Common Parasitic Diseases

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[edit] Common Parasitic Diseases

Manoj Jain

[edit] PARASITIC AND TROPICAL DISEASES

Parasitic diseases occur worldwide. Tropical diseases are only “tropical” because of climatologic factors affecting vectors and intermediate hosts. Tropical and parasitic diseases can be imported readily into nonendemic areas in an age of rapid air travel and mass migration. An individual acquiring Lassa fever in West Africa may fly to Paris, then to New York, and on to Kansas City within 24 hours, with the evolution of symptoms and the potential for spread throughout the trip. This may lead to secondary cases in persons who are in transit to dozens of other destinations.

This chapter is designed as an overview for the primary care physician to suggest diagnostic possibilities in a limited number of settings. The reader is referred to detailed textbooks of parasitic and/or tropical diseases and geographic medicine for more comprehensive coverage of particular diseases.

Many parasitic diseases are easily diagnosed and treated by well-established routine procedures and management options. The diagnosis and management of other parasitic diseases may be challenging and may require special expertise, uncommon tests, and unusual drugs. The practitioner should be aware of the services provided by the appropriate departments in medical and public health schools and by local public health agencies. The U.S. Centers for Disease Control and Prevention (CDC) provides advice in the diagnosis and management of parasitic diseases and telephone health advice for travelers. (The website for the CDC is www.cdc.com.) It is a source of unreleased and investigational drugs. The CDC also publishes information about parasitic and tropical diseases in the Morbidity and Mortality Weekly Reports and its supplements. Periodic supplements review recommendations for health aspects of world travel. Similar services are available through public health ministries and agencies in other countries, as well as from the World Health Organization (WHO).

[edit] Parasites of the Alimentary Tract

Parasitic worms of the alimentary tract are highly adapted to existence in the human gastrointestinal tract, its vasculature, and the biliary tract. Table 30-1 lists the parasitic worms that commonly infest and infect the alimentary tract and related structures. The successful parasite causes limited morbidity in its host. The vast majority of people infested with the common worm parasites are asymptomatic. In fact, symptoms are usually the result of a larger than usual number of parasites, or a heavy “worm load.” Asymptomatic infestation, however, may have chronic effects on the host that are not immediately apparent. Symptomatic bearers of worms usually have nonspecific complaints, except for peculiar clinical syndromes discussed later. Many times alimentary tract worms are discovered incidentally when stool is examined in the course of a diagnostic workup for complaints that may or may not be related to the infestation. Diarrhea caused by the protozoan parasites is discussed later.

Table 30-1 Parasitic Worms That Commonly Infest or Infect the Alimentary Tract and Associated Structures

The worm or metazoan (multicellular) parasites of the human alimentary tract and associated organs are divided between two phyla: the flatworms or Platyhelminthes and the roundworms or Nematoda. The worms of both major groups have complex life cycles involving varied intermediate and definitive hosts and larval stages.

[edit] Roundworms of the Alimentary Tract.

The intestinal nematodes, or roundworms, have a worldwide distribution and infest hundreds of millions of individuals. The human intestinal roundworms include Strongyloides stercoralis, the hookworms (Ancylostoma duodenale and Necator americanus), Ascaris lumbricoides, the whipworm (Trichuris trichiura), and the pinworm (Enterobius vermicularis). Over one billion persons worldwide are estimated to be carriers of Ascaris, at least 500 million carry Trichuris, and an estimated 42 million in the United States are infested with pinworms. Other worms include Capillaria philippinensis, which is an intestinal nematode that causes a severe disease in humans, mostly limited in distribution to parts of the Philippines, but rarely reported in other parts of the world as well. These worms live in the mucosa of the small bowel and are occasionally invasive. They are acquired by ingesting freshwater fish containing larvae. The intestinal nematodes have host dependence of varying degree. S. stercoralis can live and reproduce in soil as a free-living organism. The larvae of hookworms feed in soil but require a host for maturation and reproduction. The larvae of Ascaris, T. trichiura, and E. vermicularis develop in excreted eggs and hatch when the eggs are ingested by another host.

[edit] Strongyloides Stercoralis.

The life cycle of S. stercoralis is summarized in Fig. 30-1. Eggs hatch in the host intestine, giving rise to free-living rhabditiform larvae that are passed in the stool. In warm, moist soil the rhabditiform larvae may go on to mature to free-living adult forms or develop into filariform larvae that are capable of invading human skin. Larvae migrate from the skin to the bloodstream and are carried to the lung, where they penetrate the airway, climb the trachea, and are subsequently swallowed. In the proximal small bowel the larvae mature to the adult forms that invade the mucosa. The rhabditiform larvae also may develop into filariform larvae in the gut lumen, leading to autoinfection and maintenance of the disease despite removal of the host from an endemic area. In immunosuppressed and debilitated patients, patients with human immunodeficiency virus (HIV) infection, and patients on corticosteroids, this cycle of autoinfection may lead to a syndrome of hyperinfection with S. stercoralis.

Figure 30-1 Life of cycle of Strongyloides stercoralis. (From Brown HW, Neva FA: Basic clinical parasitology, ed 5, Norwalk, Conn, 1983, Appleton-Century-Crofts.)

Most patients with strongyloidiasis are asymptomatic. A heavy worm load can lead to epigastric pain, weakness, malaise, and watery diarrhea, perhaps due to an absorptive defect. Upper gastrointestinal radiographic studies may show duodenal and jejunal mucosal edema. Ulceration and even intestinal perforation may occur. The hyperinfective syndrome can be an overwhelming systemic disease that is often fatal. Extensive migration of larvae can lead to derangement of multiple organs, abscesses in the liver and other organs, and development of adult worms in the bronchial tree. The diagnosis of strongyloidiasis is made by demonstrating larval forms in the stool (Fig. 30-2) or parasites in duodenal aspirates or biopsies.

Figure 30-2 Worm eggs (A) encountered during microscopic examination of stool. Fecal vegetable artifacts (B) that may be confused with ova and parasites. (From Brown HW, Neva FA: Basic clinical parasitology, ed 6, Norwalk, Conn, 1994, Appleton-Century-Crofts.)

[edit] Hookworm.

Hookworm disease is transmitted by passage of eggs in the stool, which hatch in warm, moist soil, forming rhabditiform larvae that develop within a few days into filariform larvae. There are no free-living adult forms. Filariform larvae invade the skin and migrate in the same way as the larvae of S. stercoralis. The life cycle of the hookworm is summarized in Fig. 30-3. Once the larvae reach the small intestine, they mature to adults that attach to the duodenal and jejunal mucosa and suck blood. An adult A. duodenale is capable of sucking up to 0.1 to 0.3 ml of blood per day; N. americanus removes somewhat less. The worms produce an anticoagulant that causes blood to ooze around the feeding worm, leading to blood in the stool and more blood loss. Worm load can be in the thousands, and the life span of adult hookworms may be several years. Humans may develop infestation with other species of hookworm that have animals, such as dogs and cats, as primary hosts.

