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Baron S, editor. Medical Microbiology. 4th edition. Galveston (TX): University of Texas Medical Branch at Galveston; 1996.

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Medical Microbiology. 4th edition.

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Chapter 82Hemoflagellates

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General Concepts

American Trypanosomiasis (Chagas Disease)

Clinical Manifestations

Symptoms of acute disease may include fever, local or general edema, lymphadenopathy, tachycardia, heart enlargement, and myocarditis. Heart alterations and, occasionally, megaesophagus or megacolon may appear as late sequelae.

Structure

Typical, small trypomastigotes are found in peripheral blood and intracellular amastigotes in tissues.

Classification and Antigenic Types

Strains of Trypanosoma cruzi are differentiated by isoenzyme patterns and DNA sequencing. No antigenic variation is observed.

Multiplication and Life Cycle

Intracellular amastigotes divide to form pseudocysts, which release nondividing trypomastigotes into the blood. Trypomastigotes ingested by a vector bug transform in the insect intestine into epimastigotes, which reproduce to form infective metacyclic trypomastigotes, which are expelled in feces and enter a new host through skin abrasions.

Pathogenesis

Inflammatory reactions around pseudocysts lead to myocarditis and destruction of parasympathetic ganglia (mainly of the heart and myenteric plexus). An autoimmune reaction may develop.

Host Defenses

Inflammatory reactions, antibodies, and cell-mediated responses all develop.

Epidemiology

The disease is vectored by triatomine (cone-nosed) bugs and may also be transmitted congenitally and by transfusion. Animal reservoirs include opossums, armadillos, rodents, dogs, and cats. Outbreaks are associated with mud, thatched, or dirt-floored dwellings that harbor the vector.

Diagnosis

The clinical picture is suggestive; direct demonstration of parasites or serologic tests are definitive.

Control

Insecticides should be used to kill vectors in dwellings. Serologic screening of blood donors is important in endemic regions. Drug treatment is effective only in the acute phase.

African Trypanosomiasis (Sleeping Sickness)

Clinical Manifestations

Early symptoms are an inoculation chancre, fever, headache, and lymphadenopathy. Victims later develop meningoencephalitis, become somnolent, and die unless treated.

Structure

Typical, sometimes pleomorphic trypomastigotes are found in blood and cerebrospinal fluid.

Classification and Antigenic Types

Sleeping sickness is caused by Trypanosoma brucei subspp rhodesiense and gambiense. Frequent variation of surface antigens allows the parasites to evade specific immunity.

Multiplication and Life Cycle

Trypomastigotes multiply in blood. When ingested by a vector tsetse fly, the parasites multiply as epimastigotes in the salivary glands, producing infective trypomastigotes which enter a new host when the fly bites.

Pathogenesis

Inflammatory changes (possibly autoimmune) cause CNS demyelination. Immunosuppression by the parasite facilitates secondary infections.

Host Defenses

Inflammatory responses, high IgM antibody levels, and cell-mediated immunity occur.

Epidemiology

T b rhodesiense is maintained in various mammals of open savannahs; T b gambiense is maintained mainly in domestic animals.

Diagnosis

Parasites appear first in the blood and lymph nodes and later in the cerebrospinal fluid. The diagnosis is made by inoculating susceptible laboratory animals or by serologic tests.

Control

Control centers on reducing the population of tsetse flies. Humans are treated with pentamidine and arsenical drugs.

Cutaneous and Mucocutaneous Leishmaniasis

Clinical Manifestations

This form of leishmaniasis consists of skin or mucosal lesions, which are frequently ulcerated. Lesions may be self-healing or chronic; localized or spreading.

Structure

Leishmania occurs as an intracellular amastigote in the mammalian host and as promastigotes in the intestine of the sand fly vector.

Classification and Antigenic Types

Numerous species of Leishmania cause forms of leishmaniasis in various geographic areas. Different antigens are recognized by monoclonal antibodies.

Multiplication and Life Cycle

Amastigotes divide in mammalian macrophages and other reticuloendothelial cells. When ingested by a sand fly vector, they multiply in the gut as promastigotes, migrate to the proboscis, and enter a new host when the fly bites.

