Case presentation

Case presentation Case 15 Reporter: I2 姚信宇 Date: 94/11/14

Chief complaint, present illness, & personal/past/family history • A 24-year-old male Pakistani medical resident was seen in the emergency department at midnight; he was acutely ill with weakness, fever, abdominal pain, and diarrhea. • He had visited relatives in Pakistan several months earlier. • He had recently lost 20 lb inexplicably.

Physical examination • Physical examination revealed hepatomegaly, splenomegaly, and lymphadenopathy. • The patient had darkened areas of skin on his forehead and around his mouth.

Laboratory tests • Anemic, with a hemoglobin level of 10 g/dl. • Leukopenia and thrombocytopenia. • Liver enzyme levels were slightly elevated. • Giemsa-stained buffy coat smears: a few macrophages containing oval, nonflagellatedprotozoan forms, about 2 to 3 μm long(Fig.15.1). A large nucleus, a small kinetoplast, and an axoneme were visible in several parasites.

Fig.15.1

Leishmaniasis (利什曼原蟲病) • Intracellular amastigotes in macrophages of humans and other mammalian hosts . • Extracellularpromastigotes in the gut of sandfly vectors.

Leishmaniasis (利什曼原蟲病) • In humans and other susceptible mammals: in cells of reticuloendothelial origin as intracellular amastigotes, which are 2 to 3 m in length, oval or round, and lack an flagellum.

Leishmaniasis (利什曼原蟲病) • In Wright- and Giemsa-stain:  the cytoplasm appears blue.  the nucleus is relatively large, eccentrically located, and red.  the distinct, rod-shaped, red-staining kinetoplast (a specialized mitochondrial structure) contains extranuclear DNA arranged as catenated minicircles and maxicircles.

1. Amastigotes in a bone marrow specimen from a patient with visceral leishmaniasis. 2. Each amastigote has a nucleus and kinetoplast. 3. Visualization of the kinetoplast is essential in differentiating leishmaniasis from diseases such as histoplasmosis.

Leishmaniasis (利什曼原蟲病) • Anti-leishmanial antibodies and complement are deposited on the parasite surface. • Promastigotes are phagocytosed by macrophages. Promastigotes convert within them to amastigotes. • Amastigotes are released and infect other mononuclear phagocytes. • Cell-mediated immune response (predominant Th1 response).

Visceral Leishmaniasis (內臟型利什曼原蟲病) • Etiology:  Typical:L. donovani(Indian subcontinent, northern and eastern China, Pakistan, Nepal, eastern Africa), L. infantum(Middle East, Mediterranean littoral, Balkans, central and southwestern Asia, northern and western China, North and sub-Saharan Africa), and L. chagasi (Latin America)  Atypical: L. amazonensis (Latin America) or L. tropica (Middle East or Africa).

Visceral Leishmaniasis (內臟型利什曼原蟲病) • The incubation period: usually 3 to 8 months. • Symptoms/Signs: fever, weight loss, discoloration of skin (hands, feet, abdomen, or face), anemia, hepatosplenomegaly, leukopenia, and hypergammaglobulinemia. • The condition is known as kala-azar (黑熱病).

Question 1 • Which infection does this patient have? What is the name of the hemoflagellate? Which is causing his infection?

Answer 1 • Due to the patient’s symptoms & signs, visceral leishmaniasis causes the patient’s infection.

Question 2 • Name the three species belonging to this complex. In which parts of the world are these species located?

Answer 2 • L. donovani: Indian subcontinent, northern and eastern China, Pakistan, Nepal, eastern Africa. • L. infantum: Middle East, Mediterranean littoral, Balkans, central and southwestern Asia, northern and western China, North and sub-Saharan Africa. • L. chagasi: Latin America

Question 3 • Which vectors are responsible for the transmission of this infection?

Answer 3 • Transmission is by Phlebotomus argentipes and other anthropophilic Phlebotomus spp. (白蛉).

Question 4 • List four forms of infection caused by this genus of hemoflagellates. How does this patient's infection differ from the other three?

Answer 4 • Cutaneous leishmaniasis:  typically there is, first, a papule, which enlarges, becomes crusted, and then ulcerates. Ulcers have a diameter of about 2 cm and an indurated border.  regional lymphadenopathy is common.  patients usually have no fever,

1. Ulcerative skin lesions with raised outer borders on the arm of a patient with New World (American) cutaneous leishmaniasis acquired in Costa Rica.

Diffuse cutaneous leishmaniasis:  observed in Ethiopia, Venezuela, Brazil, and the Dominican Republic.  the lesions are widespread and typically remain as macules or papules without ulceration.  the mucous membranes may be involved, but not the viscera.  lesions contain sparse lymphocytes, and there is cutaneous anergy to leishmanial antigens.

Mucocutaneous leishmaniasis (espundia):  caused by L. braziliensis and is especially prevalent in Brazil south of the Amazon.  in patients with cutaneous lesions the likelihood of subsequent mucous membrane involvement is about 80%.  more than 90% of patients with espundia have scars of previous cutaneous involvement.  nasal lesions tend to destroy the cartilage of the septum and spread to the buccal mucosa, pharynx, and larynx.

Question 5 • How is the diagnosis of this infection made?

Answer 5 • Definitive diagnosis: amastigotes in tissue or the isolation of promastigotes in culture. • Antileishmanial antibodies: high titer in immunocompetent patients with visceral leishmaniasis. • ELISA (recombinant L. chagasi antigen rk39): highly sensitive and specific in detecting visceral leishmaniasis in immunocompetent persons.

The leishmanin (Montenegro) skin test:  negative results in patients with progressive visceral leishmaniasis.  the result becomes positive in the majority of persons in whom infection spontaneously resolves and in those who have undergone successful chemotherapy.

Differential diagnosis • Acute stage: malaria, typhoid fever, typhus, acute Chagas' disease, schistosomiasis, miliary tuberculosis, or amebic liver abscess. • Subacute or chronic stages: brucellosis, Salmonella bacteremia, histoplasmosis, infectious mononucleosis, hepatosplenic schistosomiasis, and splenomegaly due to chronic malaria.

Question 6 • What is the significance of the time of day (midnight) at which the patient was seen in the emergency department?

Answer 6 • The incubation period is usually in the range of 3 to 8 months.

Question 7 • What causes the enlargement of the liver and spleen?

Answer 7 • Large numbers of amastigote-infected mononuclear phagocytes in the liver and spleen result in progressive hypertrophy. • The spleen: massively enlarged as splenic lymphoid follicles are replaced by parasitized mononuclear cells. • The liver: marked increase in the number and size of Kupffer cells, many of which contain amastigotes.

Question 8 • What causes the anemia and leukopenia characteristic of this infection?

Answer 8 • Anemia:  severe; normocytic and normochromic.  hemolysis, marrow replacement with leishmania-infected macrophages, hemorrhage, splenic sequestration of erythrocytes, hemodilution, and effects of cytokines such as TNF-alpha. • Leukopenia:  increased margination, splenic sequestration, or an autoimmune process.

Question 9 • Which complication may occur in this infection?

Answer 9 • Post-kala-azar dermal leishmaniasis:  follows the treatment of visceralleishmaniasis in a subset of persons in Africa and India.  the skin lesions vary from hyperpigmented macules to frank nodules.  they are found on the face, trunk, extremities, oral mucous membranes, and occasionally, on the genitals.

Question 10 • How is this infection treated?

Answer 10

References • Harrison's Principles of Internal Medicine - 16th Ed. (2005) • Internal Medicine, Stein - 5th Ed. (1998) • Schlossberg: Current Therapy of Infectious Disease

Case presentation