|
|
| (7 intermediate revisions by 4 users not shown) |
| Line 3: |
Line 3: |
| Image = 9306215.jpg| | | Image = 9306215.jpg| |
| Caption = Amastigotes in a chorionic villus| | | Caption = Amastigotes in a chorionic villus| |
| DiseasesDB = 7070 |
| | |
| ICD10 = {{ICD10|B|55|0|b|50}} |
| |
| ICD9 = {{ICD9|085.0}}|
| |
| ICDO = |
| |
| OMIM = |
| |
| MedlinePlus = |
| |
| eMedicineSubj = emerg |
| |
| eMedicineTopic = 296 |
| |
| MeshID = D007898 |
| |
| }} | | }} |
| | {{Visceral leishmaniasis}} |
|
| |
|
| {{CMG}} | | {{CMG}}; '''Associate Editor-In-Chief:''' {{CZ}} |
| {{SI}}
| |
| {{Editor Help}} | |
|
| |
|
| ==Overview==
| | {{SK}} Burdwan fever; dumdum fever |
| '''Visceral leishmaniasis''' (VL), also known as '''kala-azar''' and '''black fever''', is the most severe form of [[leishmaniasis]], a [[disease]] caused by [[parasite]]s of the ''[[Leishmania]]'' genus. It is the second-largest parasitic killer in the world (after [[malaria]]), responsible for an estimated 60 000 who die from the disease each year out of half-million infections worldwide.<ref>[http://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 parasite migrates to the visceral organs such as [[liver]], [[spleen]] and [[bone marrow]] and if left untreated will almost always result in the death of the [[mammal]]ian host. Signs and symptoms include [[fever]], weight loss, [[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<sup>[http://www.who.int/mediacentre/factsheets/fs116/en/]</sup>.
| |
|
| |
|
| ==Species that give rise to VL== | | ==[[Visceral leishmaniasis overview|Overview]]== |
| Several species of Leishmania are known to give rise to the visceral form of the disease. The "Old World" (Africa, Asia, Europe) species are ''L. donovani'' and ''L. infantum'' and the "New World" (South America) species is ''L. chagasi''.
| |
|
| |
|
| ==Life-cycle of the parasite== | | ==[[Visceral leishmaniasis historical perspective|Historical Perspective]]== |
| Kala-azar is spread through an insect [[Vector (biology)|vector]], the sandfly of the ''Phlebotomus'' [[genus]] in the Old World and the ''Lutzomyia'' genus in the New World. Leishmania are tiny creatures, 3-6 micrometers long by 1.5-3 micrometers in diameter, and found in tropical or temperate regions throughout the world. Sand fly larvae grow in warm, moist organic matter, so old trees, house walls or garbage are their most common breeding centers — 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.
| | ==[[Visceral leishmaniasis pathophysiology|Pathophysiology]]== |
|
| |
|
| 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.
| | ==[[Visceral leishmaniasis causes|Causes]]== |
|
| |
|
| 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.
| | ==[[Visceral leishmaniasis differential diagnosis|Differentiating Visceral Leishmaniasis from other Diseases]]== |
|
| |
|
| ==Disease progression== | | ==[[Visceral leishmaniasis epidemiology and demographics|Epidemiology and Demographics]]== |
| 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. Patients whose immune systems produce large numbers of TH1-type [[T-Cell]]s, which strengthen cell defenses but do not encourage [[antibody]] formation, often recover easily from infection on their own, and after recovery are immune to reinfection. Patients whose systems produce more TH2-type cells, which prompt antibody formation but do nothing for cellular health, are likely to quickly succumb to leishmaniasis. Sadly, some of the stronger strains of ''L. donovani'' appear to be able to force a switch in the host from a TH1 to a TH2-type immune response as the infection progresses.
| |
|
| |
|
| 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 infections]] 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.
| | ==[[Visceral leishmaniasis risk factors|Risk Factors]]== |
|
| |
|
| 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).
| | ==[[Visceral leishmaniasis natural history, complications and prognosis|Natural History, Complications and Prognosis]]== |
|
| |
|
| ==Diagnosis== | | ==Diagnosis== |
| The gold standard for diagnosis is visualisation of the [[amastigotes]] in splenic aspirate or [[Bone marrow aspiration|bone marrow aspirate]]. This is a technically challenging procedure that is frequently unavailable in areas of the world where visceral leishmaniasis is endemic.