Pathogenesis

The severity of disease depends on the infecting species and on the host's immune response. There may be lymphatic and hematogenous spread.

Host Defenses

Host defense relies on cell-mediated immunity; antibody titers are low. The response ranges from a local tuberculoid granuloma with few parasites to a histiocytoma with many parasites.

Epidemiology

Some species are zoonotic; others are transmitted in a human-fly-human cycle. Transmission is determined by the range and habits of the vector.

Diagnosis

The diagnosis is confirmed if parasites are seen in scrapings or cultures from the lesion. Serologic and skin tests are also useful.

Control

Control centers on elimination of sand flies whenever possible. Disease is treated with organic antimonials and amphotericin B.

Visceral Leishmaniasis (Kala-Azar)

Clinical Manifestations

In visceral leishmaniasis, the parasite infects the entire reticuloendothelial system. Most infections are mild and self-limiting. Classic kala-azar, which is progressive and fatal if not treated, is marked by hepatosplenomegaly, lymphadenopathy, anemia, leukopenia, and emaciation.

Classification and Antigenic Types

Kala-azar is caused by at least three species of Leishmania.

Pathogenesis

The parasite invades reticuloendothelial cells of the liver, spleen, bone marrow, and lymph nodes, causing histiocytic hyperplasia and hypertrophy. Hematopoietic tissues are replaced by macrophages.

Host Defenses

Cellular immunity is responsible for resolving mild disease. High levels of antibodies are found.

Epidemiology

Human-sand fly-human cycles occur in some areas (India); in others, rodents or canines serve as reservoirs.

Diagnosis

Parasites are visible in stained or cultured bone marrow and spleen samples. Serologic tests are also necessary.

Control

Control is as with cutaneous leishmaniasis; pentamidine and antimonials are used in treatment.

Introduction

The family Trypanosomatidae consists of many parasitic flagellate protozoans. Two genera, Trypanosoma and Leishmania, include important pathogens of humans and domestic animals. The diseases caused by these protozoa are endemic or enzootic in different parts of the world and constitute serious medical and economic problems. Because these protozoans require hematin obtained from blood hemoglobin for aerobic respiration, they are called hemoflagellates. The digenetic (two-host) life cycles of both genera involve an insect and a vertebrate. The family also includes the digenetic genus Phytomonas, which infects plants, and some monogenetic (one-host) species which infect only invertebrate hosts.

The hemoflagellates have up to eight life cycle stages which differ in the placement and origin of the flagellum. Two stages—the amastigote and the trypomastigote—may occur in vertebrate hosts, and three stages,—the promastigote, paramastigote, and epimastigote—in invertebrate hosts (Fig. 82-1).

Figure 82-1. Five of the eight morphologic stages of 2 trypanosomatid flagellate.

Figure 82-1

Five of the eight morphologic stages of 2 trypanosomatid flagellate.

Besides the nucleus and the flagellum, a trypanosomatic cell has a unique organelle called the kinetoplast. The kinetoplast appears to be a special part of the mitochondrion and is rich in DNA. Two types of DNA molecules, maxicircles which encode mainly certain important mitochondrial enzymes, and minicircles which serve a function in the processof RNA editing, have been found in the kinetoplast; when Giemsa stained, the kinetoplast is reddish purple and darker than the nucleus, contrasting with the pale blue cytoplasm.

Monogenetic trypanosomatids are more primitive than the digenetic species and grow easily in synthetic culture media. Some digenetic species can be cultivated in complex synthetic media. The medium most commonly used is NNN medium, which has a solid phase of rabbit blood agar and a liquid phase of a physiologic salt solution. Liquid media are also available. Only the invertebrate stages appear in such media, and they may or may not be infectious for the vertebrate hosts, depending on the species.

Replication of trypanosomatids occurs by single or multiple fission, involving first the kinetoplast, then the nucleus, and finally the cytoplasm. However, evidence for sexual reproduction has been presented.

