Summaries of Organisms
Practice Questions: USMLE & Course Examinations
The medically important organisms in this category of protozoa consist of the sporozoans Plasmodium and Toxoplasma and the flagellates Trypanosoma and Leishmania. Pneumocystis is discussed in this book as a protozoan because it is considered as such from a medical point of view. However, molecular data indicate that it is related to yeasts such as Saccharomyces cerevisiae. Table 51–2 summarizes several important features of these blood and tissue protozoa.
The medically important stages in the life cycle of the blood and tissue protozoa are described in Table 52–1.
TABLE 52–1 Medically Important Stages in Life Cycle of Blood and Tissue Protozoa
Malaria is caused by four plasmodia: Plasmodium vivax, Plasmodium ovale, Plasmodium malariae, and Plasmodium falciparum. P. vivax and P. falciparum are more common causes of malaria than are P. ovale and P. malariae. Worldwide, malaria is one of the most common infectious diseases and a leading cause of death.
The life cycle of Plasmodium species is shown in Figure 52–1. The vector and definitive host for plasmodia is the female Anopheles mosquito (only the female takes a blood meal). There are two phases in the life cycle: the sexual cycle, which occurs primarily in mosquitoes, and the asexual cycle, which occurs in humans, the intermediate hosts.1
FIGURE 52–1 Plasmodium species. Life cycle. Right side of figure describes the stages within the human (blue arrows). Cycle A (top right) is the exo-erythrocyte stage that occurs in the liver. Cycle B (bottom right) is the erythrocyte stage that occurs in the red blood cell. Note that at step 6 in the cycle, merozoites released from the ruptured schizonts then infect other red blood cells. The synchronized release of merozoites causes the periodic fever and chills characteristic of malaria. Left side of figure describes the stages within the mosquito (red arrows). Humans are infected at step 1 when mosquito injects sporozoites. Mosquito is infected at step 8 when mosquito ingests gametocytes in human blood. (Provider: Centers for Disease Control and Prevention/Dr. Alexander J. da Silva and Melanie Moser.)
The sexual cycle is called sporogony because sporozoites are produced (sporogonic cycle is labeled C in Figure 52–1), and the asexual cycle is called schizogony because schizonts are made.
The life cycle in humans begins with the introduction of sporozoites into the blood from the saliva of the biting mosquito. The sporozoites are taken up by hepatocytes within 30 minutes. This “exoerythrocytic” phase (labeled A in Figure 52–1) consists of cell multiplication and differentiation into merozoites. P. vivax and P. ovale produce a latent form (hypnozoite) in the liver; this form is the cause of relapses seen with vivax and ovale malaria.
Merozoites are released from the liver cells and infect red blood cells. During the erythrocytic phase (labeled B in Figure 52–1), the organism differentiates into a ring-shaped trophozoite (Figures 52–2A and B and 52–3). The ring form grows into an ameboid form and then differentiates into a schizont filled with merozoites (Figure 52–2C). After release, the merozoites infect other erythrocytes (step 6 in Figure 52–1). This cycle in the red blood cell repeats at regular intervals typical for each species. The periodic release of merozoites causes the typical recurrent symptoms of chills, fever, and sweats seen in malaria patients.
FIGURE 52–2 A: Plasmodium vivax signet-ring trophozoite within a red blood cell. B: Plasmodium vivax ameboid trophozoite within a red blood cell, showing Schüffner’s dots. C: Plasmodium vivax mature schizont with merozoites inside. D: Plasmodium vivax microgametocyte. E: Plasmodium vivax macrogametocyte. F: Plasmodium falciparum “banana-shaped” gametocyte with attached red cell ghost. G: Toxoplasma gondii trophozoites within macrophage. H: Pneumocystis jiroveci cysts. (A–G, 1200×; H, 800×.)
FIGURE 52–3 Plasmodium falciparum—ring-shaped trophozoite. Long arrow points to a red blood cell containing a ring-shaped trophozoite. Arrowhead points to a red blood cell containing four ring-shaped trophozoites. Note the very high percentage of red cells containing ring forms. This high-level parasitemia is more often seen in Plasmodium falciparum infection than in infection by the other plasmodia. (Figure courtesy of Dr. S. Glenn, Public Health Image Library, Centers for Disease Control and Prevention.)
The sexual cycle begins in the human red blood cells when some merozoites develop into male and others into female gametocytes (Figures 52–2D to F and 52–4, and step 7 in Figure 52–1). The gametocyte-containing red blood cells are ingested by the female Anopheles mosquito and, within her gut, produce a female macrogamete and eight spermlike male microgametes. After fertilization, the diploid zygote differentiates into a motile ookinete that burrows into the gut wall, where it grows into an oocyst within which many haploid sporozoites are produced. The sporozoites are released and migrate to the salivary glands, ready to complete the cycle when the mosquito takes her next blood meal.
FIGURE 52–4 Plasmodium falciparum—gametocyte. Arrow points to a “banana-shaped” gametocyte of Plasmodium falciparum. (Figure courtesy of Dr. S. Glenn, Public Health Image Library, Centers for Disease Control and Prevention.)
A very important feature of P. falciparum is chloroquine resistance. Chloroquine-resistant strains now predominate in most areas of the world where malaria is endemic. Chloroquine resistance is mediated by a mutation in the gene encoding the chloroquine transporter in the cell membrane of the organism.
Pathogenesis & Epidemiology
Most of the pathologic findings of malaria result from the destruction of red blood cells. Red cells are destroyed both by the release of the merozoites and by the action of the spleen to first sequester the infected red cells and then to lyse them. The enlarged spleen characteristic of malaria is due to congestion of sinusoids with erythrocytes, coupled with hyperplasia of lymphocytes and macrophages.
