzia |last10=Prete |first10=Arcangelo |last11=Lanari |first11=Marcello |date=2022-09-21 |title=Visceral Leishmaniasis: Epidemiology, Diagnosis, and Treatment Regimens in Different Geographical Areas with a Focus on Pediatrics |url= |journal=Microorganisms |volume=10 |issue=10 |page=1887 |doi=10.3390/microorganisms10101887 |doi-access=free |issn=2076-2607 |pmc=9609364 |pmid=36296164}}</ref> In Iran this includes Ardabil, Fars, and North Khorasan.<ref>{{Cite journal |last=Mohebali |first=Mehdi |date=2013 |title=Visceral leishmaniasis in Iran: Review of the Epidemiological and Clinical Features |url= |journal=Iranian Journal of Parasitology |volume=8 |issue=3 |pages=348–358 |issn=1735-7020 |pmc=3887234 |pmid=24454426}}</ref><ref>{{Cite journal |last1=Shamsian |first1=Seyed Aliakbar |last2=Fata |first2=Abdolmajid |last3=Alinezhad |first3=Reza |last4=Mohebali |first4=Mehdi |last5=Sadabadi |first5=Fatemeh |last6=Moghaddas |first6=Elham |last7=Fakhar |first7=Mahdi |date=2020 |title=Clinical and Laboratory Findings of Visceral Leishmaniasis in Children Hospitalized in Mashhad, Northeastern Iran: A Twenty-Year Retrospective Study |url= |journal=Iranian Journal of Parasitology |volume=15 |issue=4 |pages=495–499 |doi=10.18502/ijpa.v15i4.4854 |issn=1735-7020 |pmc=8039489 |pmid=33884006}}</ref>
However, 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|South Sudan, Sudan]], Ethiopia, [[Kenya]], and [[Somalia]]. Living conditions here have changed very little in the past century, and the people are not normally very mobile. Parts of South Sudan, in particular the [[Upper Nile, Sudan|Upper Nile]] region, are almost totally cut off from the rest of the country, and most people tend to remain at their place of birth although there have been huge population movements due to the civil war, leading to severe epidemics.<ref name="Jean1995">{{cite journal | author= Jean, Francois | year=1995 | journal= Life, Death and Aid: The Médecins Sans Frontières Report on World Crisis Intervention | title= Sudan: Speak no Evil, Do no Good}}</ref>
==History== {{See also|Leishmaniasis#History}}
Kala-azar first came to the attention of Western doctors in 1824 in [[Jessore (city)|Jessore]], British Raj (now [[Bangladesh]]), where it was initially thought to be a form of [[malaria]]. [[Assam]] gave kala-azar one of its common names, ''Assam fever''.<ref name="Medical Encyclopedia">{{cite web | author = "Mosby's Medical Dictionary, 8th edition. © 2009, Elsevier." | url = http://www.medical-dictionary.thefreedictionary.com/kala-azar | title = kala-azar | access-date = 2010-01-21 }}</ref> Another common name, ''kala-azar'' ([[Hindustani language|Hindustani]]: काला आज़ार <small>([[Devanagari]])</small> کالا آزار <small>([[Nastaleeq]])</small> ''kālā āzār''), is derived from ''kala'' which means black in [[Sanskrit]], as well as in the [[Indo-Aryan languages|languages descended]] from it, including [[Assamese language|Assamese]],<ref