American Trypanosomiasis (Chagas Disease)

Clinical Manifestations

Chagas disease begins as a localized infection that is followed by parasitemia and colonization of internal organs and tissues. Infection may first be evidenced by a small tumor (chagoma) of the skin or, when the port of entry is the conjunctiva, by Romaña's sign (unilateral bipalpebral edema) (Fig. 82-2). These typical inflammatory reactions are usually accompanied by a swelling of the satellite lymph nodes that persists for 1 to 2 months. Symptoms and signs include fever, general edema, adenopathy, moderate hepatosplenomegaly, myocarditis with or without heart enlargement, and sometimes, in children, meningoencephalitis. The acute disease is frequently subclinical and patients may become lifelong asymptomatic carriers. This chronic phase may result after 10 to 20 years in a cardiopathy and, in some geographic areas, in enlargement of parts of the digestive tract (megaesophagus, megacolon).

Figure 82-2. Romaña's sign in an acute case of Chagas disease.

Figure 82-2

Romaña's sign in an acute case of Chagas disease.

Structure

Trypanosoma cruzi is found in the peripheral blood as a 20 µm trypomastigote with a large kinetoplast and a poorly developed undulating membrane. In the tissues (mainly heart, skeletal and smooth muscle, and reticuloendothelial cells) the parasite occurs as a 3 to 5 µm amastigote.

Classification and Antigenic Types

Studies with isolates of T cruzi from various hosts have shown intraspecific variation. Biochemical methods such as analysis of isoenzyme patterns (yielding zymodemes) and DNA molecular sequences (yielding schizodemes) are used to group different strains. At least three zymodemes differentiate sylvatic strains from those of domestic origin. Surface membrane glycoproteins specific for different stages of the parasite have been detected, although antigenic variation has not been observed. The glycoprotein detected in blood trypomastigotes can induce partially protective immunity in mice challenged with a virulent strain.

Multiplication and Life Cycle

In the vertebrate host, multiplication is carried out only by the amastigote form, which divides inside cells or muscle fibers to form groups called pseudocysts. Trypomastigotes, ingested when the insect takes a blood meal from an infected host, transform into epimastigotes in the intestine (Fig. 82-3). In the rectal sac these attach by the flagellar sheath mainly to the surface of the epithelium on the rectal gland, where they reproduce actively (Figs. 82-4 and 82-5). In about 8 to 10 days, metacyclic trypomastigote forms appear which are flushed out of the gut with the feces of the insect. These organisms are able to penetrate the vertebrate host only through the mucosa or abrasions of the skin; hence, transmission does not necessarily occur at every blood meal. Within the vertebrate the trypomastigotes transform into amastigotes. After a period of intracellular multiplication at the portal of entry, the amastigotes are released into the blood as trypanosomes which may then invade other cells or tissues, becoming amastigotes again.

Figure 82-3. Life cycle of T cruzi in the intestine of a triatomine bug and in the vertebrate host.

Figure 82-3

Life cycle of T cruzi in the intestine of a triatomine bug and in the vertebrate host. After entering the bug in infected blood (A) the trypanosomes transform to epimastigotes in the stomach and midgut. B) Epimastigotes attach to the walls of the rectal (more...)

Figure 82-4. Metacyclic trypomastigotes and epimastigotes of T cruzi attached to the epithelium of the rectal gland of Triatoma dimidiata.

Figure 82-4

Metacyclic trypomastigotes and epimastigotes of T cruzi attached to the epithelium of the rectal gland of Triatoma dimidiata. (From Zeledón R: Life cycle of Trypanosoma cruzi in the insect vector. In Brenner RR, Stoka Am (eds.): Chagas’ (more...)

Figure 82-5. Transmission electron micrograph showing flagellates of T cruzi attached by hemidesmosomes to the epithelium of the rectal gland of Triatoma dimidiata.

Figure 82-5

Transmission electron micrograph showing flagellates of T cruzi attached by hemidesmosomes to the epithelium of the rectal gland of Triatoma dimidiata. [From Zeledón R: Life cycle of Trypanosoma cruzi in the insect vector. In Brenner RR, Stoka (more...)