Malaria caused by P. falciparum is more severe than that caused by other plasmodia. It is characterized by infection of far more red cells than the other malarial species and by occlusion of the capillaries with aggregates of parasitized red cells. This leads to life-threatening hemorrhage and necrosis, particularly in the brain (cerebral malaria). Furthermore, extensive hemolysis and kidney damage occur, with resulting hemoglobinuria. The dark color of the patient’s urine has given rise to the term “blackwater fever.” The hemoglobinuria can lead to acute renal failure.
The timing of the fever cycle is 72 hours for P. malariae and 48 hours for the other plasmodia. Disease caused by P. malariae is called quartan malaria because it recurs every fourth day, whereas malaria caused by the other plasmodia is called tertian malaria because it recurs every third day. Tertian malaria is subdivided into malignant malaria, caused by P. falciparum, and benign malaria, caused by P. vivax and P. ovale.
P. falciparum causes a high level of parasitemia because it can infect red cells of all ages. In contrast, P. vivax infects only reticulocytes and P. malariae infects only mature red cells; therefore, they produce much lower levels of parasites in the blood. Individuals with sickle cell trait (heterozygotes) are protected against malaria because their red cells have too little ATPase activity and cannot produce sufficient energy to support the growth of the parasite. People with homozygous sickle cell anemia are also protected but rarely live long enough to obtain much benefit.
The receptor for P. vivax is the Duffy blood group antigen. People who are homozygous recessive for the genes that encode this protein are resistant to infection by P. vivax. More than 90% of black West Africans and many of their American descendants do not produce the Duffy antigen and are thereby resistant to vivax malaria.
People with glucose-6-phosphate dehydrogenase (G6PD) deficiency are also protected against the severe effects of falciparum malaria. G6PD deficiency is an X-linked hemoglobinopathy found in high frequency in tropical areas where malaria is endemic. Both male and female carriers of the mutated gene are protected against malaria.
Malaria is transmitted primarily by mosquito bites, but transmission across the placenta, in blood transfusions, and by intravenous drug use also occurs.
Partial immunity based on humoral antibodies that block merozoites from invading the red cells occurs in infected individuals. A low level of parasitemia and low-grade symptoms result; this condition is known as premunition. In contrast, a nonimmune person, such as a first-time traveler to an area where falciparum malaria is endemic, is at risk of severe, life-threatening disease.
More than 200 million people worldwide have malaria, and more than 1 million die of it each year, making it the most common lethal infectious disease. It occurs primarily in tropical and subtropical areas, especially in Asia, Africa, and Central and South America. Malaria in the United States is seen in Americans who travel to areas of endemic infection without adequate chemoprophylaxis and in immigrants from areas of endemic infection. It is not endemic in the United States. Certain regions in Southeast Asia, South America, and east Africa are particularly affected by chloroquine-resistant strains of P. falciparum. People who have lived or traveled in areas where malaria occurs should seek medical attention for febrile illnesses up to 3 years after leaving the malarious area.
Malaria presents with abrupt onset of fever and chills, accompanied by headache, myalgias, and arthralgias, about 2 weeks after the mosquito bite. Fever may be continuous early in the disease; the typical periodic cycle does not develop for several days after onset. The fever spike, which can reach 41°C, is frequently accompanied by shaking chills, nausea, vomiting, and abdominal pain. The fever is followed by drenching sweats. Patients usually feel well between the febrile episodes. Splenomegaly is seen in most patients, and hepatomegaly occurs in roughly one-third. Anemia is prominent.
Untreated malaria caused by P. falciparum is potentially life-threatening as a result of extensive brain (cerebral malaria) and kidney (blackwater fever) damage. Malaria caused by the other three plasmodia is usually self-limited, with a low mortality rate. However, relapses of P. vivax and P. ovale malaria can occur up to several years after the initial illness as a result of hypnozoites latent in the liver.
Diagnosis rests on microscopic examination of blood, using both thick and thin Giemsa-stained smears. The thick smear is used to screen for the presence of organisms, and the thin smear is used for species identification. It is important to identify the species because the treatment of different species can differ. Ring-shaped trophozoites can be seen within infected red blood cells (Figure 52–3). The gametocytes of P. falciparum are crescent-shaped (“banana-shaped”), whereas those of the other plasmodia are spherical (Figure 52–2F). If more than 5% of red blood cells are parasitized, the diagnosis is usually P. falciparum malaria.
If blood smears do not reveal the diagnosis, then a polymerase chain reaction (PCR)-based test for Plasmodium nucleic acids or an enzyme-linked immunosorbent assay (ELISA) test for a protein specific for P. falciparum can be useful.
The treatment of malaria is complicated, and the details are beyond the scope of this book. Table 52–2 presents the drugs commonly used in the United States. The main criteria used for choosing specific drugs are the severity of the disease and whether the organism is resistant to chloroquine. Chloroquine resistance is determined by the geographical location where the infection was acquired rather than by laboratory testing.
TABLE 52–2 Drugs Commonly Used for the Treatment of Malaria in the United States
Chloroquine is the drug of choice for treatment of uncomplicated malaria caused by non-falciparum species in areas without chloroquine resistance. Chloroquine kills the merozoites, thereby reducing the parasitemia, but does not affect the hypnozoites of P. vivax and P. ovale in the liver. These are killed by primaquine, which must be used to prevent relapses. Primaquine may induce severe hemolysis in those with G6PD deficiency, so testing for this enzyme should be done before the drug is given. Primaquine should not be given if the patient is severely G6PD deficient. If primaquine is not given, one approach is to wait to see whether symptoms recur and then treat with chloroquine.
Uncomplicated, chloroquine-resistant P. falciparum infection is treated with either Coartem (artemether plus lumefantrine) or Malarone (atovaquone and proguanil). In severe complicated cases of chloroquine-resistant falciparum malaria, intravenous administration of either artesunate or quinidine is used.