Figure 30-3 Life cycle of the hookworm. Filariform larvae in (A) the soil penetrate the skin and are carried in the circulation to the lungs (B) where they break out of the capillary bed into the alveolar spaces, are swept up the bronchial tree, are swallowed, and become adult worms (C) in the small intestine. (From Beck JW, Davies JE: Medical parasitology, ed 3, St Louis, 1981, Mosby.)

The most important clinical manifestation of hookworm disease is anemia. The degree of anemia is a function of the worm load. This iron deficiency anemia is due to chronic blood loss and is compounded by malnutrition; it may be severe enough to lead to cardiomegaly. Varying degrees of malabsorption are a concomitant of the infestation and further complicate the disease. Children with significant worm loads may experience growth retardation and inanition. Individuals with hookworm disease may also complain of hunger and nondescript abdominal pain. The diagnosis is made by demonstrating the hookworm ova in the stool (see Fig. 30-2). Hookworm should be suspected in any patient with hypochromic, microcytic anemia who is living in a warm climate with direct exposure to moist soil.

The filariform larvae of S. stercoralis and the hookworms can cause a localized dermatitis, called ground itch, when they invade the skin. The usual setting is warm, moist soil and bare feet. Likewise, larval migration through tissues may lead to systemic and pulmonary symptomatology. Skin and systemic syndromes produced by migrating nematode larvae are discussed later.

[edit] Ascaris Lumbricoides.

A. lumbricoides is the largest intestinal roundworm, reaching lengths of up to 30 cm. The life cycle of the worm is presented in Fig. 30-4. The infestation is acquired when embryonated eggs, which are passed in the stool and mature in soil, are ingested. The larvae hatch in the bowel, invade the bowel wall, and are carried to the lungs, where they penetrate the alveoli, climb the trachea, and are swallowed. This migration can lead to marked peripheral eosinophilia and pulmonary infiltrates. The adult worms mature in the small intestinal lumen, and the mature female worm can produce more than 200,000 eggs a day.

Figure 30-4 Life cycle of Ascaris lumbricoides. Infective eggs, ingested in contaminated food and water, hatch in the small intestine where penetration of the mucosa (A) results in invasion of the bloodstream by the larvae, which are carried to the lungs. The larvae, too large to cross the capillary bed, break out into the alveolar spaces (B), are carried up the bronchial tree, are swallowed, and reach the small intestine where they become adult worms (C). (From Beck JW, Davies JE: Medical parasitology, ed 3, St Louis, 1981, Mosby.)

The major symptoms of ascariasis are due to the migrating larvae. These systemic symptoms are discussed later in the chapter. Individuals carrying adult worms are usually asymptomatic. Symptoms, when they occur, are related to the worm load. With light to moderate infestation, vague abdominal pain may occur. With heavy infestation, especially in children, the major complication is mechanical obstruction of the intestine caused by the mass of worms. Worms may migrate to aberrant locations causing biliary tract obstruction, pancreatitis, or appendicitis. Occasionally bowel perforation and peritonitis occur. Diagnosis of ascariasis is made by demonstrating fertilized and unfertilized eggs in stool (see Fig. 30-2). Adult worms in the bowel lumen may appear on intestinal radiographic contrast studies.

[edit] Trichuris Trichiura.

The adult T. trichiura, the whipworm, attaches to the colonic mucosa. Eggs passed in the stool mature in the soil. Ingested eggs hatch in the small bowel, and the larvae pass into the colon where they mature. The larvae do not invade tissue. Most patients with whipworm are asymptomatic. Heavy infestation may lead to dysentery-like symptoms and occasionally hemorrhage and anemia. Rectal prolapse may occur, and the small white worms may be seen attached to the prolapsed mucosa (“coconut cake” rectum). Diagnosis is made by demonstrating the typical eggs in the stool (see Fig. 30-2).

[edit] Enterobius Vermicularis.

The pinworm, E. vermicularis, also inhabits the colon. Adult female worms migrate through the anus at night and deposit eggs on the perianal and perineal skin. The migration causes intense pruritus. The eggs become infective within hours and are resistant to drying. They can disseminate widely, similar to dust particles, leading to autoinfection as well as family and institutional outbreaks (Fig. 30-5). Whole families typically become infested. After ingestion, the eggs hatch in the small bowel and migrate to the colon, where they mature. There is no tissue invasion.

Figure 30-5 Life cycle of Enterobius vermicularis and the procedure for the adhesive tape test to reveal migrating worms. (From Brown HW, Neva FA: Basic clinical parasitology, ed 5, Norwalk, Conn, 1983, Appleton-Century-Crofts.)

The primary symptoms of pinworm infestation are related to the nocturnal migration of the gravid female worms. Moderate to severe perianal pruritus occurs, and excoriation from scratching results. Migration to the vagina may cause vaginitis. The diagnosis may be made by demonstrating eggs or worms in the stool, but it is more easily established by microscopic examination of transparent (Scotch) tape, the adhesive side of which has been pressed to the anus and perianal skin (see Fig. 30-5). The highest yield is obtained during the night or early morning. Adult female worms are captured on the adhesive tape.

The treatment for intestinal nematodes has been made simpler by the availability of mebendazole (Vermox). This agent can be used for all the worms except S. stercoralis. Asymptomatic, light infestation with hookworms, without anemia, need not be treated. In the case of mixed infestations, including Ascaris, treatment is directed against Ascaris first, since inadequate treatment of these worms may result in their aberrant migration. Entire families of patients with pinworm should be treated to prevent recurrence. S. stercoralis infestations are treated with thiabendazole. Current recommendations for the treatment of persons with intestinal roundworms are summarized in Table 30-2. Mebendazole is teratogenic in animals and should not be used during pregnancy (albendazole is a related benzimidazole), although the alternative, pyrantel pamoate, has not been established as safe in pregnant women and the fetus.

Table 30-2 Treatment for Intestinal Roundworms

[edit] Tapeworms.

The tapeworms, or cestodes, are hermaphroditic flatworms. Adults live in the gut lumen of the definitive host. These worms have no gut and absorb nutrients across their integument. Larval forms encyst in the tissues of intermediate hosts.

Four tapeworms are important human intestinal parasites: Taenia saginata (beef tapeworm), T. solium (pork tapeworm), Diphyllobothrium latum (broad or fish tapeworm), and Hymenolepis nana (dwarf tapeworm). The first three are named after the usual food source from which people acquire the parasite. Larval forms, encysted in meat or fish (the cysticercus or plerocercoid, respectively), are ingested and develop into adult forms in the gut lumen. H. nana uses the human as both definitive and intermediate host. Cysticerci of this species develop in the bowel wall, and larvae are released into the lumen to form more adults. H. nana is transmitted through ingestion of ova passed in stool. T. solium (Fig. 30-6) also is capable of using humans as its intermediate host. Ova may be ingested with material contaminated with stool from an affected person, or ova may reach the stomach or duodenum by reverse peristalsis. The ova hatch, producing larvae that invade tissue, leading to cysticercosis, a disease discussed below in the section dealing with parasites that cause mass lesions in tissue.