| |
|
| |
| [[Serology|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 [[Direct agglutination test|DAT]] anti-leishmania antigen test is 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 | author=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 cisceral leishmaniasis | journal=Brit Med J | volume=333 | issue=7571 | pages=723–6 | doi=10.1136/bmj.38917.503056.7C }}</ref>
| |
|
| |
| 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.<ref>{{cite journal | author=Sundar S, Singh RK, Maurya R, ''et al.'' | title=Serological diagnosis of Indian visceral leishmaniasis: dirrect agglutination test versus rK39 strip test | journal=Trans R Soc Trop Med Hyg | volume=100 | pages=533–7 }}</ref><ref>{{cite journal | author=Sundar S, Maurya R, Singh RK, ''et al.'' | title=Rapid, noninvastive diagnosis of visceral leishmaniasis in INdia: comparison of two immunochromatographic strip tests for detection of anti-K39 antibody | journal=J Clin Microbiol | year=2006 | volume=44 | pages=251–3 }}</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 | author=Lockwood DNJ, Sundar S. | title=Serological tests for visceral leishmaniasis | journal=Brit Med J | year=2006 | volume=333 | pages=711–12 }}</ref> Likewise, patients with abnormal immune systems (e.g., HIV infection) will have false-negative tests.<ref>{{cite journal | author=Pasquau F, Ena J, Sanchez R, ''et al.'' | title=Leishmaniasis as an oppotunistic 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 | year=2005 | volume=24 | pages=411–18 }}</ref>
| |
|
| |
| 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.<ref name="Lockwood"/>
| |
|
| |
| ==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. 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 or may not 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,<ref name="Sundar2000">{{cite journal | author=Sundar S ''et al.'' | year=2000 | journal=Clin Infect Dis | title=Failure of pentavalent antimony in visceral leishmaniasis in India: report from the center of the Indian epidemic | volume=31 | pages=1104–7 }}</ref><ref name="Thakur2004">{{cite journal | author= Thakur CP ''et al.'' | title=Epidemiological, clinical & pharmacological study of antimony-resistant visceral leishmaniasis in Bihar, India | year=2004 | journal=Clin Infect Dis | volume=120 | pages=166–72 }}</ref> and the treatment of choice for visceral leishmaniasis acquired in India is now [[Amphotericin B]]<ref name="Thakur1999">{{cite journal | author=Thakur CP, Singh RK, Hassan SM, Kumar R, Narain S, Kumar A | title=Amphotericin B deoxycholate treatment of visceral leishmaniasis with never modes of administration and precautions: a study of 938 cases | journal=Trans R Soc Trop Med Hyg | volume=93 | pages=319–23 }}</ref> in its various preparations ([[Amphotericin B|Ambisome]]®,<ref name="Thakur1996">{{cite journal | author=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 | year=1996 | volume=90 | pages=319–22 }}</ref> [[Amphotericin B|Abelcet]]®, [[Amphotericin B|Amphocil]]®<ref name="Sundar2006">{{cite journal | author=Sundar S ''et al.'' | title=Amphotericin B Colloidal Dispersion for the Treatment of Indian Visceral Leishmaniasis | year=2006 | journal=Clin Infect Dis | volume=42 | issue=5 | pages=608–13 }}</ref>)
| |
|
| |
| *AmBisome dose: total dose 21mg/kg (Mediterranean/Brazilian VL); total dose 7.5mg/kg over 6 days (Indian VL)
| |
| *Amphocil dose: total dose 7.5mg/kg over 6 days (Indian VL)
| |
| A low dose (0.5–1mg/kg) is given on the first day, increasing to 1–2mg/kg on the second day, followed by 1.5–3mg/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 hospitalisation is avoided, which makes it a drug of choice.
