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Synonyms: cutaneous leishmaniasis, visceral leishmaniasis, kala azar, Dum Dum fever
This is a parasitic infection caused by a protozoan of the genus Leishmania.
- There are up to 24 different species. Different species cause different clinical forms of the disease in various parts of the world.
- It is transmitted by the bite of the sandfly. There are about 1,000 different species of sandfly of which around 70 can transmit the disease. The sandfly bites a human or other mammal and is infected.
- The protozoan multiplies in the insect vector and is then inoculated into another mammalian recipient, possibly a human.
- The protozoan is engulfed by macrophages but may survive and even replicate inside them. The manifestation of the disease is due to an imbalance between the virulence of the organism and the defences of the host.
- The most common affected areas are: the Mediterranean, India, Bangladesh, Brazil and Sudan.
The cutaneous form affects just the skin and possibly the mucous membranes. The visceral form is more generalised, especially in the reticuloendothelial system. Kala azar is a Hindi word applied to the visceral form.
- Each year there are about 1.5 million new cases of cutaneous disease and 0.5 million new cases of visceral disease.
- There are 2 cases annually seen in the UK which usually result from travel to the Mediterranean.
- More than 12 million people in 88 countries are known to be infected but many cases are asymptomatic. Furthermore, reporting is far from complete in many areas and true numbers are almost certainly very much higher.
- It causes 70,000 deaths a year worldwide.
- The male to female ratio is about 2:1, probably due to greater exposure to places where there is a risk of sandfly bites.
Usually transmission is by the bite of the female sandfly. In some areas there are animal reservoirs but in others humans are the only mammalian source. It is a disease associated with poverty.
Other risk factors include:
- Poor housing and sanitation
- HIV infection
- Rarely - through sharing of needles, sexual intercourse, transplacental infection, organ transplantation
Presentation will vary significantly according to the species of infection and the location in the world. The following are generalisations:
Cutaneous leishmaniasis (CL)
- Lesions tend to occur on exposed parts which are easily bitten by sandflies.
- In the New World they are usually solitary lesions but in the Old World they are often multiple.
- They start as erythematous patches but change to plaques or ulcers that are usually painless unless there is secondary bacterial infection.
- These lesions often heal spontaneously in anything from 2 to 15 months, depending largely upon the species involved.
- They may leave pigmentation and scars.
- New World disease may progress to mucocutaneous leishmaniasis (MCL).
Diffuse cutaneous leishmaniasis
- Occurs with a poor immune response.
- There is a primary lesion which spreads to involve multiple areas of the skin.
- Plaques, ulcers and nodules may form over the entire body.
- It may look similar to lepromatous leprosy but there is no involvement of nerves and there is no systemic invasion.
- Infection is chronic and may recur despite treatment.
- Can occur years after a cutaneous lesion has healed and is often on the face.
- New ulcers and papules form over the edge of the old scar.
- Dormant parasites or new infection may be the cause but these infections tend to be resistant to treatment.
Post-kala azar dermal leishmaniasis
- Found mostly in Africa and India.
- In the Indian variety it occurs several years after recovery from visceral leishmaniasis and presents as multiple, hypopigmented, erythematous macules.
- With time, they can become large plaques and nodules on the face and trunk and it looks similar to lepromatous leprosy.
- The African form starts soon after treatment of visceral leishmaniasis (VL) and shows an erythematous papular rash on the face, buttocks, and extremities.
- The African form heals spontaneously over several months but the Indian form requires intensive treatment.
- Usually from New World species of sandfly.
- Initial infection gives a persistent cutaneous lesion that eventually heals, although 30% deny previous leishmaniasis.
- Several years later the oral and respiratory mucosa is involved, with inflammation and mutilation of the nose, mouth, oropharynx, and trachea.
- It may arise after inadequate treatment of some species.
- Respiratory difficulties and malnutrition can cause death.
Visceral leishmaniasis (VL)
- VL is more devastating and more likely to be fatal.
- It can occur in both Old and New World disease.
- In Africa a cutaneous nodule may precede systemic disease by weeks or months, but is rare in other parts of the world.