Figure 30-6 Life cycle of Taenia solium. (From Brown HW, Neva FA: Basic clinical parasitology, ed 5, Norwalk, Conn, 1983, Appleton-Century-Crofts.)

Several tapeworms, which are primarily parasites of other animals, are occasionally found in the human gut. Of note are Dipylidium caninum (dog or cat tapeworm) and H. diminuta (rat tapeworm), which infect humans when the intermediate host, the flea, is inadvertently ingested.

Tapeworms are composed of a scolex, or head, that attaches to the intestinal mucosa, and a chain of progressively mature segments (proglottids) that contain the reproductive parts and produce ova. Gravid proglottids and eggs are shed in the stool. These ova may then reinfect in the case of H. nana or are ingested by intermediate hosts, hatch, invade, and form tissue cysts. Tapeworms are cosmopolitan parasites. Epidemics of D. latum in the United States have been associated with eating certain types of fish from Midwestern lakes. Control measures for tapeworms include adequate cooking of meat and fish, sanitary hygiene practices, and assurance of safe feed for hogs and cattle.

Most patients with tapeworms are asymptomatic. Worms may be harbored in the gut for many years. Symptoms, when they occur, may be related to heavy worm load and are usually nondescript; they include mild abdominal pain, diarrhea, malaise, and occasionally constipation. The motile proglottids of Taenia sometime force their way through the anus. D. latum can successfully compete with the host for vitamin B₁₂ and infestation with this tapeworm can lead to megaloblastic anemia. The ability of H. nana to autoinoculate may lead to heavy worm loads and cramping pain, diarrhea, nausea and vomiting, and headache. Intestinal erosions may occur. In children, heavy H. nana infestation may be associated with irritability and rarely seizures. These neurologic manifestations have been ascribed to absorption of toxic substances produced by the worms. The diagnosis of tapeworm infestation is made by demonstrating eggs (see Fig. 30-2) or proglottids in the stool.

Praziquantel is the drug of choice for tapeworm disease. The oral dose is 5 to 10 mg/kg in one dose for T. solium, T. saginata, and D. latum and 25 mg/kg in one dose for H. nana. The alternative agent for tapeworms is niclosamide in an adult dose of 2 gm once for all the tapeworms except for H. nana, which is treated with 2 gm as one dose, then 1 gm/day for 6 days, as the drug is inactive against the cysticerci in the bowel wall that erupt after 4 days. The pediatric doses of niclosamide are adjusted to 1.0 or 1.5 gm.

[edit] Flukes

[edit] Schistosomiasis (Blood Flukes).

Acute schistosomiasis may present as a febrile, systemic process. It occurs 1 to 2 months after exposure to cercariae, at a time corresponding to the onset of egg production by the parasite. It is characterized by fever, weight loss, diarrhea, cough, abdominal pain, and headache. Acute disease may be especially severe with Schistosoma japonicum infection and is called Katayama fever. Peripheral blood eosinophilia is often of marked degree.

Several trematode worms, or flukes, are capable of infecting humans. The most important human flukes are in the genus Schistosoma. More than 200 million people worldwide have schistosomiasis. The predominant species that infect humans are S. mansoni, S. japonicum, S. mekongi, and S. haematobium. S. malayensis occurs in Southeast Asia and resembles S. japonicum and S. mekongi. S. intercalatum is closely related to S. haematobium and is an increasing problem in Africa.

Schistosomes have complex life cycles (Fig. 30-7), which involve specific snails as intermediate hosts. The disease occurs in many parts of the world. Its distribution depends on the distribution of particular species of snail. The disease is acquired by exposure to fresh water containing the fork-tailed larvae, called cercariae, which are released from the intermediate host. Cercariae are capable of penetrating the skin, where they lose their tails and become schistosomula. Schistosomulae migrate to the lung, then the liver, where they mature to adult forms. The adult forms then join in permanent sexual coupling and migrate to their final intravascular location, the mesenteric veins in the case of S. mansoni, S. japonicum, S. mekongi, and S. malayensis; the perirectal venules in the case of S. intercalatum; and the venous plexus of the urinary bladder in the case of S. haematobium. The mating pair of adult worms produce hundreds to thousands of eggs daily over several years. These eggs make their way across the intestinal and bladder mucosae and are excreted. In fresh water the eggs hatch larvae, called miracidia, which invade snails and continue the cycle.

Figure 30-7 Life cycle of Schistosoma mansoni. (From Brown HW, Neva FA: Basic clinical parasitology, ed 5, Norwalk, Conn, 1983, Appleton-Century-Crofts.)

The signs and symptoms of schistosomiasis depend on the worm load. An acute illness usually occurs about 1 month (2 weeks to 2 months) after exposure to the cercariae and correlates with the time of initial egg production. This syndrome is characterized by fever, abdominal pain, diarrhea, and pulmonary complaints associated with marked peripheral blood eosinophilia. S. japonicum is the most prodigious egg producer, and the syndrome it produces, Katayama fever, usually occurs with the most severe infection due to other species, but it may occur with heavy infection due to other species. Most of the morbidity of schistosomiasis is seen with chronic infection. Chronically affected individuals may have systemic complaints, diarrhea, and abdominal pain. Presinusoidal portal hypertension may result from eggs lodging in the sinusoids of the liver with resultant chronic inflammation. Eggs may be shunted to the systemic circulation with deposition in the lungs, central nervous system (CNS), and other organs. Involvement of the urinary tract with S. haematobium can lead to structural abnormalities due to granuloma formation with obstruction, secondary infection, and uremia.

The diagnosis of schistosomiasis is made by demonstrating the characteristic eggs in stool or urine (see Fig. 30-2). Urine is best collected between noon and 2 pm. Because eggs may continue to make their way into excreta for a prolonged period, a count of viable eggs, allowed to hatch in vitro, is a better indicator of live worm load than simple stool examination. Rectal biopsy with demonstration of eggs in the mucosa may be used to diagnose all species.

Praziquantel is the drug of choice for the treatment of schistosomiasis. Recommended doses vary depending on the species of schistosome. Oxamniquine also is effective in the treatment of S. mansoni infection. Metriphonate is an alternative drug for the treatment of S. haematobium. The latter drugs and advice about their use are available through the CDC. Current recommendations for the treatment of schistosomiasis are summarized in Table 30-3. Many patients with schistosomiasis have a small worm burden and do not require therapy. The decision to treat should be based on the severity of symptoms, clinical activity, and worm load.