Outside the United States, the artemisinins, such as artesunate or artemether, are widely used in combination with other antimalarial drugs. The artemisinins are inexpensive and have few side effects, and most plasmodia have not developed resistance to these drugs. However, resistance to artesunate has emerged in some strains of P. falciparum in Southeast Asia (e.g., Cambodia, Myanmar, and Thailand).
Chemoprophylaxis of malaria for travelers to areas where chloroquine-resistant P. falciparum is endemic consists of mefloquine or doxycycline. A combination of atovaquone and proguanil (Malarone), in a fixed dose, can also be used. Chloroquine should be used in areas where P. falciparum is sensitive to that drug. Travelers to areas where the other three plasmodia are found should take chloroquine starting 2 weeks before arrival in the endemic area and continuing for 6 weeks after departure. This should be followed by a 2-week course of primaquine if exposure was high. Primaquine will kill the hypnozoites of P. vivax and P. ovale.
Other preventive measures include the use of mosquito netting, window screens, protective clothing, and insect repellents. The mosquitoes feed from dusk to dawn, so protection is particularly important during the night. Communal preventive measures are directed against reducing the mosquito population. Many insecticide sprays, such as DDT, are no longer effective because the mosquitoes have developed resistance. Drainage of stagnant water in swamps and ditches reduces the breeding areas. There is no vaccine.
Toxoplasma gondii causes toxoplasmosis, including congenital toxoplasmosis.
The life cycle of T. gondii is shown in Figure 52–5. The definitive host is the domestic cat and other felines; humans and other mammals are intermediate hosts. Infection of humans begins with the ingestion of cysts in undercooked meat or from accidental contact with cysts in cat feces. In the small intestine, the cysts rupture and release forms that invade the gut wall, where they are ingested by macrophages and differentiate into rapidly multiplying trophozoites (tachyzoites), which kill the cells and infect other cells (Figures 52–2G and 52–6). Cell-mediated immunity usually limits the spread of tachyzoites, and the parasites enter host cells in the brain, muscle, and other tissues, where they develop into cysts in which the parasites multiply slowly. These forms are called bradyzoites. These tissue cysts are both an important diagnostic feature and a source of organisms when the tissue cyst breaks in an immunocompromised patient.
FIGURE 52–5 Toxoplasma gondii. Life cycle. Top red arrows show the natural life cycle as T. gondii circulates between cats (#1), which excrete oocysts in the feces that are eaten by mice, but also by domestic animals such as pigs and sheep. Cysts form in tissue such as muscle and brain. The natural cycle is completed when cats eat mice. Humans are accidental hosts. They can be infected by the ingestion of under-cooked pork and lamb (blue arrow #2) containing tissue cysts in muscle or by ingestion of food contaminated with cat feces containing oocysts (blue arrow #3). (Provider: Centers for Disease Control and Prevention/Dr. Alexander J. da Silva and Melanie Moser.)
FIGURE 52–6 Toxoplasma gondii—tachyzoite. Arrow points to a tachyzoite of T. gondii in cardiac muscle. (Figure courtesy of Dr. E. Ewing, Jr., Public Health Image Library, Centers for Disease Control and Prevention.)
The cycle within the cat begins with the ingestion of cysts in raw meat (e.g., mice). Bradyzoites are released from the cysts in the small intestine, infect the mucosal cells, and differentiate into male and female gametocytes, whose gametes fuse to form oocysts that are excreted in cat feces. The cycle is completed when soil contaminated with cat feces is accidentally ingested. Human infection usually occurs from eating undercooked meat (e.g., lamb and pork) from animals that grazed in soil contaminated with infected cat feces.
Pathogenesis & Epidemiology
T. gondii is usually acquired by ingestion of cysts in uncooked meat or cat feces.
Transplacental transmission from an infected mother to the fetus occurs also. Human-to-human transmission, other than transplacental transmission, does not occur. After infection of the intestinal epithelium, the organisms spread to other organs, especially the brain, lungs, liver, and eyes. Progression of the infection is usually limited by a competent immune system. Cell-mediated immunity plays the major role, but circulating antibody enhances killing of the organism. Most initial infections are asymptomatic. When contained, the organisms persist as cysts within tissues. There is no inflammation, and the individual remains well unless immunosuppression allows activation of organisms in the cysts.
Congenital infection of the fetus occurs only when the mother is infected during pregnancy. If she is infected before the pregnancy, the organism will be in the cyst form and there will be no trophozoites to pass through the placenta. The mother who is reinfected during pregnancy but who has immunity from a previous infection will not transmit the organism to her child. Roughly one-third of mothers infected during pregnancy give birth to infected infants, but only 10% of these infants are symptomatic.
Infection by T. gondii occurs worldwide. Serologic surveys reveal that in the United States antibodies are found in 5% to 50% of people in various regions. Infection is usually sporadic, but outbreaks associated with ingestion of raw meat or contaminated water occur. Approximately 1% of domestic cats in the United States shed Toxoplasma cysts.
Most primary infections in immunocompetent adults are asymptomatic, but some resemble infectious mononucleosis, except that the heterophil antibody test is negative. Congenital infection can result in abortion, stillbirth, or neonatal disease with encephalitis, chorioretinitis, and hepatosplenomegaly. Fever, jaundice, and intracranial calcifications are also seen. Most infected newborns are asymptomatic, but chorioretinitis or mental retardation will develop in some children months or years later. Congenital infection with Toxoplasma is one of the leading causes of blindness in children. In patients with reduced cell-mediated immunity (e.g., patients with acquired immunodeficiency syndrome [AIDS]), life-threatening disseminated disease, primarily encephalitis, occurs.