name="Collins English Dictionary" /> [[Hindi]] and [[Urdu]];<ref name="MWKA">{{cite web | author = Merriam-Webster's online dictionary | url = http://www.merriam-webster.com/dictionary/kala-azar | title = kala-azar | access-date = 2010-01-21 }}</ref> the word ''azar'' is a [[Persian language|Persian]] loanword in [[Hindustani language|Hindustani]] that means "fever";<ref name="Collins English Dictionary">{{cite web | author = HarperCollins Publishers, 1991, 1994, 1998, 2000, 2003. | url = http://www.thefreedictionary.com/kala-azar | title = kala-azar | access-date = 2010-01-21 }}</ref><ref>{{cite book|title=Framework for Industrialization in Africa|url=https://books.google.com/books?id=I7JNoIcUycQC&q=hindustani+azar+fever&pg=PA77|first=Thomas A.|last=Taku|publisher=Greenwood Publishing Group|page=77|quote=Locally, the disease was called kala-azar or black fever, which is the meaning in the Hindustani language.|isbn=978-0-275-96498-6|year=1999}}</ref> as such the disease is named for the darkening of the skin on the extremities and abdomen that is a symptom of the Indian form of the disease. It is also pronounced ''kālāzar'' (कालाज़ार کالا زار).<ref>{{cite web |title=kaalaa-zaar |url=https://www.rekhtadictionary.com/meaning-of-kaalaa-zaar?lang=hi |website=Rekhta Dictionary |access-date=30 September 2024 |language=en}}</ref> The agent of the disease was also first isolated in India by Scottish doctor [[William Leishman]] (who observed the parasite in spleen smears of a soldier who died of the disease in [[Dum Dum|Dumdum, Calcutta, India]]<ref>{{cite book|title = Textbook of Medical Parasitology|last = Paniker|first = C.K. Jayaram|publisher = Jaypee Brothers, Medical Publishers|year = 2013|isbn = 978-93-5090-534-0|location = Shorakhutte, Kathmandu, Nepal|page = 51|url = https://books.google.com/books?id=H-CLAgAAQBAJ&q=sir+william+leishman+dumdum+india&pg=PA51}}</ref> - hence the name ''dumdum fever'') and Irish physician [[Charles Donovan]], working independently of each other. As they published their discovery almost simultaneously, the species was named by Sir [[Ronald Ross]] for both of them—''Leishmania donovani''.<ref>{{Cite journal |last=Gibson |first=M E |date=1983 |title=The identification of kala-azar and the discovery of Leishmania donovani. |journal=Medical History |volume=27 |issue=2 |pages=203–213 |doi=10.1017/s0025727300042691 |issn=0025-7273 |pmc=1139308 |pmid=6345968}}</ref><ref>{{Cite journal |last=Steverding |first=Dietmar |date=2017-02-15 |title=The history of leishmaniasis |url= |journal=Parasites & Vectors |volume=10 |issue=1 |article-number=82 |doi=10.1186/s13071-017-2028-5 |doi-access=free |issn=1756-3305 |pmc=5312593 |pmid=28202044}}</ref> [[File:Number of Deaths from Kala-Azar in Assam.svg|thumb|left|The miracle of urea stibamine, drawn by [[Upendranath Brahmachari]] himself. The death rate has drastically declined from nearly 6300 to 750 within ten years in Assam.]]