- There is infection of the liver, spleen and bone marrow to produce the classical features of:
- Night sweats, weakness and anorexia, which are typical
- Weight loss
- Hepatomegaly (can be marked)
- Splenomegaly (often enormous)
- Pancytopenia (can lead to death from haemorrhage or infection)
- Dark pigmentation of the skin is uncommon but the name kala azar is Hindi for black fever
- Cutaneous leishmaniasis (CL) may look like other skin diseases, especially lepromatous leprosy, but also sarcoidosis.
- Visceral leishmaniasis (VL) may resemble malaria or haematological malignancies.
- Diagnosis is based on identification of the organism in tissue samples or culture. The specimen should show parasites at the stage of amastigotes in the form of Leishman-Donovan bodies.
- Cutaneous leishmaniasis (CL) requires a punch or wedge biopsy from the raised edge of an active lesion where the parasites are most likely to be present. The necrotic centre is unlikely to yield results.
- Saline aspiration, scalpel scrapings, or slit incisions can also provide samples.
- Microscopy and culture are about 85% sensitive.
- In mucocutaneous leishmaniasis (MCL), dental scrapings or mucosal granuloma biopsy can be used but parasites may be difficult to find.
- In visceral disease, bone-marrow aspiration is the safest technique, although splenic aspiration may be used in difficult cases. Splenic aspiration has a higher sensitivity but greater risks.
- Contra-indications to splenic aspiration include low platelet count, abnormal prothrombin time, and a spleen palpable 4 cm or more below the costophrenic angle.
- Liver biopsy and lymph node dissection may also provide material.
- Various serological tests are available, but most cutaneous cases do not develop a significant antibody response. They are attractive as they require less resources than tissue diagnosis.
- There are 2 serological tests - direct agglutination test (DAT) and Ks30 dipstick, currently under investigation. Both appear to perform well in a meta-analysis. However, their main downside is that they remain positive for years after successful therapy. Other tests are also under design.
- In CL most usual blood parameters will be normal but in visceral leishmaniasis (VL) there will be pancytopenia on FBC, elevated globulin and slight abnormality of LFTs. Prothrombin time should be normal.
- Since the 1930s the mainstay of treatment has been pentavalent antimony compounds. The main one is sodium stibogluconate.
- In Bihar state the response rate to antimony has fallen to 35% compared with 90% elsewhere and so alternatives are required. Bihar includes about 90% of cases in India and 45% worldwide.
- In the cutaneous leishmaniasis (CL) types that heal spontaneously the question is whether any treatment should be offered, especially as it can be quite toxic.
- New World CL may progress to mucocutaneous disease and so should be adequately treated. Old World CL may be left alone or treated if lesions are slow to heal or disfiguring.
- Topical treatment is more desirable for local disease and options include injection of antimonials into the border of the lesion, cryosurgery, ultrasound-induced local hyperthermia, excision, topical 15% paromomycin sulfate/12% methylbenzethonium chloride in white paraffin. Topical treatments must penetrate the dermis.
- In visceral leishmaniasis (VL) the prognosis is so much worse that treatment is required.
- Sodium stibogluconate is usually diluted in a large quantity of 5% dextrose and run in IV over about 15 minutes to prevent thrombophlebitis. This is done daily for 20 to 30 days.
- Chemical pancreatitis, nausea and abdominal pain, arthralgia and fatigue are common. ECG changes may occur.
- Where there is resistance to pentamidine, amphotericin B is effective. It can be given in a liposomal formulation that is less toxic and requires only 5 to 10 days of treatment or even as a one-off stat dose. In India it is 90% effective.
- Ketoconazole, itraconazole, fluconazole, allopurinol, and dapsone are all less effective than the previously mentioned drugs.
- Miltefosine is the first oral treatment, and lacks the serious reactions associated with other drugs. Experience is still limited but results are promising. One advantage appears to be that it is safe to use in an outpatient setting.
- In VL attention should also be paid towards adequate nutrition to enhance the immune system.
- In mucocutaneous disease, plastic surgery may be required.
- In visceral leishmaniasis (VL) about 90% of patients will improve whilst 10% will die. As they improve they become afebrile, blood parameters improve and the spleen shrinks.
- Between 5 and 10% of those cured will relapse within 6 months.
- Untreated VL has a mortality rate of between 75 and 95%.
- Malnutrition and tuberculosis are complications.