Table 30-3 Treatment for Schistosomiasis

[edit] Intestinal Flukes.

The intestinal flukes, Fasciolopsis buski, Heterophyes heterophyes, and Metagonimus yokogawai, inhabit the small bowel. These worms have a complex life cycle involving snails and aquatic plants or fish as intermediate hosts. They occur primarily in Asia, but H. heterophyes also is seen in Egypt. Most affected individuals are symptomatic, although abdominal pain and diarrhea are occasionally associated with infestation. Diagnosis is made by demonstrating eggs in stool (see Fig. 30-2). Praziquantel in doses of 25 mg/kg three times in 1 day is effective for the treatment of intestinal flukes.

[edit] Liver Flukes.

Five species of liver fluke are most likely to infect humans: Clonorchis sinensis, Opisthorchis felineus, O. viverrini, Fasciola hepatica, and F. gigantica. The first three occur primarily in Asia and Eastern Europe, whereas Fasciola species are common parasites of sheep and cattle and are distributed widely. The liver flukes have a complex life cycle, with snails as primary intermediate hosts; secondary intermediate hosts include fish and aquatic plants. The adult worms live in the biliary tract. The vast majority of individuals with liver flukes are asymptomatic, but early in F. hepatica infection the migration of worms into the biliary tract may be associated with fever, hepatomegaly, right upper quadrant pain, and eosinophilia. Occasionally, biliary obstruction and cholangitis occur. Eggs appear in bile and stool.

Praziquantel in a dose of 25 mg/kg three times in 1 day is effective therapy for Opisthorchis species and C. sinensis. Bithionol (available from the CDC) in a dose of 20 mg/kg twice a day, every other day, for 10 to 15 doses is currently recommended for F. hepatica. Triclabendazole, a veterinary drug that may have fewer side effects, also has been used to treat sheep liver flukes.

[edit] Protozoan Infections

Protozoa are single cell organisms that cause a wide range of infections. Protozoa invade various organs of the body causing infection of the intestine, blood, or deep tissues. Some protozoa, such as Pneumocystis carinii, Toxoplasma gondii, and Cryptosporidium have become significant causes of morbidity and mortality among acquired immunodeficiency syndrome (AIDS) patients.

[edit] Intestinal Protozoan Infections

[edit] Entamoeba Histolytica (see Chapter 111 ).

The diagnosis of amebiasis is made by demonstrating trophozoites or cysts in the stool of the affected individual (Fig. 30-8). These are best demonstrated in a fresh stool sample. Several other amebae that are of little or no pathogenic significance may be found in the stool, so that examination of the stool requires an experienced observer.

Figure 30-8 Entamoeba histolytica.A, Trophozoite containing phagocytized red blood cells. B, Precystic ameba. C, Young cyst. D, Binucleate cyst. E, Mature cyst (with four nuclei). c, Chromatoid bodies; ect., ectoplasm; end., endoplasm; g, glycogen acuole; k, karyosome; n, nucleus; r.b.c., red blood cells. (From Brown HW, Neva FA: Basic clinical parasitology, ed 6, Norwalk, Conn, 1994, Appleton-Century-Crofts.)

Effective treatment of symptomatic intestinal amebiasis must be directed toward eradication of both invasive organisms and luminal trophozoites and cysts. Metronidazole (750 mg, by mouth, three times a day for 10 days) is the drug of choice for the former, followed by iodoquinol (650 mg, by mouth, three times a day for 20 days; exceeding the dose carries the risk of optic neuritis) or diloxanide furoate (500 mg, by mouth, three times a day for 10 days; available only through the CDC) for the latter. Tinidazole, a drug closely related to metronidazole, may replace metronidazole as the drug of choice. Asymptomatic carriers of cysts and/or trophozoites may be treated with diloxanide furoate to prevent evolution of invasive disease and transmission of the agent. Iodoquinol (650 mg, by mouth, three times a day for 20 days) is an alternative to diloxanide, but doses in excess of those recommended have been associated with optic neuritis.

[edit] Giardia Lamblia.

G. lamblia is a flagellate protozoan parasite of the intestine that is being increasingly recognized as a cause of diarrhea. The parasite attaches to the epithelium of the proximal small bowel and causes abdominal cramps, bloating, and diarrhea. Symptoms may be remittent. Cyst forms passed in the stool transmit the infection.

The natural history of the parasite is poorly elucidated, and several primary animal hosts have been proposed. Most outbreaks of giardiasis have been associated with waterborne transmission, although the fecal-oral route is clearly important in households, family day care, and institutional transmission. Sporadic cases of giardiasis occur throughout the world, and it is a frequent cause of diarrhea in travelers.

The diagnosis of giardiasis depends on demonstrating the trophozoite or cyst in stool or other specimens. If stool is negative, and if the diagnosis is strongly suspected on clinical and epidemiologic grounds, aspiration of duodenal contents or the “string test” may be undertaken. The string test is accomplished by having the patient swallow a commercially available gelatin capsule containing 140 cm of nylon string, the free end of which is secured to the face. The string usually passes to the duodenum and may be gently removed after several hours. Examination of material expressed from the distal end of the string is examined for parasites.

Treatment of giardiasis is with quinacrine (100 mg, by mouth, three times a day for 5 days) or metronidazole (250 to 750 mg, by mouth, three times a day for 5 to 10 days). Metronidazole appears to be safe and effective, but larger than usual doses may be required in some cases. Treatment of asymptomatic as well as symptomatic household contacts may be indicated.

[edit] Blastocystis Hominis.

B. hominis is a protozoan parasite first described in the early part of this century. It has been associated with diarrhea for many years, but its role as a cause of diarrheal illness has not been clearly established. Diarrhea with B. hominis in the stool in large numbers (>5 per oil immersion field) has been linked epidemiologically with travel and with drinking of untreated water. The drug of choice has not been determined. Metronidazole is usually selected because of its efficacy in other similar infections, and iodoquinol or trimethoprim-sulfamethoxazole has been used as an alternative.

[edit] Other Intestinal Protozoan Infections.

Recently a newly recognized protozoan parasite has been described in association with outbreaks of diarrhea in widespread parts of the world. This organism is thought to be either a cyanobacterium or a coccidian parasite and has been named Cyclospora cayetanensis. The disease has an abrupt onset of watery diarrhea, nausea, and anorexia with a waxing and waning prolonged course of 2 to 12 weeks. Resolution is also abrupt, but may be followed by prolonged fatigue. Organisms have been seen in duodenal aspirates, as well as in stool. The disease tends to occur during warm and wet seasons. Transmission seems to be predominantly waterborne. Sporadic cases may occur in the absence of a recognized outbreak. Successive infections in the same individual have been documented. Treatment options are under investigation, but trimethoprim-sulfamethoxazole appears to be promising.