For the diagnosis of acute and congenital infections, an immunofluorescence assay for IgM antibody is used. IgM is used to diagnose congenital infection, because IgG can be maternal in origin. Tests of IgG antibody can be used to diagnose acute infections if a significant rise in antibody titer in paired sera is observed.
Microscopic examination of Giemsa-stained preparations shows crescent-shaped trophozoites during acute infections. Cysts may be seen in the tissue. The organism can be grown in cell culture. Inoculation into mice can confirm the diagnosis.
Congenital toxoplasmosis, whether symptomatic or asymptomatic, should be treated with a combination of sulfadiazine and pyrimethamine. These drugs also constitute the treatment of choice for disseminated disease in immunocompromised patients. Acute toxoplasmosis in an immunocompetent individual is usually self-limited, but any patient with chorioretinitis should be treated.
The most effective means of preventing toxoplasmosis is to cook meat thoroughly to kill the cysts. Pregnant women should be especially careful to avoid undercooked meat and contact with cat feces. They should refrain from emptying cat litter boxes. Cats should not be fed raw meat. Trimethoprim-sulfamethoxazole is used to prevent Toxoplasma encephalitis in patients infected with human immunodeficiency virus (HIV).
Pneumocystis jiroveci is an important cause of pneumonia in immunocompromised individuals. In 2002, taxonomists renamed the human species of Pneumocystis as P. jiroveci and recommended that Pneumocystis carinii be used only to describe the rat species of Pneumocystis.
The classification and life cycle of Pneumocystis are unclear. Many aspects of its biochemistry indicate that it is a yeast, but it also has several attributes of a protozoan. An analysis of rRNA sequences published in 1988 indicates that Pneumocystis should be classified as a fungus related to yeasts such as Saccharomyces cerevisiae. Subsequent analysis of mitochondrial DNA and of various enzymes supports the idea that it is a fungus. However, it does not have ergosterol in its membranes as do the fungi. It has cholesterol.
Medically, it is still thought of as a protozoan. In tissue, it appears as a cyst that resembles the cysts of protozoa (Figures 52–2H and 52–7). The findings that it does not grow on fungal media and that antifungal drugs are ineffective have delayed acceptance of its classification as a fungus.
FIGURE 52–7 Pneumocystis jiroveci—arrow points to a cyst of P. jiroveci in lung tissue. (Figure courtesy of Dr. E. Ewing, Jr., Public Health Image Library, Centers for Disease Control and Prevention.)
Pneumocystis species are found in domestic animals such as horses and sheep and in a variety of rodents, but it is thought that these animals are not a reservoir for human infection. Each mammalian species is thought to have its own species of Pneumocystis.
Pneumocystis species have a major surface glycoprotein that exhibits significant antigenic variation in a manner similar to that of Trypanosoma brucei. Pneumocystis species have multiple genes encoding these surface proteins, but only one is expressed at a time. This process of programmed rearrangements was first observed in T. brucei.
Pathogenesis & Epidemiology
Transmission occurs by inhalation, and infection is predominantly in the lungs. The presence of cysts in the alveoli induces an inflammatory response consisting primarily of plasma cells, resulting in a frothy exudate that blocks oxygen exchange. (The presence of plasma cells has led to the name “plasma cell pneumonia.”) The organism does not invade the lung tissue.
Pneumonia occurs when host defenses (e.g., the number of CD4-positive [helper] T cells) are reduced. This accounts for the prominence of Pneumocystis pneumonia in patients with AIDS and in premature or debilitated infants. Hospital outbreaks do not occur, and patients with Pneumocystis pneumonia are not isolated.
P. jiroveci is distributed worldwide. It is estimated that 70% of people have been infected. Most 5-year-old children in the United States have antibodies to this organism. Asymptomatic infection is therefore quite common. Prior to the advent of immunosuppressive therapy, Pneumocystis pneumonia was rarely seen in the United States. Its incidence has paralleled the increase in immunosuppression and the rise in the number of AIDS cases.
Most Pneumocystis infections in AIDS patients are new rather than a reactivation of a prior latent infection. This conclusion is based on the finding that Pneumocystis recovered from AIDS patients shows resistance to drugs that the patients have not taken.
The sudden onset of fever, nonproductive cough, dyspnea, and tachypnea is typical of Pneumocystis pneumonia. Bilateral rales and rhonchi are heard, and the chest X-ray shows a diffuse interstitial pneumonia with “ground glass” infiltrates bilaterally. In infants, the disease usually has a more gradual onset. Extrapulmonary Pneumocystis infections occur in the late stages of AIDS and affect primarily the liver, spleen, lymph nodes, and bone marrow. The mortality rate of untreated Pneumocystis pneumonia approaches 100%.
Diagnosis is made by finding the typical cysts by microscopic examination of lung tissue or fluids obtained by bronchoscopy, bronchial lavage, or open lung biopsy (Figure 52–7). Sputum is usually less suitable. The cysts can be visualized with methenamine silver, Giemsa, or other tissue stains. Fluorescent-antibody staining is also commonly used for diagnosis. PCR-based tests using respiratory tract specimens are also useful. The organism stains poorly with Gram stain. There is no serologic test, and the organism has not been grown in culture.
The treatment of choice is a combination of trimethoprim and sulfamethoxazole (Bactrim, Septra). Pentamidine and atovaquone are alternative drugs.
Trimethoprim-sulfamethoxazole or aerosolized pentamidine should be used as chemoprophylaxis in patients whose CD4 counts are below 200.