Pathogenesis

Surface glycoproteins and certain serum factors bound to the parasite may be important in adherence to and penetration of cells. Inflammatory reactions at the sites of rupturing pseudocysts can lead to pathologic manifestations, such as acute myocarditis and destruction of parasympathetic ganglia of the heart and myenteric plexus, which may cause the changes observed in the chronic phase of the illness. Parasite enzymes may also cause cell and tissue damage. In the absence of parasites an autoimmune pathological process seems to be mediated by T lymphocytes (CD4+) and by the production of certain cytokines; these induce a polyclonal activation of B lymphocytes and the secretion of large quantities of autoantibodies. Antibodies against endocardial-vascular-interstitial tissue (EVI), neurons, striated muscle, and laminin have been demonstrated. Chronic myocardiopathy, may be accompanied by focal myocarditis, extensive fibrosis, myocytolysis, collagenolysis, destruction of nerve fibers, and microvascular involvement, which can lead to sudden death. Thromboemboli can be caused by heart damage, and thinning of the apex of the left ventricle is a characteristic lesion.

Host Defenses

The host response includes both inflammatory and immune reactions. During the acute stage, rupture of pseudocysts stimulates an infiltration of polymorphonuclear neutrophils, monocytes, and lymphocytes, accompanied by edema, particularly in the heart. IgM antibodies are produced early and are subsequently replaced by IgG. Apparently only lytic antibodies (detectable by a complement-mediated lysis test using blood stages of the parasite) are involved in host resistance. There is also evidence that cell-mediated immune mechanisms are involved in controlling infection in experimental hosts.

Epidemiology

Chagas disease is transmitted by cone-nosed triatomine bugs of several genera (Triatoma, Rhodnius, Panstrongylus). Congenital and blood transfusion transmission also can occur.

Natural foci of Chagas disease exist among wild mammals and their associated triatomines. Humans and domestic animals became involved in the epidemiologic chain several centuries ago, when insects living under wild conditions began adapting to households. Opossums, armadillos, and wild rodents are reservoirs of the parasite, linking the wild and domestic cycles (Fig. 82-6). Case of human trypanosomiasis have been reported in almost all countries of the Americas, including the southern United States, but the main foci are in poor rural areas of Latin America.

Figure 82-6. Wild and domiciliary life cycles of Chagas disease.

Figure 82-6

Wild and domiciliary life cycles of Chagas disease. Some triatomine bugs transmit T cruzi to various wild animals (cycles 1–4). Other bugs are adapted to houses and transmit the parasite among humans and domestic animals (cycles 5 and 6). [Modified (more...)

Different vectors are associated with different types of dwellings: Rhodnius prolixus prefers huts with palm-thatch roofs; Triatoma infestans is found mainly in houses with mud and cane walls; T dimidiata has a preference for dirt floors.

Diagnosis

In the acute phase, the symptoms and signs described above suggest the disease. In the chronic phase electrocardiographic alterations, particularly arrhythmia and right bundle branch block in young adults, are indicative. In the early stages of the disease the parasite is demonstrated relatively easily by direct microscopic blood examination, by xenodiagnosis (allowing clean, laboratory-reared insects to feed on a suspected victim and later examining the insect feces), or by culturing the blood. In the chronic phase, xenodiagnosis and culturing, alone or in combination, reveal the parasite in only 30 to 60 percent of cases, but serologic tests [indirect hemagglutination, indirect immunofluorescence, enzyme-linked immunosorbent assay (ELISA)] can be diagnostic.

Control

The only practical control measures for Chagas disease are the use of insecticides to eliminate the vector bugs from dwellings. Improving the household environment helps considerably by eliminating lodging places for the insects. Community participation strategies, including education, housing improvements and vector surveillance appear to be more cost-effective than vertical programs for control. Vaccination trials in animals have yielded only partial protection. Live attenuated vaccines apparently are most effective but are too risky for use in humans. In endemic areas, serologic screening in blood banks is important to prevent transmission by transfusion. Nitrofurans (nifurtimox) and benznidazole are used with good or partial success in acute cases, but new drugs effective against both the trypomastigotes and the amastigotes are needed.

African Trypanosomiasis (Sleeping Sickness)

Clinical Manifestations

Sleeping sickness (African trypanosomiasis) is caused by Trypanosoma brucei. An initial chancre with regional lymphadenitis is frequently observed in patients infected by Trypanosoma brucei rhodesiense but seldom in patients infected by T b gambiense. The lesion persists for several weeks. After a period of local multiplication, the trypanosomes enter the general circulation via the lymphatics, and recurrent fever, headache, lymphadenopathy, and splenomegaly may occur. Later, signs of meningoencephalitis appear, followed by somnolence, cachexia, coma, and death. Enlargement of the posterior cervical chain of lymph nodes (Winterbottom's sign) is more common in T b gambiense infection.

