Leishmaniasis
Prevalence, Epidemiology, and Life Cycle
Leishmania has caused major epidemics in eastern India, Bangladesh, and East Africa. Urban outbreaks have been reported in the cities of northeastern Brazil.
A small number of American military personnel contracted leishmaniasis during the Persian Gulf War in 1991 and in Afghanistan more recently. Indigenous cases have been reported occasionally in the United States, but most U.S. cases result from travel to a tropical country.
Leishmaniasis has emerged as an opportunistic infection in patients with HIV or an organ transplant.
The Leishmania parasite is transmitted by the female phlebotomine sandfly. Sandflies breed in cracks in the walls of dwellings, in rubbish, and in rodent burrows. Because they are weak fliers, sandflies remain close to the ground near their breeding sites, resulting in localized pockets of infectious insects.
Potential Severity
Visceral leishmaniasis is a chronic disease that can cause severe morbidity and death in debilitated and immunocompromised hosts.
About the Epidemiology and Life Cycle of Leishmania
- Contracted in tropical areas where the phlebotomine sandfly is common; rare in the United States Found in South America, India, Bangladesh, the Middle East, and East Africa.
- Flagellated promastigote introduced by the sandfly is ingested by macrophages.
- In the macrophage, Leishmania develops into a nonflagellated amastigote that lives happily within the macrophage phagolysosome.
- This intracellular parasite is controlled by activation oftheThl cell-mediated immune response that increases levels of interferon 7.
- Leishmaniasis can be an opportunistic infection in patients with HIV or an organ transplant.
Humans and other animals infected with Leishmania serve as reservoirs. The sandfly bites the infected host and ingests blood containing the nonflagellated form called an amastigote. In the digestive tract of the insect, the amastigote develops into a flagellated spindle-shaped promastigote.
When the infected sandfly takes its blood meal from an uninfected human, the promastigote enters the host’s bloodstream.
The promastigote then binds to complement receptors on macrophages and is ingested. Within the phagolysosome the promastigote differentiates into an amastigote. The amastigote is resistant to lysozyme damage and depends on the lowpH of the phagolysosome for uptake of nutrients.
The parasite multiplies by simple division and eventually is released to infect other cells. Cell-mediated immunity plays an important role in controlling leishmaniasis. Interferon 7 activates macrophages to kill the amastigote by inducing the production of nitric oxide. Resolution of leishmanial infection is associated with the expression of CD4+ T cells of the Thl type, which secrete interferon 7 and interleukin 2.
Progression of infection is associated with Leishmania-induced expansion of CD4+ cells of the Th2 type that produce interleukin 4, a cytokine that inhibits the production of Thl cells and the activation of interferon 7 production.
Clinical Presentation
There are three forms of leishmaniasis: visceral, cutaneous, and mucosal. A single species can produce more than one syndrome, and each syndrome is produced by multiple different species.
Visceral Leishmaniasis (Kalaazar)
In different areas of the world, certain Leishmania species tend to be most commonly associated with the visceral form of the disease: L. donovani (in India), L. infantum (Middle East), L. chagasi (Latin America), and L. amazonensis (Brazil).
After inoculation of pro-mastigotes into the skin, a small papule may be noticed. Leishmania amastigotes subsequently silently invade macrophages throughout the reticuloendothelial system.
Usually 3 to 8 months pass before the burden of organisms increases to a level that causes symptoms. The onset of symptoms can be gradual or sudden. In subacute cases, the patient will experience slow but progressive enlargement of the abdomen as a result of hepatosplenomegaly. Increased abdominal girth is accompanied by intermittent fever, weakness, loss of appetite, and weight loss.
This presentation can be mistaken for lymphoma, infectious mononucleosis, brucellosis, chronic malaria, and hepatosplenic schistosomiasis. In acute cases, an abrupt onset of high fever and chills mimics malaria or an acute bacterial infection. On physical examination, the spleen may be massively enlarged, hard, and nontender. Hepatomegaly is also present. The skin tends to be dry and thin, and in light-skinned individuals, it takes on a grayish tint.