| |
|
| |
| The nonprofit Institute for OneWorld Health has developed the drug [[paromomycin]], which they claim is effective and cheap. A treatment with paromomycin will cost about $10. The drug had originally been identified in th 1960's, but had been abandoned because it would not be profitable, as the disease mostly affects poor people.<ref>[http://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 in August 2006.<ref>[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'', Sept 8, 2006.</ref>
| |
|
| |
| ==History and epidemiology==
| |
| ''See also [[leishmaniasis#History|History of leishmaniasis]]''
| |
|
| |
|
| Kala-azar first came to the attention of Western doctors in 1824 in Jessore, India, where it was initially thought to be a form of [[malaria]]. India gave kala-azar its common name, which is the Hindi for “black fever”, 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''.
| | [[Visceral leishmaniasis history and symptoms|History and Symptoms]] | [[Visceral leishmaniasis physical examination|Physical Examination]] | [[Visceral leishmaniasis laboratory findings|Laboratory Findings]] | [[Visceral leishmaniasis other diagnostic studies|Other Diagnostic Studies]] |
|
| |
| 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, and a slightly different strain of the pathogen, ''L. chagasi'', is responsible for leishmaniasis in the new world.
| |
|
| |
|
| 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.<ref name="Jean1995">{{cite journal | author= Jean, Francois | year=1995 | journal= Life, Death and Aid: The Medicins Sans Frontieres Report on World Crisis Intervention | title= Sudan: Speak no Evil, Do no Good}}</ref>
| | ==Treatment== |
|
| |
|
| 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">{{cite journal | author= Jean, Francois | year=1995 | journal= Life, Death and Aid: The Medicins Sans Frontieres Report on World Crisis Intervention | title= Sudan: Speak no Evil, Do no Good}}</ref>
| | [[Visceral leishmaniasis medical therapy|Medical Therapy]] | [[Visceral leishmaniasis primary prevention|Primary Prevention]] | [[Visceral leishmaniasis secondary prevention|Secondary Prevention]] | [[Visceral leishmaniasis cost-effectiveness of therapy|Cost-Effectiveness of Therapy]] | [[Visceral leishmaniasis future or investigational therapies|Future or Investigational Therapies]] |
|
| |
|
| 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 Medicins Sans Frontieres, “Where else in the world could 50% of a population die without anyone knowing?”<ref name="Dowell1997">{{cite journal | author= Dowell, William | year=1997 | journal=Time| title= Rescue in Sudan}}</ref>
| | ==Case Studies== |
| | [[Visceral leishmaniasis case study one|Case #1]] |
|
| |
|
| The world’s failure to notice the epidemic was not due solely to its primitive setting, but also to the realities of politics. When, in 1991, a group of Sudanese researchers with the [[World Health Organization]] warned of a coming kala-azar epidemic and proposed the construction of a treatment center, the Sudanese government stepped in and denied the existence of any epidemic. At war with its own people, the government in Khartoum did not wish to have foreigners aiding the population, and preferred to use limitations on foreign aid as a means of political control. The WHO, a non-governmental organization, could do nothing in the face of opposition from its host government, and so nothing was done. For much of the nineties, Medecins Sans Frontieres battled the disease essentially alone, working not only without borders but without hospitals or visas.<ref name="Jean1995">{{cite journal | author= Jean, Francois | year=1995 | journal= Life, Death and Aid: The Medicins Sans Frontieres Report on World Crisis Intervention | title= Sudan: Speak no Evil, Do no Good}}</ref>
| | ==Related Chapters== |
| | |
| == See also==
| |
| *[[Leishmaniasis]] | | *[[Leishmaniasis]] |
| *[[Leishmania]] | | *[[Leishmania]] |
| Line 85: |
Line 44: |
| *[[Malaria]] | | *[[Malaria]] |
|
| |
|
|
| |
| ==References==
| |
| {{Reflist|2}}
| |
| {{SIB}}
| |
| {{Protozoal diseases}} | | {{Protozoal diseases}} |
|
| |
|
| Line 94: |
Line 49: |
| {{WikiDoc Sources}} | | {{WikiDoc Sources}} |
|
| |
|
| | [[Category:Disease]] |
| [[Category:Parasitic diseases]] | | [[Category:Parasitic diseases]] |
| [[Category:Neglected diseases]] | | [[Category:Neglected diseases]] |
| [[Category:Infectious disease]]
| |