Structure

The two subspecies of T brucei are morphologically indistinguishable. They may be pleomorphic, ranging from 12 to 42 µm long (mean, 30 µm), and have a small kinetoplast and a well-developed undulating membrane. The posterior end is more rounded than that of T cruzi.

Classification and Antigenic Types

The various subspecies of T brucei differ in their capacity to infect mammals other than man. The subspecies that do not infect man are killed by human serum. Trypanosoma brucei subspecies also can be separated into zymodemes, schizodemes, and groups based on DNA hybridization. Both metacyclic and blood forms are covered by variant surface glycoprotein (VSG) antigens, which are expressed in certain sequences of variable antigenic types (VAT) by activation of the specific genes. This variability allows the trypanosomes to evade specific antibodies. The so-called common antigens include structural and functional immunogenic components. When the trypanosomes enter the midgut of the vector or are cultivated at room temperature, the VSG is replaced by another glycoprotein, the procyclic acidic repetitive protein (PARP).

Multiplication and Life Cycle

Trypanosoma brucei trypanosomes, unlike those of T cruzi, multiply while in the blood or cerebrospinal fluid. Trypanosomes ingested by a feeding fly must reach the salivary glands within a few days, where they reproduce actively as epimastigotes attached to the microvilli of the gland until they transform into metacyclic trypomastigotes, which are found free in the lumen. Around 15 to 35 days after infection the fly becomes infective through its bite.

Pathogenesis

As the disease progresses, inflammatory changes lead to a demyelinating encephalitis. Antibodies against myelin have been detected, suggesting that this condition may have an autoimmune basis. The immunosuppressive action of components of the parasite's membrane is probably responsible for such concomitant infections as pneumonia. The GSV antigens stimulate high concentrations of IgM antibodies. Periodic changes occur in the surface antigens, thereby circumventing the host's immune responses (see Ch. 78). On the other hand, the common antigens are liberated in every trypanolytic crisis (episode of trypanosome lysis) and lead to antibody and cell-mediated hypersensitivity reactions. It is believed that some cytotoxic and physiopathologic processes are the result of biochemical and immune mechanisms.

Host Defenses

Inflammatory reactions occur initially at the site of inoculation and are accompanied by regional lymphadenitis; inflammation in the heart and brain soon develops. A vasculitis with perivascular infiltration by lymphocytes and plasma cells is the most common lesion. In addition to the high levels of IgM antibody, active cell-mediated immune responses occur.

Epidemiology

Both forms of African trypanosomiasis are transmitted during the daytime by the bite of infected tsetse flies ( Glossina species), which inhabit the open savannah of eastern Africa ( T b rhodesiense) or riverine areas in western and central Africa ( T b gambiense). Wild game mammals (bushbuck, hartebeest, lion, hyena) as well as cattle act as reservoirs of T b rhodesiense. This zoonotic subspecies, which is the more virulent of the two, is thus maintained in the most resistant reservoirs, resulting in continuous selection of aggressive strains. Trypanosoma b gambiense has been found mostly in domestic pigs, cattle, and dogs, although there is evidence that antelopes in certain areas may also carry the parasite. Man-fly-man transmission is hence more common in west and central Africa. Asymptomatic persons can carry the parasites in their blood for long periods and could be continuously infective for the vectors (Fig. 82-7).

Figure 82-7. Domestic and wild cycles of Gambian and Rhodesian types of African sleeping sickness.

Figure 82-7

Domestic and wild cycles of Gambian and Rhodesian types of African sleeping sickness. (A) in West Africa, riverine tsetse flies ( palpalis group) living in the bush transmit the Gambian forms to humans (man-fly cycle) and sometimes to domestic animals, (more...)

