Visceral leishmaniasis
Visceral leishmaniasis kālā āzār | |
---|---|
Other names | Black fever, and Dumdum fever[1] |
Amastigotes in a chorionic villus | |
Pronunciation |
|
Specialty | Infectious diseases |
Visceral leishmaniasis (VL), also known as kala-azar (
The parasite migrates to the internal organs such as the
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.[5][6]
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.[7]
Signs and symptoms
When people develop visceral leishmaniasis, the most typical symptoms are
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.)[8]
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 L. donovani and the species found in Europe, North Africa, and Latin America is L. infantum, also known as L. chagasi.[9]
The insect
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 seymouri (LS). The latter parasite (LS) further contained a 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 a RNA virus in LS, the co-infecting parasite with LD i.e. the "LD-LS-Lepsey NLV1 triple pathogen" phenomenon.[11][12]
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
Once inside the human host, promastigotes invade
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
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.
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.[21] IL-10 levels are elevated in B cells from VL PBMC.[27] A study of dogs with naturally acquired VL showed that the percentage of regulatory B cells increased three-fold during VL.[30] 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 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.[citation needed]
Diagnosis
The gold standard for diagnosis is visualization of the
The K39 dipstick test is easy to perform, and village health workers can be easily trained to use it. The kit may be stored at ambient temperature and no additional equipment needs to be carried to remote areas. The DAT anti-leishmania antigen test, standard within MSF, is much more cumbersome to use and appears not to have any advantages over the K39 test.[33]
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.[34][35] 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.[36] Likewise, patients with abnormal immune systems (e.g., HIV infection) will have false-negative tests.[37]
Other tests being developed include detects erythrosalicylic acid.[36]
Prevention
As of 2018, there are no vaccines or preventive drugs for visceral leishmaniasis, but vaccines are in development.[38][39] 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:[citation needed]
- Outdoors:
1. Avoid outdoor activities, especially from dusk to dawn, when sand flies generally are 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)."[38]
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.[40]
The traditional treatment is with pentavalent antimonials such as sodium stibogluconate and meglumine antimoniate. Resistance is now common in India, and rates of resistance have been shown to be as high as 60% in parts of Bihar, India.[41][42]
The treatment of choice for visceral leishmaniasis acquired in India is now amphotericin B[43] in its various liposomal preparations.[44][45] In East Africa, the WHO recommended treatment is SSG&PM (sodium stibogluconate and paromomycin) developed by Drugs for Neglected Diseases initiative (DNDi) in 2010.[46]
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 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, in Germany in 2004 and in U.S.A. in 2014.
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[48] 2) it is teratogenic and cannot be used in women of child-bearing age without anticonception during and for 4 months after treatment.[citation needed]
Incomplete treatment has been cited as a major reason of death from visceral leishmaniasis.[3]
The nonprofit
Prognosis
Protective immunity
Immunity to Leishmania is determined by the interplay of
Leishmania antigen stimulation of PBMC from cured patients show a mixed T helper cell and
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
Epidemiology
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.
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
History
Kala-azar first came to the attention of Western doctors in 1824 in
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
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
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 systems 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?"[83] Due to the South Sudanese Civil War, kala-azar has spread rapidly among the population.[84]
The Indian medical practitioner Upendra Nath Brahmachari was nominated for the Nobel Prize in Physiology or Medicine in 1929 for his discovery of ureastibamine (an antimonial compound for the treatment of kala-azar) and a new disease, post kala-azar dermal leishmaniasis.[85] Brahmachari's cure for visceral leishmaniasis was the urea salt of para-amino-phenyl stibnic acid which he called Urea Stibamine.[86]
During the nineteenth century, kala-azar was discovered near moving bodies of water in southeast Asia.[87] Dr. Jean Dow and Dr. 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.[88] This work continued under Ernest Struthers and Lionel Napier at the School of Tropical Medicine at Calcutta to discover that kala-azar was transmitted by sandflies.[89][90]
On 31 October 2023, Bangladesh has been declared to be the first country to totally eradicate the disease.[91]
Research
Combination drug therapies are currently under investigation, particularly by the
DNDi has a number of compounds in preclinical and phase 1 development,[94] but no novel drugs are expected in the next 5 years.[95] 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.[96][97][98]
A 2018 study published details of a new potential preclinical drug candidate for the treatment for visceral leishmaniasis with an anti-leishmanial drug-like chemical series based on a pyrazolopyrimidine scaffold.[99]
There is no good vaccine candidate which prevents kala azar. A 2019 paper described designing an immunologic adjuvant which would make a VL vaccine more effective.[100]
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