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 [[Canidae|canines]] serve as reservoir hosts of ''L. infantum (chagasi)''.<ref>{{Cite journal |last1=Ribeiro |first1=Raul Rio |last2=Michalick |first2=Marilene Suzan Marques |last3=da Silva |first3=Manoel Eduardo |last4=Dos Santos |first4=Cristiano Cheim Peixoto |last5=Frézard |first5=Frédéric Jean Georges |last6=da Silva |first6=Sydnei Magno |date=2018 |title=Canine Leishmaniasis: An Overview of the Current Status and Strategies for Control |url= |journal=BioMed Research International |volume=2018 |article-number=3296893 |doi=10.1155/2018/3296893 |doi-access=free |issn=2314-6141 |pmc=5896350 |pmid=29789784}}</ref><ref>{{Cite journal |last1=Morales-Yuste |first1=Manuel |last2=Martín-Sánchez |first2=Joaquina |last3=Corpas-Lopez |first3=Victoriano |date=2022-07-27 |title=Canine Leishmaniasis: Update on Epidemiology, Diagnosis, Treatment, and Prevention |url= |journal=Veterinary Sciences |volume=9 |issue=8 |page=387 |doi=10.3390/vetsci9080387 |doi-access=free |issn=2306-7381 |pmc=9416075 |pmid=36006301}}</ref>
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.<ref name="Jean1995"/>
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 [[Indigenous peoples of the Americas|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 1980s to the mid-1990s, a total of 100,000 died from 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?"<ref name="Dowell1997">{{cite magazine | author= Dowell, William | year=1997 | magazine=Time| title= Rescue in Sudan}}</ref> Due to the [[South Sudanese Civil War]], kala-azar has spread rapidly among the population.<ref name="veconomist" >{{cite news|title=As South Sudan implodes, America reconsiders its support for the regime|url=https://www.economist.com/news/middle-east-and-africa/21730154-american-officials-are-fed-up-being-lied-violent-crooked|newspaper=[[The Economist]]|date=12 October 2017}}</ref> [[File:Scientist Sir Upendra Nath Brahmachari.png|thumb|right|[[Upendranath Brahmachari]]]] The Indian medical practitioner [[Upendranath Brahmachari]] was nominated for the [[Nobel Prize in Physiology or Medicine]] in 1929 for his discovery of ureastibamine (an [[antimony|antimonial]] [[Chemical compound|compound]] for the treatment of kala-azar) and a new disease, post kala-azar dermal leishmaniasis.<ref name=nobel_foundation_UPB>[[Nobel Foundation]] (2008).[http://nobelprize.org/nomination/medicine/nomination.php?action=show&showid=2791 ''The Nomination Database for the Nobel Prize in Physiology or Medicine, 1901-1951'']</ref> Brahmachari's cure for visceral leishmaniasis was the urea salt of para-amino-phenyl stibnic acid which he called Urea Stibamine.<ref name="Vigyan_prasar_UNB">[http://www.vigyanprasar.gov.in/scientists/UNBrahmachari.htm ''Upendra Nath Brahmachari: A Pioneer of Modern Medicine in India''] {{Webarchive|url=https://web.archive.org/web/20181225002311/http://vigyanprasar.gov.in/scientists/UNBrahmachari.htm |date=2018-12-25 }}. Vigyan Prasar: Government of India</ref>
During the nineteenth century, kala-azar was discovered near moving bodies of water in Southeast Asia.<ref>{{cite book|title=In War and Famine: Missionaries in China's Honan Province in the 1940s|last=Christensen|first=Erleen|publisher=MQUP|year=2005|isbn=978-0-7735-7259-1|pages=195}}</ref> [[Jean Dow]] and William McClure, are credited with finding the cure for the disease in China. Largely uncredited for her contribution, Dow was one of the first to isolate the microorganism in China and conduct clinical studies on its origin.<ref>{{cite book|title=Figuring it out: science, gender, and visual culture|date=2006|publisher=Dartmouth College Press|others=Shteir, Ann B.; Lightman, Bernard V. |isbn=1-58465-602-6|edition=1st|location=Hanover, N.H.