The genus Trypanosoma includes three major pathogens: Trypanosoma cruzi, Trypanosoma gambiense, and Trypanosoma rhodesiense.2
1. Trypanosoma cruzi
T. cruzi is the cause of Chagas’ disease (American trypanosomiasis).
The life cycle of T. cruzi is shown in Figure 52–8. The life cycle involves the reduviid bug (Triatoma, cone-nose or kissing bug) as the vector, and both humans and animals as reservoir hosts. The animal reservoirs include domestic cats and dogs and wild species such as the armadillo, raccoon, and rat. The cycle in the reduviid bug begins with ingestion of trypomastigotes in the blood of the reservoir host. In the insect gut, they multiply and differentiate first into epimastigotes and then into trypomastigotes. When the bug bites again, the site is contaminated with feces containing trypomastigotes, which enter the blood of the person (or other reservoir) and form nonflagellated amastigotes within host cells. Many cells can be affected, but myocardial, glial, and reticuloendothelial cells are the most frequent sites. To complete the cycle, amastigotes differentiate into trypomastigotes, which enter the blood and are taken up by the reduviid bug (Figures 52–9A to C and 52–10).
FIGURE 52–8 Trypanosoma cruzi. Life cycle. Right side of figure describes the stages within the human (blue arrows). Humans are infected at step 1 when triatomine (reduviid) bug bites human and defecates at bite site. Trypomastigotes in feces enter bite wound. Amastigotes form within cells, especially heart muscle and neural tissue. Reduviid bug is infected at step 5 when it ingests trypomastigotes in human blood. Left side of figure describes the stages within the reduviid bug (red arrows). (Provider: Centers for Disease Control and Prevention/Dr. Alexander J. da Silva and Melanie Moser.)
FIGURE 52–9 A: Trypanosoma cruzi trypomastigote found in human blood (1200×). B: T. cruzi amastigotes found in cardiac muscle (850×). C: T. cruzi epimastigote found in reduviid bug (1200×). D: Trypanosoma brucei gambiense or rhodesiense trypomastigote found in human blood (1200×). E: Leishmania donovani amastigotes within splenic macrophages (1000×). (Circle with inner dotted line represents a red blood cell.)
FIGURE 52–10 Trypanosoma cruzi—amastigotes. Arrow points to an amastigote (nonflagellated form) in cytoplasm. (Figure courtesy of Dr. A. J. Sulzer, Public Health Image Library, Centers for Disease Control and Prevention.)
Pathogenesis & Epidemiology
Chagas’ disease occurs primarily in rural Central and South America. Acute Chagas’ disease occurs rarely in the United States, but the chronic form causing myocarditis and congestive heart failure is seen with increasing frequency in immigrants from Latin America. The disease is seen primarily in rural areas because the reduviid bug lives in the walls of rural huts and feeds at night. It bites preferentially around the mouth or eyes, hence the name “kissing bug.”
The amastigotes can kill cells and cause inflammation, consisting mainly of mononuclear cells. Cardiac muscle is the most frequently and severely affected tissue. In addition, neuronal damage leads to cardiac arrhythmias and loss of tone in the colon (megacolon) and esophagus (megaesophagus). During the acute phase, there are both trypomastigotes in the blood and amastigotes intracellularly in the tissues. In the chronic phase, the organism persists in the amastigote form.
Chagas’ disease has occurred in the United States in recipients of either blood transfusions or organ transplants from infected donors. The organism can also be transmitted congenitally from an infected mother to the fetus across the placenta.
The acute phase of Chagas’ disease consists of facial edema and a nodule (chagoma) near the bite, coupled with fever, lymphadenopathy, and hepatosplenomegaly. A bite around the eye can result in unilateral palpebral swelling called Romaña’s sign. The acute phase resolves in about 2 months. Most individuals then remain asymptomatic, but some progress to the chronic form with myocarditis and megacolon. Death from chronic Chagas’ disease is usually due to cardiac arrhythmias or congestive heart failure.
Acute disease is diagnosed by demonstrating the presence of trypomastigotes in thick or thin films of the patient’s blood. Both stained and wet preparations should be examined, the latter for motile organisms. Because the trypomastigotes are not numerous in the blood, other diagnostic methods may be required, namely, (1) a stained preparation of a bone marrow aspirate or muscle biopsy specimen (which may reveal amastigotes); (2) culture of the organism on special medium; and (3) xenodiagnosis, which consists of allowing an uninfected, laboratory-raised reduviid bug to feed on the patient and, after several weeks, examining the intestinal contents of the bug for the organism.
Serologic tests can be helpful also. The indirect fluorescent antibody test is the earliest to become positive. Indirect hemagglutination and complement fixation tests are also available. Diagnosis of chronic disease is difficult because there are few trypomastigotes in the blood. Xenodiagnosis and serologic tests are used.
The drug of choice for the acute phase is nifurtimox, which kills trypomastigotes in the blood but is much less effective against amastigotes in tissue. Benznidazole is an alternative drug. There is no effective drug against the chronic form.
Prevention involves protection from the reduviid bite, improved housing, and insect control. No prophylactic drug or vaccine is available. Blood for transfusion is tested for the presence of antibodies to T. cruzi. Blood containing antibodies should not be used.
2. Trypanosoma gambiense & Trypanosoma rhodesiense
These organisms cause sleeping sickness (African trypanosomiasis). They are also known as Trypanosoma brucei gambiense and Trypanosoma brucei rhodesiense.
The life cycle of Trypanosoma brucei is shown in Figure 52–11. The morphology and life cycle of the two species are similar. The vector for both is the tsetse fly, Glossina, but different species of fly are involved for each. Humans are the reservoir for T. gambiense, whereas T. rhodesiense has reservoirs in both domestic animals (especially cattle) and wild animals (e.g., antelopes).
FIGURE 52–11 Trypanosoma brucei. Life cycle. Right side of figure describes the stages within the human (blue arrows). Humans are infected at step 1 when the tsetse fly bites human and injects trypomastigotes into bloodstream. Tsetse fly is infected at step 5 when it ingests trypomastigotes in human blood. Left side of figure describes the stages within the tsetse fly (red arrows). (Provider: Centers for Disease Control and Prevention/Dr. Alexander J. da Silva and Melanie Moser.)