Diagnosis

The Rhodesian type of sleeping sickness evolves more acutely to death and its neurologic effects are less characteristic. The Gambian form tends to be more chronic and sometimes takes several years to develop central nervous system (CNS) involvement. In the early stages of the disease, the parasites can be demonstrated in lymph nodes and blood; later, they appear in the cerebrospinal fluid. In the Rhodesian type, lumbar puncture is indicated because of early CNS invasion. Culture or laboratory animal inoculations can be useful. Serologic tests, such as indirect immunofluorescence, direct card agglutination, and indirect hemagglutination, are used successfully for diagnosis.

Control

Tsetse fly populations have been reduced successfully by the use of insecticides or traps with an attractant bait plus insecticide. No reliable vaccine is available, and the variability in antigenic composition of the blood populations makes vaccination a difficult goal. Drugs such as pentamidine and the arsenical suramin, are successful in treatment, particularly in the early phase, and melarsoprol, another arsenical, and, more recently, eflornithine (difluoromethyl-ornithine), are used in advanced disease.

Cutaneous and Mucocutaneous Leishmaniasis

Clinical Manifestations

Leishmaniasis is a general term for diseases caused by species of the genus Leishmania, which are transmitted by the bite of infected sand flies. The lesions of cutaneous and mucocutaneous leishmaniasis are limited to the skin and mucous membranes. The much more severe disease, visceral leishmaniasis, which involves the entire reticuloendothelial system, is discussed in the next section. Cutaneous leishmaniasis appears 2 to 3 weeks after the bite of an infected sand fly as a small cutaneous papule. This lesion slowly grows, becoming indurated and often ulcerated, and develops secondary infection. Secondary or diffuse lesions may develop. The disease is occasionally self-limiting but usually chronic. Leishmaniasis from a primary skin lesion may involve the oral and nasopharyngeal mucosa.

Structure

All species of Leishmania parasitic in man are morphologically similar and appear as intracellular amastigotes 3 to 6 µm long by 1.5 to 3 µm in diameter. Promastigotes develop in the intestine of the sand fly.

Classification and Antigenic Types

The criteria used to differentiate Leishmania species are clinical, morphologic, behavioral (vector specificity, laboratory animal patterns, in vitro culture), immunologic (monoclonal antibodies), and biochemical (restriction enzymes, DNA probes, isoenzymes). The main species in the Old World are Leishmania tropica, L major, and L aethiopica (causing oriental sore); in the New World, L mexicana (causing chiclero ulcer), L amazonensis, L peruviana (causing uta), L braziliensis, L panamensis, L guyanensis (causing dermal leishmaniasis or espundia); other species occur in different geographic areas. Various Leishmania cell surface glycoproteins and lipopolysaccharides are being studied for possible use in species differentiation and with other purposes.

Multiplication and Life Cycle

In mammalian hosts, amastigotes are phagocytosed by macrophages but resist digestion and divide actively in the phagolysosome. Parasites ingested by a female sand fly that sucks the blood of an infected person or animal pass into the stomach, transform into promastigotes, and multiply actively. A paramastigote form also occurs in sand flies. The parasites finally attach by the flagellum to the walls of the esophagus, midgut, and hindgut of the fly, and some eventually reach the proboscis and are inoculated into a new host. Infective sand flies may become so blocked by parasites that probing alone leads to transmission.

Pathogenesis

Promastigotes (metacyclic forms) from the proboscis of an infected female sand fly are injected into the skin and taken up by local macrophages. Lesions of oriental sore and chiclero ulcer normally resolve spontaneously after a few months. Nevertheless, in the latter, destructive and chronic lesions of the pinna of the ear are observed in 50 to 60 percent of the patients. In L panamensis and L guyanensis infections, lesions usually become chronic, sometimes with lymphatic compromise and hematogenous dissemination (Fig. 82-8). In L braziliensis infection, highly destructive spread to the oral or nasal mucosa frequently occurs (Fig. 82-9); in the diffuse type (L mexicana, L amazonensis, L aethiopica), there is a disseminated nodular picture similar to lepromatous leprosy (Fig. 82-10). Evidence is being accumulated (use of PCR, AIDS patients) that a sterile cure of the disease is not always feasible.

Figure 82-8. Ulcerative dermal leishmaniasis of central finger of right hand produced by L panamensis.