This characteristic accounts for the Indian name Kala-azar, which means “black fever.” On laboratory examination anemia, leukopenia, and hypergam-maglobulinemia are common. The diagnosis is made when a biopsy of lymphatic tissue or bone marrow demonstrates amastigotes on Wright or Giemsa stain.
Enzyme-linked immunoabsorbent assays usually demonstrate high anti-leishmanial antibody titers. However, this test frequently cross-reacts with antibodies to other pathogens. Patients with HIV infection frequently fail to develop antibody titers.
Splenomegaly may not be present in these patients, and infection may disseminate to the lungs, pleura, gastrointestinal tract, or bone marrow (causing aplastic anemia). In patients with HIV, amastigotes may be identified in macrophages from bronchoalveolar lavage, pleural effusion, bone marrow aspiration, or even buffy coat samples of the peripheral blood.
Cutaneous Leishmaniasis
The cutaneous form of leishmaniasis is widespread, and it is a problem chiefly for farmers, settlers, troops, and tourists in the Middle East and Central and South America. The species most commonly associated with cutaneous disease are L. major and L. tropica (found in the Middle East, India, Pakistan, and Asia), and L. mexicana, L. braziliensis, L. amazonensis, and L. panamensis (in Central and South America). L. mexicana has been reported in Texas.
About Visceral Leishmaniasis
- Incubation period is 3 to 8 months.
- Subacute onset presents with increased abdominal swellinig (because of massive splenomegaly and hepatomegaly), intermittent fever, and weight loss that can be mistaken for lymphoma or infectious mononucleosis
- Acute onset presents with persistent high fever mimicking bactermia or malaria.
- Anemia, leukopenia, and hypergammaglobu-linema are common.
- Diagnosis is made by biopsy and Giemsa stain showing amastgotes
- Patients with HIV may have disseminated disease without splenomegaly.
After a sandfly bite, significant skin lesions generally take 2 weeks to several months to develop. Lesions usually develop on exposed areas. They are the result of amastigotes multiplying in mononuclear cells within the skin and causing a granulomatous inflammatory reaction. Single or multiple lesions may be found, with varying morphology. Lesions may be crusted and dry, or moist and exudative.
Shallow and circular ulcers with sharp, raised borders may develop and progressively increase in size, becoming “pizzalike” in appearance as a result of the beefy red of the ulcer base being combined with a yellow exudate.
Lesions may become secondarily infected with staphy-lococci or streptococci. The diagnosis is made from a biopsy of the raised border of the skin lesion where Leishmania-inkcted macrophages are most abundant. Amastigotes are seen on Giemsa stain.
Mucosal Leishmaniasis
Mucosal leishmaniasis is a less common manifestation that is caused primarily by L. braziliensis. Only 2% to 3% of patients with skin lesions develop this complication. Organisms invade mononuclear cells in the mucosa. The nose is most commonly involved, resulting in nasal stuffiness, discharge, pain, or epistaxis. Later, the nasal septum is destroyed, and the nose collapses. Involvement of the genital mucosa and trachea have also been reported. Diagnosis is made by biopsy.
About Cutaneous and Mucosal Leishmaniasis
- A problem for farmers, settlers, troops, and tourists; incubation period is 2 weeks to 2 months.
- Found throughout the world; cases have been reported in Texas.
- Lesions occur primarily on exposed areas.
- Dry or moist in appearance, ulcers have sharp, raised boarders; “pizza-like” lesions are common.
- Mucosal disease is rarer, usually involves the nose.
- Diagnosis is made by biopsy, always from the border of skin lesions.
Treatment
The only drug approved in the United States for treatment of leishmaniasis is liposomal amphotericin B.
For visceral leishmaniasis in immunocompetent patients, administer 3 mg/kg daily on days 1 to 5, 14, and 21. The course can be repeated if the parasite persists.
For the immunocompromised host, the recommended regimen is amphotericin В 4 mg/kg daily administered on days 1 to 5, 10, 17, 24, 31, and 38. Relapses are common in HIV-infected hosts.