|oclc=70673140}}</ref> This work continued under [[Ernest Black Struthers|Ernest Struthers]] and [[Lionel Everard Napier|Lionel Napier]] at the School of Tropical Medicine at Calcutta to discover that kala-azar was transmitted by sandflies.<ref name="IMG">{{cite journal|date=May 1943|title=Dr. L. Everard Napier|journal=Indian Medical Gazette|volume=78|issue=5|page=252|pmc=5158438|pmid=29012190}}</ref><ref name=":7">{{cite journal|last=Gewurtz|first=Margo S.|date=2017-01-01|title=Transnationalism in Missionary Medicine: The Case of Kala-azar in China and India, 1909–1946|journal=Social Sciences and Missions|language=en|volume=30|issue=1–2|pages=30–43|doi=10.1163/18748945-03001001|issn=1874-8945}}</ref>
On 31 October 2023, Bangladesh was declared to be the first country to eradicate the disease.<ref>{{cite web | url=https://thefinancialexpress.com.bd/health/bangladesh-worlds-first-black-fever-free-country-who | title=Bangladesh world's first black-fever free country }}</ref>
In May 2025, several countries signed an African Union-led agreement to eliminate visceral leishmaniasis and backed closer regional cooperation to advance elimination goals.<ref>{{cite web | title=African Nations unite to eliminate visceral leishmaniasis and boost cross-border collaboration for NTDs | website= World Health Organization (WHO) | date=2025-05-22 | url=https://www.who.int/news/item/22-05-2025-african-nations-unite-to-eliminate--visceral-leishmaniasis-and-boost-cross-border-collaboration | ref={{sfnref| World Health Organization (WHO) |2025}} | access-date=2026-03-27}}</ref>
==Research== 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 are cost-effective strategies.<ref name="Olliaro2009">{{cite journal |author=Olliaro, P., Darley, S., Laxminarayan, R.|title=Cost-effectiveness projections of single and combination therapies for visceral leishmaniasis in Bihar, India |journal=Trop Med Int Health |volume=14 |issue=8 |pages=918–925 |year=2009 |doi=10.1111/j.1365-3156.2009.02306.x|pmid=19563434|s2cid=29278489 |display-authors=etal|doi-access=free }}</ref> Comparative homology modelling of the enzyme Hypoxanthine-guanine phosphoribosyl transferase (HGPRT; EC 2.4.2.8) in ''[[L. donovani|L. donovani]]'' suggest that among all of the computationally screened compounds, [[pentamidine]], 1,3-dinitro[[adamantane]], [[acyclovir]] and analogs of acyclovir had higher binding affinities than the real substrate (guanosine monophosphate).<ref name="pmid22327112">{{cite journal |vauthors=Ansari MY, Dikhit MR, Sahoo GC, Das P | title = Comparative modeling of HGPRT enzyme of L. donovani and binding affinities of different analogs of GMP | journal = Int. J. Biol. Macromol. | volume = 50 | issue = 3 | pages = 637–49 |date=April 2012 | pmid = 22327112 |doi = 10.1016/j.ijbiomac.2012.01.010 }}</ref>
DNDi has several compounds in preclinical and phase'' ''1 development,<ref>{{cite web|url=https://www.dndi.org/diseases-projects/portfolio/|title=Portfolio – DNDi|website=www.dndi.org|language=en-GB|access-date=2020-02-13}}</ref> but no novel drugs are expected in the next 5 years.<ref name="denBoer2009">{{cite journal|author=den Boer, M.L., Alvar, J., Davidson, R.N.|title=Developments in the treatment of visceral leishmaniasis |journal= Expert Opinion on Emerging Drugs|volume=14|issue=3 |pages=395–410 |year=2009 |doi=10.1517/14728210903153862 |pmid=19708817|display-authors=etal|hdl=10144/127729 |s2cid=32952275 |hdl-access=free }}</ref> 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.<ref name="Sundar2010">{{cite journal |author=Sundar, S., Chakravarty, J., Agarwal, D.