The 3-week life cycle in the tsetse fly begins with ingestion of trypomastigotes in a blood meal from the reservoir host. They multiply in the insect gut and then migrate to the salivary glands, where they transform into epimastigotes, multiply further, and then form metacyclic trypomastigotes, which are transmitted by the tsetse fly bite. The organisms in the saliva are injected into the skin, where they enter the bloodstream, differentiate into blood-form trypomastigotes, and multiply, thereby completing the cycle (Figures 52–9D and 52–12). Note that these species are rarely found as amastigotes in tissue, in contrast to T. cruzi and Leishmania species, in which amastigotes are commonly found.
FIGURE 52–12 Trypanosoma brucei—trypomastigotes. Arrow points to a trypomastigote (the flagellated form) in the blood. (Figure courtesy of Dr. M. Schultz, Public Health Image Library, Centers for Disease Control and Prevention.)
These trypanosomes exhibit remarkable antigenic variation of their surface glycoproteins, with hundreds of antigenic types found. One antigenic type will coat the surface of the parasites for approximately 10 days, followed by other types in sequence in the new progeny. This variation is due to sequential movement of the glycoprotein genes to a preferential location on the chromosome, where only that specific gene is transcribed into mRNA. These antigenic variations allow the organism to continually evade the host immune response.
Pathogenesis & Epidemiology
The trypomastigotes spread from the skin through the blood to the lymph nodes and the brain. The typical somnolence (sleeping sickness) progresses to coma as a result of a demyelinating encephalitis.
In the acute form, a cyclical fever spike (approximately every 2 weeks) occurs that is related to antigenic variation. As antibody-mediated agglutination and lysis of the trypomastigotes occur, the fever subsides. However, a few antigenic variants survive, multiply, and cause a new fever spike. This cycle repeats itself over a long period. The lytic antibody is directed against the surface glycoprotein.
The disease is endemic in sub-Saharan Africa, the natural habitat of the tsetse fly. Both sexes of fly take blood meals and can transmit the disease. The fly is infectious throughout its 2- to 3-month lifetime. T. gambiense is the species that causes the disease along water courses in west Africa, whereas T. rhodesiense is found in the arid regions of east Africa. Both species are found in central Africa.
Although both species cause sleeping sickness, the progress of the disease differs. T. gambiense–induced disease runs a low-grade chronic course over a few years, whereas T. rhodesiense causes a more acute, rapidly progressive disease that, if untreated, is usually fatal within several months.
The initial lesion is an indurated skin ulcer (“trypanosomal chancre”) at the site of the fly bite. After the organisms enter the blood, intermittent weekly fever and lymphadenopathy develop. Enlargement of the posterior cervical lymph nodes (Winterbottom’s sign) is commonly seen. The encephalitis is characterized initially by headache, insomnia, and mood changes, followed by muscle tremors, slurred speech, and apathy that progress to somnolence and coma. Untreated disease is usually fatal as a result of pneumonia.
During the early stages, microscopic examination of the blood (either wet films or thick or thin smears) reveals trypomastigotes (Figure 52–12). An aspirate of the chancre or enlarged lymph node can also demonstrate the parasites. The presence of trypanosomes in the spinal fluid, coupled with an elevated protein level and pleocytosis, indicates that the patient has entered the late, encephalitic stage. Serologic tests, especially the ELISA for IgM antibody, can be helpful.
Treatment must be initiated before the development of encephalitis, because suramin, the most effective drug, does not pass the blood–brain barrier well. Suramin will effect a cure if given early. Pentamidine is an alternative drug. If central nervous system symptoms are present, suramin (to clear the parasitemia) followed by melarsoprol should be given.
The most important preventive measure is protection against the fly bite, using netting and protective clothing. Clearing the forest around villages and using insecticides are helpful measures. No vaccine is available.
The genus Leishmania includes four major pathogens: Leishmania donovani, Leishmania tropica, Leishmania mexicana, and Leishmania braziliensis.
1. Leishmania donovani
L. donovani is the cause of kala-azar (visceral leishmaniasis).
The life cycle of L. donovani is shown in Figure 52–13. The life cycle involves the sandfly3 as the vector and a variety of mammals such as dogs, foxes, and rodents as reservoirs.
FIGURE 52–13 Leishmania donovani. Life cycle. Right side of figure describes the stages within the human (blue arrows). Humans are infected at step 1 when the sandfly bites human and injects promastigotes. Sandfly is infected at step 5 when it ingests macrophages containing amastigotes in human blood. Left side of figure describes the stages within the sandfly (red arrows). (Provider: Centers for Disease Control and Prevention/Dr. Alexander J. da Silva and Blaine Mathison.)
Only female flies are vectors because only they take blood meals (a requirement for egg maturation). When the sandfly sucks blood from an infected host, it ingests macrophages-containing amastigotes (Figures 52–9E and 52–14).4
FIGURE 52–14 Leishmania donovani—amastigotes. Arrow points to an amastigote (nonflagellated form) in cytoplasm of bone marrow cell. (Figure courtesy of Dr. Francis Chandler, Public Health Image Library, Centers for Disease Control and Prevention.)
After dissolution of the macrophages, the freed amastigotes differentiate into promastigotes in the gut. They multiply and then migrate to the pharynx and proboscis, where they can be transmitted during the next bite. The cycle in the sandfly takes approximately 10 days.
Shortly after an infected sandfly bites a human, the promastigotes are engulfed by macrophages, where they transform into amastigotes (Figure 52–9E). Amastigotes can remain in the cytoplasm of macrophages because they can prevent fusion of the vacuole with lysosomes.