Figure 82-8

Ulcerative dermal leishmaniasis of central finger of right hand produced by L panamensis.

Figure 82-9. Mucocutaneous leishmaniasis caused by L braziliensis. (Courtesy of Carlos Ponce.).

Figure 82-9

Mucocutaneous leishmaniasis caused by L braziliensis. (Courtesy of Carlos Ponce.).

Figure 82-10. Diffuse cutaneous leishmaniasis attributed to L amazonensis. (Courtesy of Jacinto Convit, M.D.).

Figure 82-10

Diffuse cutaneous leishmaniasis attributed to L amazonensis. (Courtesy of Jacinto Convit, M.D.).

Host Defenses

Besides the role of the infecting strain, and probably of some substances present in the saliva of the vector, the immunological response of the host plays an important function in determining the features of the disease. The local granuloma consists of lymphocytes, plasma cells, and macrophages containing intracellular parasites. In diffuse cutaneous leishmaniasis, foamy histiocytes filled with parasites are found, a reaction typical of an impaired cell-mediated immune mechanism. In fact, these patients are specifically anergic to the Montenegro skin test (see Diagnosis), and the phenomenon has been attributed to the presence of a specific monocyte suppressor cell. A CD4+/ CD8+ cell ratio of 0.79 to 0.80 and a marked decrease in the number of CD4+ T helper-inducer cells, which produce interleukin-2, have been observed. As a result, interferon γ, the major lymphokine-mediating macrophage activator to destroy the parasite, is not produced. There is evidence indicating that the development of the subsets of CD4+ T cells, T helper type 1 and type 2, and the repertoire of cytokines they produce, can lead to a resistance or susceptibility stage, respectively, both in humans and in a murine model. Infections associated with AIDS are providing an opportunity for demonstration of dormant infections and for studying cellular immune reactions. Chronic lesions of the ear and nose cartilage are due to a poor immune response. When the immune response is normal, a tuberculoid picture develops with epithelioid and giant cells, lymphocytes, and plasma cells. Cell-mediated immunity is important; relatively low titers of antibodies are produced.

Epidemiology

The vectors of Leishmania are sand flies of the genus Lutzomyia in the New World and Phlebotomus in the Old World. Animal reservoirs are wild rodents, sloths, marsupials, carnivores, and others. In the Old World, anthroponotic urban foci caused by L tropica are found, whereas L major and L aethiopica are typically zoonotic, involving rodents and hyraxes, respectively, as reservoirs. In the New World, with the exception of L peruviana, all forms are zoonotic and mainly sylvatic. In the case of L panamensis the main reservoir animals are arboreal, as are the various vectors. For L mexicana, some rodents serve as reservoir species, and the transmission is accomplished mainly by forest floor sand flies (Fig. 82-11).

Figure 82-11. Simplified life cycles of L panamensis (left) and L mexicana (right).

Figure 82-11

Simplified life cycles of L panamensis (left) and L mexicana (right). At least two species of sloths are common reservoirs of L panamensis, humans become victims when they enter the tropical forest and are attacked by infected arboreal sand flies. In the (more...)

Diagnosis

The patient presents single or multiple ulcers or nodules or nasal septum, may develop, usually several years after the skin lesions have healed. In the panamensis type mucosal lesions are uncommon and are less destructive than in the braziliensis type. In the latter, the process sometimes extends from the palate to the pharynx and larynx. These destructive lesions (constituting the condition called espundia) are common in Brazil but are also observed in Sudan, produced there by L aethiopica, usually in a less severe form. The diffuse type, characterized by disseminated plaques, papules, or nodules, especially on the face or limbs, is observed in areas where organisms of the mexicana and amazonensis types exist, as well as in some parts of Africa ( L aethiopica).

Parasites can be demonstrated in scrapings of the borders of the lesions but they become scarce once ulceration and bacterial contamination occur. Culturing in blood agar media increases markedly the possibility of isolating the parasite; material from direct puncture of the lesions’ borders or lymph nodes or triturated biopsy tissue is used. Various serologic tests (ELISA, immunofluorescent antibody) are satisfactory for indirect diagnosis. The Montenegro skin test, in which an indurated area appears at the site of inoculation of the antigen after 48 to 72 hr, is usually positive after 2 to 3 months of infection and remains so throughout the patient's lifetime.

