Visceral Leishmaniasis

John D. Cahill, MD

History

In 1900, Major William Leishman performed a postmortem on an English soldier returning from Bengal who had died of "fever." He described finding enormous numbers of oval bodies 2 to 3 microns in diameter in the splenic smears of this patient. In 1903, Captain James Donovan in Madras, described similar findings in the splenic smears taken from the enlarged spleens of Indian patients who had died, presumably from malaria. It was Ronald Ross who named the new protozoa the Leishman Donovan body. (1)

Epidemiology

The World Health Organization estimates that there are 500,000 new cases of visceral leishmaniasis occurring annually. This number is probably grossly underreported, secondary to poor surveillance systems. Ninety percent of cases are found in Bangladesh, India, Nepal, Sudan, and Brazil. There are 3 distinct species: L. infantum - found in the Mediterranean basin, Central Asia and China, L. donovani - in India and Eastern Africa, and L. chagasi - in South and Central America. Leishmania are members of the family Trypanosomatidae, order Kinetoplastida.

The reservoir of infection is the amastigote form of the parasite, present in animal reservoir hosts such as rodents, dogs, foxes, jackals, and humans. Dogs are especially common reservoirs in the Mediterranean basin. The infection is usually transmitted by the bite (blood feed) of the female sandfly, although human infection has been reported from blood transfusion, congenital transmission, and by sexual intercourse. In the sandfly vectors and on culture, the parasite takes up the promastigote form.

Many different strains of leishmania can cause disease in humans with each strain differing in its reservoir, vector, geographic location, and in the pathological lesions that it gives rise to. (Cutaneous Leishmaniasis will not be discussed here.)

Pathogenesis

When the promastigote are injected into humans, they are rapidly taken up by macrophages in which they revert to the amastigote form. What then occurs depends on the cell mediated response of the host. In endemic situations there are about 30-100 subclinical infection for every case of visceral leishmaniasis. (2) If spontaneous recovery follows, the patient's cell mediated immunity increases. Such patients will develop a delayed sensitivity response resembling the tuberculin reaction if a suspension of killed promastigotes is injected intradermally. This is known as the leishmanin or Montenegro test.

If the individual is unable to mount an appropriate immune response, the parasite disseminates in the reticuloendothelial cells of the body. The incubation period can vary from 3 _ 18 months. However, the parasite may remain dormant and not present itself until one has a compromised immune system. (3)

Clinical Presentation

Patients tend to present with fever and impressive splenomegaly. Despite high fevers, patients usually feel quite well. Cough is not an uncommon symptom. An immune complex reaction can occur leading to uveitis and nephritis. In India, increase skin pigmentation occurs. Laboratory studies demonstrate a pancytopenia (normochromic/normocytic anemia, leukopenia, and thrombocytopenia), hypergammaglobinemia, and a low albumin. In endemic regions, pediatric cases are more common. As the disease progresses concurrent infections are common: TB, measles, pneumonia, and brucellosis, for example. Co-infection with HIV is becoming more common in the Mediterranean region and in Brazil. Malabsorption and malnutrition may also be seen. Atypical presentations are common in this population and amastigotes may be found in any organ. Treatment can be difficult, with relapses not uncommon.

Diagnosis

Most patients can be readily diagnosed by directly visualizing the amastigotes in a splenic aspirate. The procedure is relatively simple, tolerated well by most patients, and very rewarding when the diagnosis is made underneath the microscope. One needs to ensure that the platelets and coagulation profile is within normal limits before undertaking this procedure. Amastigotes can also be directly visualized in bone marrow and lymph nodes. A non specific test is the Formol gel test, which is based upon the hyperglobinemia state of the patient. This author finds the Leishmanin skin test to be of little use in the initial diagnosis. More difficult or expensive tests available include: ELISA, DAT (direct agglutination test), or culture of the promastigotes on NNN or Schneider's medium.

Treatment & Prevention

The mortality approaches 90% for untreated patients, whereas most patients will recover if treated. Treatment for visceral leishmaniasis is expensive and complicated by the fact that current medications are given IV or IM. Traditionally the pentavalent antimony compounds such as Sodium stibogluconate (Pentostam) and Meglumine antimonate (Glucantime) are used. Sodium stibogluconate is available from the CDC in the USA. Duration of treatment for all these agents is generally 28 days. Potential side effects include malaise, GI upset, pancreatitis, prolongation of the QT interval, and headache. (4) Amphotericin B desoxycholate and Liposomal Amphotericin B may also be used. Aminosidine (Paromomycin) can be used alone or along with the pentavalent antimonials for its synergistic action. The first oral agent, Miltefosine is currently undergoing trials. Treatment must also address concurrent infections, anemia, and the nutritional status of the patient.

Post Kala Azar Dermal Leishmaniasis is caused by L. donovani and presents with cutaneous eruption of skin nodules or depigmented macules. It is more commonly seen several months to years after treatment in India and East Africa. The Indian variant may last for years and the African variant usually resolves within months. This syndrome can be quite disfiguring and may be mistaken for leprosy.

Prevention is best accomplished by eliminating the reservoirs. Insecticide should be used to decrease the amount of sand flies. Personal protection with repellants, permethrin-impregnated bed nets, and suitable clothing. Individuals should be advised to, ideally, sleep on the second floor of a building, since the flight of the sandfly is limited to 10 feet.

References

1. Cahill KM, O'Brien W. Tropical Medicine A Clinical Text. Mount Salus Press, Dublin ,1989, p33-34.
2. Desjeux P: Human leishmaniasis: Epidemiology and public health aspects. World Health Stat Q 45:267-275, 1992.
3. Pampiglione S, Manson-Bahr PEC, Giungi F, Giunti G, Parenti A, Canestri TG. Studies on Mediterranean Leishmaniasis, Asymptomatic cases of visceral leishmaniasis. Trans R Soc Trop Med Hyg 1974;68:447-453.
4. Ho M, Siongok TK, Lyerly WH, Smith DH. Prevalence and disease spectrum in a new focus of visceral leishmaniasis in Kenya. Trans R Soc Trop Med Hyg 1982;76:741-746.
5. Gasser RA, Jr., Magill AJ, Oster CN, et al: Pancreatitis induced by Pentavalent antimonials agents during treatment of leishmaniasis Clin Infect Dis 18:83-90, 1994.

John is a member of the Department of Infectious Disease and Emergency Medicine, Brown University School of Medicine, Providence, Rhode Island, USA. He has contributed several articles to NewsShare.