The infected cells die and release progeny amastigotes that infect other macrophages and reticuloendothelial cells. The cycle is completed when the fly ingests macrophages containing the amastigotes.
Pathogenesis & Epidemiology
In visceral leishmaniasis, the organs of the reticuloendothelial system (liver, spleen, and bone marrow) are the most severely affected. Reduced bone marrow activity, coupled with cellular destruction in the spleen, results in anemia, leukopenia, and thrombocytopenia. This leads to secondary infections and a tendency to bleed. The striking enlargement of the spleen is due to a combination of proliferating macrophages and sequestered blood cells. The marked increase in IgG is neither specific nor protective.
Kala-azar occurs in three distinct epidemiologic patterns. In one area, which includes the Mediterranean basin, the Middle East, southern Russia, and parts of China, the reservoir hosts are primarily dogs and foxes. In sub-Saharan Africa, rats and small carnivores (e.g., civets) are the main reservoirs. A third pattern is seen in India and neighboring countries (and Kenya), in which humans appear to be the only reservoir.
Symptoms begin with intermittent fever, weakness, and weight loss. Massive enlargement of the spleen is characteristic. Hyperpigmentation of the skin is seen in light-skinned patients (kala-azar means black sickness). The course of the disease runs for months to years. Initially, patients feel reasonably well despite persistent fever. As anemia, leukopenia, and thrombocytopenia become more profound, weakness, infection, and gastrointestinal bleeding occur. Untreated severe disease is nearly always fatal as a result of secondary infection.
Diagnosis is usually made by detecting amastigotes in a bone marrow, spleen, or lymph node biopsy or “touch” preparation (Figure 52–14). The organisms can also be cultured. Serologic (indirect immunofluorescence) tests are positive in most patients. Although not diagnostic, a very high concentration of IgG is indicative of infection. A skin test using a crude homogenate of promastigotes (leishmanin) as the antigen is available. The skin test is negative during active disease but positive in patients who have recovered.
The drug of choice is either liposomal amphotericin B or sodium stibogluconate. With proper therapy, the mortality rate is reduced to almost 5%. Recovery results in permanent immunity.
Prevention involves protection from sandfly bites (use of netting, protective clothing, and insect repellents) and insecticide spraying.
2. Leishmania tropica, Leishmania mexicana, & Leishmania braziliensis
L. tropica and L. mexicana both cause cutaneous leishmaniasis; the former organism is found in the Old World, whereas the latter is found only in the Americas. L. braziliensis causes mucocutaneous leishmaniasis, which occurs only in Central and South America.
Sandflies are the vectors for these three organisms, as they are for L. donovani, and forest rodents are their main reservoirs. The life cycle of these parasites is essentially the same as that of L. donovani.
Pathogenesis & Epidemiology
The lesions are confined to the skin in cutaneous leishmaniasis and to the mucous membranes, cartilage, and skin in mucocutaneous leishmaniasis. A granulomatous response occurs, and a necrotic ulcer forms at the bite site. The lesions tend to become superinfected with bacteria.
Old World cutaneous leishmaniasis (Oriental sore, Delhi boil), caused by L. tropica, is endemic in the Middle East, Africa, and India. New World cutaneous leishmaniasis (chicle ulcer, bay sore), caused by L. mexicana, is found in Central and South America. Mucocutaneous leishmaniasis (espundia), caused by L. braziliensis, occurs mostly in Brazil and Central America, primarily in forestry and construction workers.
The initial lesion of cutaneous leishmaniasis is a red papule at the bite site, usually on an exposed extremity. This enlarges slowly to form multiple satellite nodules that coalesce and ulcerate. There is usually a single lesion that heals spontaneously in patients with a competent immune system. However, in certain individuals, if cell-mediated immunity does not develop, the lesions can spread to involve large areas of skin and contain enormous numbers of organisms.
Mucocutaneous leishmaniasis begins with a papule at the bite site, but then metastatic lesions form, usually at the mucocutaneous junction of the nose and mouth. Disfiguring granulomatous, ulcerating lesions destroy nasal cartilage but not adjacent bone. These lesions heal slowly, if at all. Death can occur from secondary infection.
Diagnosis is usually made microscopically by demonstrating the presence of amastigotes in a smear taken from the skin lesion. The leishmanin skin test becomes positive when the skin ulcer appears and can be used to diagnose cases outside the area of endemic infection.
The drug of choice is sodium stibogluconate, but the results are frequently unsatisfactory.
Prevention involves protection from sandfly bites by using netting, window screens, protective clothing, and insect repellents.
1. Regarding Plasmodium species, which one of the following is most accurate?
(A) These organisms are transmitted by the bite of female Anopheles mosquitoes.
(B) The bite of the vector injects merozoites into the bloodstream that then infect red blood cells.
(C) Both male and female gametocytes are formed in the vector and are injected into the person at the time of the bite.
(D) Hypnozoites are produced by P. falciparum and can cause relapses of malaria after the acute phase is over.
(E) Malaria caused by P. vivax is characterized by a cerebral malaria and blackwater fever more often than malaria caused by the other three species.
2. Regarding drugs used to treat or prevent malaria, which one of the following is most accurate?
(A) The combination of atovaquone and proguanil is useful for the treatment of acute malaria but not for prevention.
(B) Chloroquine is the drug of choice in malaria caused by P. falciparum because resistance to the drug is rare.
(C) Mefloquine is useful for the prevention of chloroquine-sensitive P. falciparum but not for chloroquine-resistant strains.
(D) Artemisinin derivatives, such as artesunate and artemether, are effective in the treatment of multiple-drug resistant P. falciparum.
(E) Primaquine is useful in the treatment of infections caused by P. falciparum because it kills the hypnozoites residing in the liver.