Human infection with protozoal parasites of the gastrointestinal tract of domesticated animals is becoming recognized in widespread parts of the world. In immunocompetent hosts, symptomatic disease related to these parasites appears to be confined to a self-limited episode of gastroenteritis, although asymptomatic carriage of organisms may be prolonged. Severe, intractable diarrhea has been observed in patients with AIDS due to C. parvum, Isospora belli, and other protozoa. Effective drugs against these parasites that are safe for use in humans, are not available. Recently, a large epidemic of C. parvum infection that was related to contamination of drinking water with cysts occurred in Milwaukee. C. parvum is commonly found in surface waters and probably causes a number of sporadic diarrheal illnesses in persons with altered immune function due to underlying disease or age. Vigorous pursuit of more effective water treatment methods is underway.

[edit] Blood and Tissue Protozoan Infections

[edit] Malaria.

The first known description of malaria is that of Hippocrates during the fourth century bc. It was only during the late nineteenth and early twentieth centuries that the etiology and natural history of malaria were elucidated. Great strides were made in the control and treatment of malaria during the first half of this century. Whereas in many areas, such as Europe and the United States, the disease has been eradicated, in other areas of the world the parasite is making new gains. The emergence of mosquitoes resistant to pesticides has contributed to this increase, as have sociopolitical setbacks. These factors and others have led to a resurgence of the disease in the tropics. The ability of the parasite to develop resistance to antimalarial drugs has made treatment and prevention more difficult. Thus malaria is an increasing world health problem. The effect of this disease on the health and economy of the world is immeasurable. In the United States most cases of malaria are imported. Failure to diagnose and treat early results in a more than tenfold increase in mortality rate over that observed when the diagnosis is considered at clinical presentation.

Human malaria is caused by four species of the protozoan genus Plasmodium: P. falciparum, P. vivax, P. ovale, and P. malariae. Disease is transmitted by infection of the sporozoite form through the bite of an anopheline mosquito. Sporozoites invade liver parenchymal cells, and after 2 weeks merozoites are released into the bloodstream. Merozoites invade erythrocytes and the parasite develops into a trophozoite. Trophozoites differentiate in erythrocytes to produce either more merozoites or gametocytes. Merozoites continue the cycle of erythrocyte parasitism.

Male and female gametocytes, taken up by mosquitoes during a blood meal, initiate a phase of sexual reproduction, and development ultimately produces sporozoites. The life cycle of Plasmodium is summarized in Fig. 30-9. P. vivax and P. ovale are capable of latent infection of liver cells, which may give rise to merozoites and therefore clinical disease at times distant from exposure. P. falciparum does not have an exoerythrocytic phase. Malaria also may be transmitted by blood transfusion and intravenous injection using contaminated needles.

Figure 30-9 Life cycle of the malaria Plasmodium in humans. The sporozoite is introduced in the saliva of the biting mosquito. (From Brown HW, Neva FA: Basic clinical parasitology, ed 5, Norwalk, Conn, 1983, Appleton-Century-Crofts.)

Clinical signs and symptoms of malaria relate directly to red blood cell parasitism. Erythrocytes parasitized with developing parasites lodge in the microvasculature, causing tissue ischemia with resultant dysfunction and damage. Such tissue ischemia contributes to the dangerous process of cerebral malaria. The malarial paroxysm consists of chills and headache progressing to high fever, severe headache, myalgia, abdominal pain, delirium, nausea, and vomiting. The classic paroxysm of malaria occurs every 2 days, or in the case of P. malariae every 3 days, during the early evening at the time when the vectors, anopheline mosquitoes, usually feed. With acute malaria and malaria in the nonimmune person, the classic paroxysm with regular periodicity usually is not seen. Patients are often persistently febrile and symptomatic or have irregularly intermittent fever and symptoms. The paroxysm is associated with the lysis of parasitized erythrocytes with release of merozoites and other parasite products. The release of these products leads to fever and other systemic effects.

Another important pathophysiologic consequence is the hemolytic anemia resulting from destruction of red blood cells and the sequestration of parasitized erythrocytes in the spleen. Anemia may vary from mild to severe. Severe hemolysis may lead to hemoglobinuria and renal failure. Symptoms and anemia are usually most severe with P. falciparum infection, as this organism tends to cause the heaviest parasitemia because of its ability to invade erythrocytes of all ages (the other species have a predilection for young or old cells). Splenomegaly is frequent and splenic rupture is a dangerous but uncommon complication. Severe P. falciparum infection may be complicated by encephalopathy, “cerebral malaria,” due to hypoxia resulting from deep vascular sequestration of parasitized erythrocytes. Nephrotic syndrome occurs only with P. malariae infection. This is probably related to the chronic, low-grade, subclinical parasitism that occurs with this species. Such subclinical parasitism accounts for the observation that most transfusion-related cases of malaria are caused by P. malariae.

The diagnosis of malaria is made by examining stained smears of the peripheral blood. In a patient with unexplained fever, suspicion of malaria should be aroused by a history of residence in an endemic area. Blood smears may show ring forms, trophozoites, schizonts, and gametocytes. Interpretation of smears as to species usually requires expert consultation. Simultaneous infection with more than one species may occur.

The therapy of malaria is complicated by the widespread emergence of chloroquine resistance by P. falciparum, the species that causes the most severe disease. Chloroquine has been an effective, relatively inexpensive, and safe therapy for all forms of malaria. P. falciparum, probably related to the high levels of parasitemia it achieves, is capable of evolving mechanisms of drug resistance through pressure of natural selection. The widespread use of chloroquine provided this selective pressure. Chloroquine-resistant strains of this species are present, and new treatment strategies have been developed and are under investigation. Unfortunately, P. falciparum is becoming more resistant to other agents as well.

Treatment of choice for uncomplicated malaria caused by P. vivax, P. ovale, and P. malariae is chloroquine phosphate, 1 gram (600 mg base) orally, followed by half this dose at 6 hours and then once a day for 2 days. The equivalent initial pediatric dose would be 10 mg base/kg. Severe illness is treated with intravenous quinidine gluconate (with electrocardiographic [ECG] monitoring) followed by oral therapy if possible. Treatment of P. vivax and P. ovale must include primaquine phosphate, 15 mg base daily for 14 days or 45 mg base weekly for 8 weeks (0.3 mg base/kg/day for 14 days in children) for “radical” cure with elimination of exoerythrocytic forms. Glucose-6-phosphate dehydrogenase deficiency must be ruled out before initiating primaquine therapy, because the drug may precipitate hemolysis. Chloroquine- resistant P. falciparum is treated with quinine sulfate (650 mg, by mouth, every 8 hours for 3 to 7 days) combined with pyrimethamine/sulfadoxine (three tablets on the last day of quinine), tetracycline, or clindamycin. Mefloquine and halofantrine are alternative agents. Intravenous quinidine gluconate is used for severe disease or if oral therapy is not possible. Suspected or documented P. falciparum acquired in areas where chloroquine resistance is known to occur is treated as if it were chloroquine-resistant. Suppressive and chemoprophylactic therapy of malaria is discussed later (see Advice to Travelers).