- Control of reservoir hosts and sandfly vectors involves spraying with insecticide, including indoors.
- Avoid being bitten by sandflies by using repellants, long sleeves and trousers and mosquito nets. Nets impregnated with insecticide are best. The creature is very small and so a small mesh net is required. This may reduce the circulation of air and be uncomfortable at night in hot climates.
- No vaccine is yet available but there are hopes for the fairly near future.
- Old World cutaneous leishmaniasis (CL), or oriental sore, has been described in texts dating back to 1500-2500 BC. Arab physicians provided more detailed descriptions in the 10th century.
- James Homer Wright (1869-1928), American pathologist, who is also remembered for his eponymous blood stain, and Homer Wright pseudorosettes of neuroblastoma, is generally credited with identification of the parasite.
- Old World visceral leishmaniasis (VL), kala azar, was first described in 1824 in what is now Bangladesh, and the parasite, L. donovani, was discovered by Leishman and Donovan independently in 1900. The name was suggested by Sir Ronald Ross.
- Sir William Leishman (1865-1926), Director General of the Royal Army Medical Corps, was a Glaswegian, and was more famous at the time for his work on an antityphoid vaccine, which successfully protected troops in World War I. He also developed his eponymous stain for the staining of malaria, trypanosomes, and other blood parasites. It was in his honour that the group of diseases caused by trypanosomes was renamed leishmaniasis.
- Charles Donovan was Professor of Physiology at Madras University.
- The identification of the vector involved took much longer, and it was not until 1921 that proof of transmission by sandflies was made. This was followed by proof of infection via the bite of the sandfly in 1941.
Further reading & references
- Essential leishmaniasis maps, World Health Organization, Oct 2003
- Malekpour M, Esfandbod M; Images in clinical medicine. Cutaneous leishmaniasis. N Engl J Med. 2010 Feb 11;362(6):e15.
- Leishmaniasis, background information, World Health Organization
- Desjeux P; The increase in risk factors for leishmaniasis worldwide. Trans R Soc Trop Med Hyg. 2001 May-Jun;95(3):239-43.
- Lockwood DN, Sundar S; Serological tests for visceral leishmaniasis. BMJ. 2006 Oct 7;333(7571):711-2.
- Chappuis F, Rijal S, Soto A, et al; A meta-analysis of the diagnostic performance of the direct agglutination test and rK39 dipstick for visceral leishmaniasis. BMJ. 2006 Oct 7;333(7571):723. Epub 2006 Aug 1.
- Garnier T, Croft SL; Topical treatment for cutaneous leishmaniasis. Curr Opin Investig Drugs. 2002 Apr;3(4):538-44.
- Dube A, Singh N, Sundar S, et al; Refractoriness to the treatment of sodium stibogluconate in Indian kala-azar field isolates persist in in vitro and in vivo experimental models. Parasitol Res. 2005 Jun;96(4):216-23. Epub 2005 May 3.
- Berman J; Recent Developments in Leishmaniasis: Epidemiology, Diagnosis, and Treatment. Curr Infect Dis Rep. 2005 Jan;7(1):33-38.
- Sundar S, Chakravarty J, Agarwal D, et al; Single-dose liposomal amphotericin B for visceral leishmaniasis in India. N Engl J Med. 2010 Feb 11;362(6):504-12.
- Jha TK, Sundar S, Thakur CP, et al; Miltefosine, an oral agent, for the treatment of Indian visceral leishmaniasis. N Engl J Med. 1999 Dec 9;341(24):1795-800.
- Bhattacharya SK, Sinha PK, Sundar S, et al; Phase 4 trial of miltefosine for the treatment of Indian visceral leishmaniasis. J Infect Dis. 2007 Aug 15;196(4):591-8. Epub 2007 Jun 29.
- Murray HW, Berman JD, Davies CR, et al; Advances in leishmaniasis. Lancet. 2005 Oct 29-Nov 4;366(9496):1561-77.
- Coler RN, Reed SG; Second-generation vaccines against leishmaniasis. Trends Parasitol. 2005 May;21(5):244-9.
- New Vaccines against Infectious Diseases; Research and Development Status IVR, WHO, April 2005, updated February 2006.
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Dr Gurvinder Rull
Dr Gurvinder Rull