3. Regarding T. gondii, which one of the following is most accurate?
(A) One way to prevent this infection is to advise pregnant women not to drink unpasteurized milk.
(B) The form of Toxoplasma found in the tissue cysts in humans is the rapidly dividing tachyzoite.
(C) The most important definitive host (the host in which the sexual cycle occurs) for Toxoplasma is the domestic cat.
(D) Infection in people with reduced cell-mediated immunity, such as AIDS patients, is characterized by persistent watery (nonbloody) diarrhea.
(E) If your patient is a pregnant woman who has IgM antibody to Toxoplasma in her blood, then you can tell her that it is unlikely that her fetus is at risk for infection.
4. Regarding P. jiroveci, which one of the following is most accurate?
(A) The treatment of choice is a combination of penicillin G and an aminoglycoside.
(B) Finding oval cysts in bronchial lavage fluid supports a diagnosis of Pneumocystis pneumonia.
(C) Large domestic animals such as cows and sheep are an important reservoir of human infection with this organism.
(D) Patients with a CD4 count below 200 should receive the vaccine containing the surface glycoprotein as the immunogen.
(E) Transmission occurs by the ingestion of food contaminated with the organism, after which it enters the bloodstream and is transported to the lung.
5. Regarding T. cruzi, which one of the following is most accurate?
(A) Humans are the main reservoir of T. cruzi.
(B) The drug of choice for the acute phase of Chagas’ disease is chloroquine.
(C) The vector for T. cruzi, the cause of Chagas’ disease, is the reduviid (cone-nosed) bug.
(D) Seeing trypomastigotes in a muscle biopsy supports the diagnosis of Chagas’ disease.
(E) The main site of disease caused by T. cruzi is skeletal muscle, resulting in severe muscle pain.
6. Regarding leishmaniasis, which one of the following is most accurate?
(A) Mefloquine is effective in preventing disease caused by L. donovani.
(B) Large domestic animals such as cattle are the principal reservoir of L. donovani.
(C) Both visceral leishmaniasis and cutaneous leishmaniasis are transmitted by the bite of sandflies.
(D) Marked enlargement of the heart on chest X-ray is a typical finding of visceral leishmaniasis.
(E) Pathologists examining a specimen for the presence of L. donovani should look primarily at eosinophils in the peripheral blood.
7. Your patient is a 20-year-old man who, while playing soccer, experienced palpitations and dizziness and then fainted. An electrocardiogram showed right bundle branch block. Holter monitoring showed multiple runs of ventricular tachycardia. A ventricular myocardial biopsy was performed. Microscopic examination revealed a lymphocytic inflammatory process surrounding areas containing amastigotes. The patient was born and raised in rural El Salvador and came to this country 2 years ago. Of the following, which one is the most likely cause?
(A) L. donovani
(B) P. falciparum
(C) T. gondii
(D) T. brucei
(E) T. cruzi
8. Your patient is a 25-year-old man with fever and weight loss for the past 3 weeks. He is a soldier in the U.S. Army who recently returned from a tour of duty in the Middle East. Physical exam was noncontributory. Laboratory tests revealed anemia and leukopenia. Multiple blood cultures for bacteria and fungi were negative, as was a test for the p24 antigen of HIV. CT scan of the abdomen revealed splenomegaly. A bone marrow biopsy was performed, and a stained sample revealed amastigotes within mononuclear cells. Of the following, which one is the most likely cause?
(A) L. donovani
(B) P. falciparum
(C) T. gondii
(D) T. brucei
(E) T. cruzi
9. Your patient is a 55-year-old man with fever and increasing fatigue during the past week. Today, he was so weak he “could barely stand up.” He had been working in Cameroon and Chad for 2 months and returned 2 weeks ago. On examination, he was febrile to 40±C, hypotensive, and tachycardic. Pertinent lab work revealed anemia and thrombocytopenia. Blood smear revealed ring-shaped trophozoites within red blood cells. Of the following, which one is the most likely cause?
(A) L. donovani
(B) P. falciparum
(C) T. gondii
(D) T. brucei
(E) T. cruzi
10. Your patient is a 35-year-old woman who has just had a seizure. A CT scan shows a ring-enhancing lesion in her brain. History reveals that she is an intravenous drug user and is HIV antibody positive with a CD4 count of 30. Serologic tests confirm that the patient is infected with T. gondii. Which one of the following is the best choice of drug to treat her cerebral toxoplasmosis?
(E) Pyrimethamine and sulfadiazine
11. Regarding the patient in Question 10, she was treated and recovered without sequelae. Antiretroviral therapy was instituted. As long as her CD4 count remains below 100, she should receive chemoprophylaxis to prevent recurrent disease caused by T. gondii. Which one of the following is the best chemoprophylactic drug?
SUMMARIES OF ORGANISMS
Brief summaries of the organisms described in this chapter begin on page 662. Please consult these summaries for a rapid review of the essential material.
PRACTICE QUESTIONS: USMLE & COURSE EXAMINATIONS
Questions on the topics discussed in this chapter can be found in the Parasitology section of PART XIII: USMLE (National Board) Practice Questions starting on page 710. Also see PART XIV: USMLE (National Board) Practice Examination starting on page 731.
1The sexual cycle is initiated in humans with the formation of gametocytes within red blood cells (gametogony) and completed in mosquitoes with the fusion of the male and female gametes, oocyst formation, and production of many sporozoites (sporogony).
2Taxonomically, the last two organisms are morphologically identical species called T. brucei gambiense and T. brucei rhodesiense, but the shortened names are used here.
3Phlebotomus species in the Old World; Lutzomyia species in South America.
4Amastigotes are nonflagellated, in contrast to promastigotes, which have a flagellum with a characteristic anterior kinetoplast.