[edit] Babesiosis.

Babesiosis is a zoonosis caused by protozoa of the genus Babesia, which are transmitted by ticks. The parasite infects a number of mammals but is rarely transmitted to humans. The disease is not tropical. It occurs in a number of regions, but most cases have been reported from the United States, especially on Nantucket Island and Martha's Vineyard. Asplenic individuals are particularly susceptible to severe infection.

Signs and symptoms are similar to those of malaria: fever, splenomegaly, and anemia. Significant complications include massive hemolysis and renal failure. Diagnosis is made by demonstrating intraerythrocytic parasites on blood smears. Effective therapy has not been established. Chloroquine may cause symptomatic relief without eradication of the parasites. Clindamycin plus quinine are often used to treat babesiosis, but this therapy is considered investigational. Babesiosis also has been treated with exchange transfusion.

[edit] Toxoplasmosis.

Toxoplasmosis is a disease of animals and people, widely distributed throughout the world. The protozoan T. gondii is an intracellular parasite capable of invading virtually all mammalian cell types. The definitive host is the cat. In the cat the parasite undergoes sexual reproduction, producing oocysts that are passed in the stool. In tissue the parasite is capable of multiplying asexually, leading either to the release of invasive trophozoites after cell lysis or the formation of tissue cysts. Toxoplasmosis is transmitted by ingestion of oocysts, ingestion of undercooked meat containing tissue cysts, or transplacentally. Undercooked meat is the most common means of transmission. Most cases of toxoplasmosis are subclinical. Serologic evidence of past infection increases in prevalence with increasing age. In some parts of the United States, as many as 70% of adults have antibody to Toxoplasma. Tissue cysts cause latent disease that may reactivate long after the initial exposure.

Clinically evident toxoplasmosis may present in several different forms of illness. In normal immunocompetent adults and children, the disease is typically a generalized febrile illness with lymphadenopathy, malaise, myalgia, sore throat, and hepatosplenomegaly. This syndrome is similar to infectious mononucleosis, and atypical lymphocytes may appear in the peripheral blood. Occasionally, a maculopapular rash occurs. The disease also may present predominantly as a localized process involving the CNS, liver, heart, or other organ. Of special importance is ocular toxoplasmosis, which is usually the result of congenital infection, but occasionally is acquired after birth. Characteristic lesions of chorioretinitis may be seen on funduscopic examination. These lesions may remain latent or reactivate with increasing damage to vision.

Congenital toxoplasmosis occurs after primary infection during pregnancy. Congenital infection has protean manifestations ranging from asymptomatic infection to severe multisystem involvement with retardation. Chorioretinitis is common with congenital infection.

Toxoplasmosis has become an important problem in immunocompromised patients because of the ubiquitous distribution of the parasite and its ability to exist in a latent form. Severe, newly acquired, or reactivated latent disease occurs in association with AIDS, in transplant recipients, in patients with neoplastic diseases, and others receiving immunosuppressive therapy. These patients may present with severe systemic illness or disease located predominantly in one organ or organ system, especially the CNS. CNS toxoplasmosis is an important AIDS-related opportunistic infection. Toxoplasmosis is among several diseases presenting with pneumonitis and encephalitis in the immunocompromised patient.

The diagnosis of toxoplasmosis may be made by isolating the parasite or demonstrating it in histologic sections, but usually is made on the basis of serologic testing. Several serologic tests are available, including the Sabin-Feldman dye test and the indirect fluorescent antibody (IFA) test. Because of the high prevalence of positive serology in many populations, the presence of a single significant titer in these tests cannot differentiate acute from old infection. Rising titers imply recent infection. Acute toxoplasmosis may be diagnosed by the immunoglobulin M (IgM)-IFA test. A single titer of 1:80 or greater, or a rising titer on two or more observations, signifies acute infection.

Acute toxoplasmosis is usually self-limited. Treatment is limited to patients with severe disease or those who are immunocompromised. The therapy of choice is pyrimethamine combined with sulfadiazine. The dose of pyrimethamine for adults is 25 to 100 mg/day for 1 month. The dose of sulfadiazine is 1 to 1.5 gm qid for the same period. Pyrimethamine is a potent bone marrow suppressant, and patients should receive 10 mg folinic acid a day to support the marrow. Folic acid must not be given, since it inhibits the activity of pyrimethamine against T. gondii. Steroids are usually used in the treatment of ocular toxoplasmosis in addition to specific therapy, since the inflammatory response to T. gondii increases retinal damage. In patients with AIDS, suppressive therapy should be maintained indefinitely after therapy of acute disease.

[edit] Leishmaniasis.

Visceral leishmaniasis, or “kala-azar,” is a systemic disease caused by the intracellular protozoan parasite Leishmania donovani. Other species of the genus Leishmania cause cutaneous and mucocutaneous leishmaniasis. Kala-azar occurs in many parts of the world but primarily in tropical and semitropical regions. The parasite has many animal reservoirs and is transmitted by the bite of sandflies of the genus Phlebotomus. The parasites invade reticuloendothelial cells throughout the body, leading to marked proliferation and hyperplasia. Hyperglobulinemia and antigen-antibody complexes further complicate the disease and glomerulonephritis may occur. The onset may be insidious or acute and is associated with high fever. Chills and diarrhea frequently are present. The disease then has a progressive course of prolonged fever, weight loss, organomegaly (which is often of a marked degree), anemia, hypoalbuminemia, and peripheral edema. Visceral leishmaniasis may complicate HIV infection and other causes of immunocompromise.

The diagnosis is made on the basis of typical clinical findings in the right epidemiologic setting or the demonstration of parasites in tissue.

The disease is treated with stibogluconate (antimony) 20 mg/kg per day (up to 800 mg/day) intramuscularly or intravenously for 20 to 28 days. The dose in children is 10 mg/kg per day (up to 600 mg). Stibogluconate resistance has been seen in some areas of the world. Pentamidine and amphotericin B are alternative therapeutic agents when stibogluconate cannot be used or resistance is encountered. The combination of interferon-γ and stibogluconate may be superior to stibogluconate alone. Untreated, symptomatic disease is usually fatal.

[edit] Trypanosomiasis.