|title=Single-dose liposomal amphotericin B for visceral leishmaniasis in India|journal=N Engl J Med |volume=362 |issue=6 |pages=504–512 |year=2010|doi=10.1056/NEJMoa0903627 |pmid=20147716|s2cid=7070133|display-authors=etal|doi-access=free}}</ref><ref name="Wasan">{{cite journal|author=[[Kishor Wasan|Wasan, K. M.]], Wasan, E. K., Gershkovich, P.|title=Highly effective oral amphotericin B formulation against murine visceral leishmaniasis |journal=J Infect Dis |volume=200 |issue=3 |pages=357–60|year=2009 |pmid=19545212 |doi=10.1086/600105|display-authors=etal|doi-access=free }}</ref><ref>Arzamani K, Fazeli R, Shirzadi MR, Raeghi S, Arzamani M, Alavinia SM. Visceral Leishmaniasis in North Khorasan Province, Iran.</ref>
A 2018 study published details of a new potential preclinical drug candidate for the treatment of visceral leishmaniasis with an anti-leishmanial drug-like chemical series based on a pyrazolopyrimidine scaffold.<ref>{{cite journal|last1=Wyllie|first1=Susan|last2=Thomas|first2=Michael|last3=Patterson|first3=Stephen|last4=Crouch|first4=Sabrinia|last5=De Rycker|first5=Manu|last6=Lowe|first6=Rhiannon|last7=Gresham|first7=Stephanie|last8=Urbaniak|first8=Michael D.|last9=Otto|first9=Thomas D.|date=2018-07-25|title=Cyclin-dependent kinase 12 is a drug target for visceral leishmaniasis|journal=Nature|volume=560|issue=7717|pages=192–197|language=En|doi=10.1038/s41586-018-0356-z|pmid=30046105|pmc=6402543|issn=0028-0836|bibcode=2018Natur.560..192W}}</ref>
There is no good vaccine candidate that prevents kala azar. A 2019 paper described designing an [[immunologic adjuvant]] which would make a VL vaccine more effective.<ref>{{cite journal |last1=Ratnapriya |first1=S |last2=Keerti |last3=Sahasrabuddhe |first3=AA |last4=Dube |first4=A |title=Visceral leishmaniasis: An overview of vaccine adjuvants and their applications. |journal=Vaccine |date=12 June 2019 |volume=37 |issue=27 |pages=3505–3519 |doi=10.1016/j.vaccine.2019.04.092 |pmid=31103364|s2cid=159039859 }}</ref>
==References== {{Reflist}}101.<ref>{{cite journal |vauthors=Kumar P, Shivam P, Mandal S, Prasanna P, Kumar S, Prasad SR, Kumar A, Das P, Ali V, Singh SK, Mandal D |date=2019-08-20 |title=Synthesis, characterization, and mechanistic studies of a gold nanoparticle-amphotericin B covalent conjugate with enhanced antileishmanial efficacy and reduced cytotoxicity. |journal=International Journal of Nanomedicine |volume=14 |pages=6073–6101 |doi=10.2147/IJN.S196421 |doi-access=free |pmid=31686803 |pmc=6709383 }}</ref>
<ref>{{cite journal |title=Inhibition of ABC Transporters Abolishes Antimony Resistance in Leishmania Infection |journal=Antimicrobial Agents and Chemotherapy |date=2008 |volume=52 |issue=3 |pages=1080–1093|doi=10.1128/aac.01196-07 |last1=Mookerjee Basu |first1=Jayati |last2=Mookerjee |first2=Ananda |last3=Banerjee |first3=Rajdeep |last4=Saha |first4=Manik |last5=Singh |first5=Subhankar |last6=Naskar |first6=Ksudiram |last7=Tripathy |first7=Gayetri |last8=Sinha |first8=Prabhat K. |last9=Pandey |first9=Krishna |last10=Sundar |first10=Shyam |last11=Bimal |first11=Sanjeev |last12=Das |first12=Pradip K. |last13=Choudhuri |first13=Soumitra K. |last14=Roy |first14=Syamal |pmid=18056276 |pmc=2258502 }}</ref>
== External links == {{Medical resources | DiseasesDB = 7070 | ICD11 = {{ICD11|1F54.0}} | ICD10 = {{ICD10|B|55|0|b|50}} | ICD9 = {{ICD9|085.0}} | ICDO = | OMIM = | MedlinePlus = | eMedicineSubj = emerg | eMedicineTopic = 296 | MeshID = D007898 }} {{Protozoal diseases}} {{Diseases of Poverty}} {{Authority control}}
[[Category:Leishmaniasis]] [[Category:Insect-borne diseases]] [[Category:Parasitic infestations, stings, and bites of the skin]]