Control

Leishmaniasis transmitted in or near houses can be prevented with insecticides, but this procedure is not practical for the forest tegumentary type. No effective vaccine is yet available. Pentavalent antimonials, such as sodium antimony gluconate (Pentostam) and meglumine antimoniate (Glucantime), are available for treatment, but have some limitations owing to their toxic side effects. Amphotericin B has been used in cases with mucosal involvement and in cases of diffuse disease where antimonial therapy fails. Less toxic drugs that can be administered orally and that could be used for both prophylaxis and treatment are needed.

Visceral Leishmaniasis (Kala-Azar)

Clinical Manifestations

Like cutaneous leishmaniasis, visceral leishmaniasis begins with a nodule at the site of inoculation. This lesion rarely ulcerates and usually disappears spontaneously in a few weeks or months. In contrast to cutaneous leishmaniasis, symptoms and signs of systemic disease develop, such as undulating fever, malaise, diarrhea, splenomegaly, hepatomegaly, lymphadenopathy, emaciation, anemia, and leukopenia (Fig. 82-12). Infiltrative or nodular lesions of the skin may appear after treatment (post-kala-azar dermal leishmaniasis), a condition seen frequently in India. In some areas of Europe and Latin America, L infantum may cause a cutaneous form without apparent visceral involvement (Fig. 82-13). Subclinical cases also occur.

Figure 82-12. Visceral leishmaniasis in a child from Honduras with marked emaciation and hepatosplenomegaly. (Courtesy of Carlos Ponce.).

Figure 82-12

Visceral leishmaniasis in a child from Honduras with marked emaciation and hepatosplenomegaly. (Courtesy of Carlos Ponce.).

Figure 82-13. Nodular cutaneous leishmaniasis produced by L infantum in Costa Rica.

Figure 82-13

Nodular cutaneous leishmaniasis produced by L infantum in Costa Rica.

Structure, Multiplication and Life Cycle

The Leishmania species that cause kala-azar are similar in morphology and life cycle to other members of the same genus.

Classification and Antigenic Types

Kala-azar can be caused by at least three Leishmania species, which are differentiated by zymodeme, serodeme, and DNA hybridization. Leishmania donovani and L infantum are responsible for visceral leishmaniasis in the Old World; L chagasi and L infantum (which may be the same organism) cause the disease in the New World.

Pathogenesis

In more serious cases of visceral leishmaniasis the parasites, which can resist the internal body temperature, invade internal organs (liver, spleen, bone marrow, and lymph nodes) where they occupy the reticuloendothelial cells. The pathogenetic mechanisms of the disease are not fully understood, but, clearly, in those organs that exhibit marked cellular alteration, hyperplasia of histiocytes leads to hypertrophy. Parasitized macrophages replace hematopoietic tissue in the bone marrow. Patients with advanced disease are prone to superinfection with other organisms.

Host Defenses

High levels of IgG and other immunoglobulins are common. The Montenegro skin test for delayed hypersensitivity is usually negative during the disease but becomes positive after treatment.

Epidemiology

In India, transmission occurs in villages in an anthroponotic man-sand fly-man cycle without nonhuman reservoir. In Europe and Africa, several rodents may act as reservoirs. In rural semiarid zone of Latin America, both wild and domestic dogs enter the epidemiological chain and the vector is a common anthropophilic and zoophilic sand fly, L utzomyia longipalpis, abundant in and around houses. The disease is more common in children in both Latin America and the Mediterranean area.

Diagnosis

The typical symptoms, particularly hepatosplenomegaly and the pancytopenia, strongly suggest visceral leishmaniasis. The parasite usually can be demonstrated in stained or cultured bone marrow or spleen material. Serologic tests (ELISA, immunofluorescent antibody) are useful, particularly in surveys.

Control

The same insecticides and drugs that work for cutaneous leishmaniasis are used for visceral leishmaniasis. Aromatic diamidines are also used.

References

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Copyright © 1996, The University of Texas Medical Branch at Galveston.
Bookshelf ID: NBK8434PMID: 21413333

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