Trypanosomes are hemoflagellate protozoans that cause African trypanosomiasis, or sleeping sickness, and American trypanosomiasis, or Chagas' disease. Trypanosoma brucei gambiense (West African) and T. brucei rhodesiense (East African) are the etiologic agents of sleeping sickness and are transmitted by various strains of the tsetse fly. After the bite of an infected fly, a skin lesion appears at the site. The parasites reproduce in the skin lesion. Dissemination from the initial lesion leads to fever, severe headache, rash, and localized areas of edema. Lymphadenopathy then becomes prominent, especially of the posterior cervical chain. Hepatomegaly and splenomegaly may occur. The disease spreads to the CNS where cerebral damage occurs, leading to the characteristic signs of somnolence, headache, and other neurologic manifestations that eventually lead to continuous sleep. T. brucei rhodesiense tends to cause a fulminant disease over months, whereas T. brucei gambiense causes a disease that progresses over years. Inapparent infection has been described with the latter.

Diagnosis usually is made by demonstrating parasites in the blood or lymph node aspirates, although serologic tests also are available. Early disease, characterized by a predominance of systemic signs and lymphadenopathy, is treatable with suramin, eflornithine, or pentamidine, whereas CNS disease is treated with melarsoprol or eflornithine. These drugs are available through the CDC and should be used only with the guidance of the Parasitic Diseases Division of the CDC.

Chagas' disease is caused by T. cruzi and is transmitted through the feces of biting insects of the reduviid group. These insects defecate while taking their blood meal, and parasites in the feces make their way into small wounds, conjunctivae, and mucous membranes. The disease is limited to the Western Hemisphere and has occurred as far north as Texas. Reduviid bugs capable of transmitting T. cruzi are found in large parts of North America; therefore the potential for spread of infection in the United States exists wherever small mammals live in close proximity to humans. Transmission of trypanosomiasis by blood transfusion from asymptomatic, chronically infected donors also is a concern.

Among infected individuals, 10% to 30% eventually develop symptomatic disease. The morbidity of American trypanosomiasis is primarily related to chronic infection. In endemic areas, Chagas' disease is a major cause of myocarditis and cardiomyopathy, as well as alimentary tract dysfunction manifested by megaesophagus and megacolon. Acute Chagas' disease is a febrile illness that appears 1 to 2 weeks after exposure to the parasite. It is characterized by systemic toxicity, variable fever, lymphadenopathy, hepatosplenomegaly, and signs of myocarditis. A chagoma (a macular, desquamating lesion) may be seen at the site of inoculation. Romaña's sign, unilateral ophthalmia with palpebral edema, may occur. In most cases the acute disease lasts approximately 2 weeks. Acute Chagas' disease in the immunocompromised host can follow a fulminant course. This development has been observed in patients immunosuppressed from cancer chemotherapy. It can be presumed that similar severe disease may occur in patients with immunosuppression due to HIV infection.

The classic means of diagnosing acute Chagas' disease is by xenodiagnosis (i.e., allowing laboratory-bred bugs to bite the patient and examining the bugs for parasites after 1 to 2 months). Parasites also may be demonstrated directly in peripheral smears or by injection of blood into mice. Several serologic tests are available including an enzyme-linked immunosorbent assay (ELISA) that are useful in screening for chronic infection.

Acute Chagas' disease is treatable with two agents, nifurtimox and benznidazole, but the required treatment is prolonged and associated with a high rate of adverse reactions. All cases are not cured. Chronic disease is treated supportively.

[edit] Tissue-Invasive Roundworms

[edit] Filariasis.

Filarial infections are caused by a number of tissue-dwelling nematodes. These diseases occur primarily in tropical and semitropical regions and are transmitted by biting insects. The sexually mature filarial worms live in various tissues and produce microfilarial larvae that migrate in blood and tissues. Clinical manifestations of these infections result from the residence of adult forms in tissue, migration of the adult worms, and the release and migration of the larvae. Much of the morbidity results from hypersensitivity to the parasites. Filarial infections are summarized in Table 30-4.

Table 30-4 Filarial Infections in Humans

The major filarial infections, due to Wuchereria bancrofti, Brugia malayi, Loa loa, and Onchocerca volvulus, affect millions of people in endemic areas, but only a small proportion of those affected develop overt clinical disease. The adult worms cause most of the signs and symptoms of these infections, except for O. volvulus infection, in which the microfilariae cause eye damage leading to “river blindness.” Hypersensitivity reactions to microfilariae cause most of the systemic manifestations of these diseases, and eosinophilia is usually prominent (see later). Several animal filaria have been described in humans, almost all cases of which have been recognized in the United States. Human zoonotic filarial disease is basically the result of the host reaction to parasites that find themselves in an incompatible host.

Diethylcarbamazine is effective against most of the human filariae, but the adult forms of O. volvulus are not killed and go on to produce more microfilariae unless excised or treated with an effective drug such as ivermectin. Ivermectin has become the drug of choice for the treatment of O. volvulus. Diethylcarbamazine can produce an encephalopathy in patients who have a heavy infection with L. loa. Relatively severe allergic reactions can result from the breakdown of killed microfilariae of L. loa and O. volvulus when diethylcarbamazine is used. Such reactions may require treatment with steroids and antihistamines.

[edit] Trichinosis.

Trichinella spiralis is an intestinal roundworm, the invasive larvae of which encyst in muscle tissue and produce the systemic disease trichinosis. The life cycle of T. spiralis is presented in Fig. 30-10. The disease is acquired by ingestion of poorly cooked meat, especially pork, that contains encysted larvae. Outbreaks in the United States also have been associated with bear meat. The ingested larvae become sexually mature in the small intestine, and the adults attach to the mucosa and produce offspring; these larvae invade the gut, migrate to muscle tissue, and encyst. The adult worms are shed in the stool after 2 to 4 weeks. The severity of trichinosis depends on the number of invading larvae and ranges from asymptomatic to fatal.

Figure 30-10 Life cycle of Trichinella spiralis. Infective larvae, encysted in pork and other meat, when ingested, become adult worms in the small intestine. The female burrows into the mucosa and deposits larvae into lacteals and blood vessels. Circulating larvae eventually penetrate skeletal muscle and become encysted (A). In humans these larvae are at a dead end, but in the pig and other animals, they become a source of infection (B). (From Beck JW, Davies JE: Medical parasitology, ed 3, St Louis, 1981, Mosby.)

The disease manifests as an early phase of diarrhea and abdominal pain followed by characteristic periorbital edema, myalgia, fever, sweats, weakness, and eosinophilia. Myocarditis is an important cause of death, and the disease may affect the CNS.

The diagnosis is usually made on clinical grounds, especially when there is a history of ingestion of suspect meat. Diagnosis is made definitively by biopsy of muscle. Several serologic tests also are available, the simplest and most rapid being the bentonite flocculation test.

Specific therapy for muscle disease is not available. Mebendazole and steroids are usually used in severe disease. Control of this disease depends on adequate cooking of meat (freezing for 3 weeks or more is also effective) and safe food sources for swine.

[edit] Visceral Larva Migrans.