Outside the United States, pentavalent antimony continues be used; however, this treatment is associated with many side effects, including abdominal pain, anorexia, nausea and vomiting, and myalgias. Amylase and lipase levels often rise. Miltefosine, a phospho-choline analog has anti-leishmanial activity in vitro and in vivo, and acts by interfering with the parasite’s cell-signaling pathways and membrane synthesis. This agent has successfully treated Indian visceral disease. Treatment of cutaneous leishmaniasis depends on the location of the infection.
The lesions can heal spontaneously, and so, if there is no mucosal involvement and if the lesions are located in areas of no cosmetic concern, they can be followed without therapy or treated topically with 15% puromycin and 12% methylbenzethonium chloride.
Thermotherapy (warming the affected region with radiofrequency waves to 50°C for one treatment of 30 seconds) has proven effective in a high percentage of cases, and that approach compares favorably with 21 days of intralesional administration of pentavalent antimony.
Patients with mucosal involvement, progressive lesions, or lesions in cosmetically sensitive areas require treatment with intravenous or intramuscular pentavalent antimony (20 mg/kg daily for 20 days, available through the CDC). Fluconazole (500 mg twice daily for 6 weeks) has been associated with modest response rates. Miltefosine has proved successful against some forms of cutaneous leishmaniasis, but other species are refractory.
About the Treatment of Leishmaniasis
- Visceral disease: a) Liposomal amphotericin В is the only approved therapy. b) Miltefosine appears promising, but had not been approved in the United States at the time ofwriting.
- Cutaneous: a) May heal spontaneously. b) Thermotherapy is safe and effective. c) In cases of mucosal involvement, infection in a cosmetically sensitive site, or failure to heal, fluconazole or pentavalent antimony are recommended. d) Miltefosine effective for some Leishmania species, but not others.
Trypanosoma Cruzi
Potential Severity
A chronic disorder that can lead to fatal cardiomyopathy. Chagas’ disease caused by Trypanosoma cruzi is found throughout Central and South America. Between 16 and 18 million people worldwide are infected with T. cruzi, and nearly 0.5 million die from Chagas’ disease annually. With improvement of substandard housing, the incidence of this disease among young people is decreasing.
The parasite is transmitted by reduviid bugs that suck blood from their host. This insect contains trypo-mastigotes in its gut. At the same time that it bites the host, it also defecates, depositing trypomastigotes on the skin. The human host then scratches the itchy bite, introducing the parasite into the wound and subsequently into the bloodstream.
Mucous membranes, the conjunctiva, and breaks in the skin are common sites of entry. Once in the bloodstream, the trypomastigotes enter host cells and differentiate into amastigotes that multiply, filling the cell cytoplasm. They then differentiate again into trypomastigotes, and the cell ruptures, spreading the parasite to adjacent cells and into the bloodstream. Asymptomatic parasitemia is common. In endemic areas, the parasite can be transmitted by blood transfusions. Because the reduviid bug takes up residence in the cracks of primitive homes, this infection occurs almost exclusively among poor rural people.
The disease is most commonly transmitted in young children. If one member of a family presents with acute disease, all pediatric family members should be screened for asymptomatic disease. Chagas’ disease has not been reported in tourists, because they are unlikely to be exposed to primitive living quarters.
Vector control measures and educational programs have helped to reduce the incidence of disease. Insecticide impregnation of bed nets has proven to be an inexpensive and effective control measure. Acute Chagas’ disease often causes minimal symptoms. About 1 week after the parasite enters the skin, an area of localized swelling called a chagoma develops, often in association with local lymph node swelling.
Entry of the parasite via the conjunctiva causes periorbital edema (Romana’s sign). Onset of local edema is quickly followed by fever, malaise, anorexia, and edema of the face and legs. Occasionally, myocarditis or encephalitis may develop. Years to decades after the primary infection 10% to 30% of individuals go on to develop chronic Chagas’ disease.
The heart is the organ that is primarily damaged. Severe cardiomyopathy results in throm-boembolism, congestive heart failure, and life-threatening arrhythmias. Esophageal involvement can lead to megaesophagus associated with dysphagia, regurgitation, and aspiration pneumonia. Chagasic megacolon is another manifestation of chronic disease causing constipation and bowel obstruction that can lead to perforation and bacterial sepsis. In immuno-compromised hosts such as organ transplant patients and patients with AIDS, T. cruzi can reactivate, presenting with manifestations of chronic Chagas’ disease.
Unlike normal hosts, immunocompromised patients are also at risk for developing T. cruzi brain abscesses.
Key Points
About the Life Cycle of Trypanosoma Cruzi
- Transmitted by the reduviid bug, which carries thetrypomastigote in its feces.
- The host allows the parasite to enter the bloodstream by scratching and rubbing infected insect feces into the skin.
- The reduviid bug lives in the cracks of substandard housing.
- The disease affects mainly poor rural people, not tourists.
Diagnosis
Acute disease can be diagnosed by examining Giemsa-stained blood or buffy coat smears. The trypomastigotes (whose length is approximately twice the diameter of a red blood cell) can readily be seen by microscopy.
Key Points
About the Clinical Presentation of Chagas’ Disease
- Acute disease is associated ith localized areas of swelling called chagomas.
- Chronic disease develops in 10% to 30% of cases decades after intial infection
- Chronic disease affects a) the heart, causing a cardiomyopathy associated congestive heart failure, emboli, and arrhythmias; and b) The gastrointestinal tract, causing megaesophagus and megacolon.
In chronic disease, the diagnosis is made by detecting immunoglobulin G antibodies. A number of sensitive serologic tests are available, but they frequently yield false positive results. In the United States, two ELISA tests have been approved by the U.S. Food and Drug Administration for detecting clinical disease. A recently developed ELISA has been shown to have high sensitivity and specificity, and may prove useful for screening the blood supply. The polymerase chain reactionmethod has demonstrated promise, but it is not yet commercially available.
Key Points
About the Diagnosis and Treatment of Chagas’ Disease
- Acute disease is diagnosed by Giemsa stain of a peripheral blood smear.
- Chronic disease can be diagnosed by enzyme-linked immunoabsorbent assay that detects immunoglobulin G antibody to Trypanosoma cruzi.
- Acute and chronic disease should both be treated with nifurtimox or benznidazole.
- Treatment reduces mortality and progression of chronic disease.
Treatment
77 cruzi is not sensitive to most antiparasitic drugs. Nifurtimox cures about 70% of acute cases. This drug causes gastrointestinal and neurologic side effects in many patients. Benznidazole has a similar cure rate. Peripheral neuropathy, granulocytopenia, and rash are the most common side effects with that agent. Treatment with these two agents is now recommended for chronic Chagas’ disease. Recent studies have shown that treatment slows the progression of heart disease.
Trypanosoma Brucei Complex
Potential Severity
Over weeks to months, this disease can progress to coma, followed by death.
Key Points
About Trypanosoma brucei
- Transmitted by the blood-sucking tsetse fly.
- Survives in the bloodstream by continually changing its outer coat antigens.
- Some forms cause lymphadenitis and fever.
77 brucei complex refers to several Trypanosoma subspecies that are spread by the blood-sucking tsetse fly. Unlike 77 cruzi, which takes up residence within cells, 77 brucei trypomastigotes multiply within the bloodstream, evading the humoral immune system indefinitely by changing their surface antigens every 5 days. This disease is confined to Africa. No more than a single case per year is imported to the United States.
After the initial bite, the infection progresses slowly, with systemic symptoms of fever and lymph node swelling being noted weeks to months later. In the West African form, neurologic manifestations do not develop until months or years after the initial symptoms. In East African trypanosomiasis, systemic complaints may develop days after the insect bite, and Central nervous system complaints may develop within weeks.
Symptoms include somnolence, which explains the name “sleeping sickness” and choreiform movements, tremors, and ataxia mimicking Parkinson’s disease. Coma and death frequently ensue.
The diagnosis is made by observation of trypomastigotes in Giemsa-stained thick and thin smears of peripheral blood. Trypomastigotes can also be found in the cerebrospinal fluid. The treatment for 77 brucei is complex and depends on the species of the infecting parasite, whether the Central nervous system is involved, and tolerance to the side effects of the treatment regimen. Potential medications include eflornithine; suramin alone or in combination with the arsenical tryparsamide; pentami-dine; and the arsenical melarsoprol