Visceral larva migrans is a systemic disease, usually occurring in children, that is caused by tissue migration of the larvae of nonhuman ascarid parasites of the genus Toxocara. The usual host of T. canis is the dog and of T. cati the cat. Eggs are shed in the feces of young dogs and cats. Children become infected by ingesting contaminated soil. The eggs hatch in the intestine, and larvae invade the bowel and begin a persistent migration through the liver, CNS, muscle, and other organs. This migration may persist for weeks to months to years.

Most patients with visceral larva migrans are asymptomatic but may have pronounced peripheral blood eosinophilia. Symptomatic disease is primarily due to the host response to the parasite and is characterized by fever, cough, bronchospasm, hepatomegaly, and abdominal pain. CNS abnormalities and seizures may predominate. Endophthalmitis also may occur, usually in older children and often without significant systemic signs.

The diagnosis is made by association of the clinical picture with eosinophilia and a history of pica. These larval parasites share A and B blood group antigens with humans, and elevated titers of isoagglutinins may be helpful in diagnosis.

The disease is usually self-limited, and symptoms usually resolve despite continued eosinophilia. Severe disease is treated with diethylcarbamazine, 2 mg/kg, three times a day for 7 to 10 days; alternatives are mebendazole and albendazole. Endophthalmitis is treated with adjunctive steroids.

[edit] Enteric Bacterial Infections

[edit] Vibrio Cholerae.

Cholera due to Vibrio cholerae still occurs in many parts of the world. The seventh pandemic caused by the eltor strain began in 1961 in southern Asia and has spread to central Asia, Africa, and South America, with occasional outbreaks in southern Europe and the South Pacific. Cases resulting from earlier strains of the organism surviving in natural habitats for long periods have occurred along the Gulf Coast of the United States.

When sufficient numbers of V. cholerae are ingested to provide an infective dose, they multiply in the small intestine lumen and adhere to epithelial cells without damaging them. They then produce cholera toxin, which stimulates epithelial cell adenylate cyclase. This produces elevated levels of cyclic adenosine monophosphate (AMP), blocking sodium uptake by the cells and causing massive flux of water, bicarbonate, and chloride into the lumen. The organisms do not invade tissue. The severe watery diarrhea produced by the physiologic derangement resulting from cholera toxin is abrupt in onset and may lead to severe dehydration, nausea, muscle cramps, and shock. The disease state is the product of the water and electrolyte loss.

Diagnosis is based on the epidemiologic circumstances and the severe, watery diarrhea. Microscopic examination of stained stool smears may show a monotonous flora of curved gram-negative rods. Treatment is designed to compensate for the water and electrolyte losses with intravenous fluids. Oral replacement fluid composed of sodium and potassium chloride, glucose, and bicarbonate is used. This solution provides sodium in the presence of glucose. The glucose-linked uptake of sodium by the intestinal epithelium is a system independent of the sodium uptake system blocked by the effect of cholera toxin. Preparations of oral rehydration solution ingredients are available for use in cases of diarrhea of any cause and are the mainstay of supportive treatment of moderate to severe diarrhea. Tetracycline and other antimicrobial agents are used to eradicate organisms.

Some strains of V. Cholerae are not of the 01 serotype (which includes the classic and eltor strains). These so-called nonagglutinable or non-01 strains occasionally have been implicated in small outbreaks of diarrheal illness and cases of invasive diarrhea similar to shigellosis. In 1992, a non-01 V. cholerae of the 0139 serotype caused epidemics of cholera-like illness in Bangladesh and India. V. cholerae 0139 produces cholera toxin and causes illness indistinguishable from cholera. It has continued to spread and cause epidemic disease and may be on its way to causing the eighth pandemic of cholera. The management of infection and disease with V. cholerae 0139 is the same for V. cholerae 01 of both the classic and eltor varieties.

[edit] Typhoid Fever.

Typhoid fever is the systemic infection caused by the gram-negative bacillus Salmonella typhi. Although all the salmonellae that are pathogenic for humans are capable of causing disseminated infection after gastrointestinal invasion (i.e., enteric fever), such disease is the rule with S. typhi. This organism has a special virulence for humans, and people are its only natural hosts. The disease is still a major health problem in parts of the developing world. Approximately 400 to 500 cases are reported in the United States each year, with about half occurring in recent travelers.

Typhoid is transmitted by the fecal-oral route. Chronic carriers are important sources of disease in areas where the disease occurs sporadically. In places where there are many cases and sanitation is poor, sewage contamination of water and foodstuffs is important. The organisms reproduce in the small intestine and, like all the salmonellae, are capable of penetrating the intestinal mucosa. The organisms are then phagocytosed by macrophages, but are resistant to killing, so they reproduce intracellularly and eventually cause bacteremia and disseminated foci of viable bacteria in the reticuloendothelial system. The incubation period from ingestion to clinical disease is usually 1 to 2 weeks; however, it may be as long as 1 month.

Patients with typhoid fever may present with severe toxemia or relatively mild fever and systemic complaints of headache and myalgia. They then go on to develop increasing abdominal pain, constipation, and abdominal distention. Rose spots, the maculopapular rash that is classic for typhoid fever, may appear, usually on the trunk, during the full-blown evolution of the disease. Bleeding in the rectum may occur. The disease is characterized by persistent bacteremia. Complications include bowel perforation, hemorrhage, and metastatic foci (e.g., osteomyelitis, meningitis, and pyelonephritis). Most patients have peripheral leukopenia during the disease. Overwhelming disease may lead to hepatic and renal damage. The untreated disease may progress for weeks with increasing fever and debilitation, or it may remit after 2 to 3 weeks (with the possibility of relapse). Some patients (about 3%) retain a focus of gallbladder infection after acute disease and remain chronic asymptomatic carriers of the organism and potential sources of new infection.

The diagnosis of typhoid fever is made in a patient who has the characteristic signs and symptoms of the illness with a history of possible exposure consistent with the epidemiology of the disease. Blood cultures provide the definitive diagnosis. During the first 1 to 2 weeks of illness, blood cultures are almost always positive. Later these cultures may be negative, but they usually become positive with relapse. Stool and urine cultures are more likely to be positive late in the disease. Serologic tests are available and a fourfold rise in agglutination (Widal's test) titer is consistent with disease, although cross-reactions with other salmonellae may occur.

Ciprofloxacin and third-generation cephalosporin antibiotics, such as ceftriaxone and cefoperazone, have become drugs of choice for the treatment of typhoid fever. Although chloramphenicol, trimethoprim-sulfamethoxazole, and ampicillin have remained effective for susceptible strains of S. typhi, many multidrug-resistant strains that are resistant to some or all of these agents are being isolated in developing countries. Ciprofloxacin in a dose of 400 mg, intravenously, every 12 hours for 10 to 14 days and orally, 500 mg, twice a day for an additional 7 to 11 days should be effective in most cases. In patients with mild illness who are capable of oral therapy, ciprofloxacin 500 to 750 mg orally twice a day for 14 to 21 days may be used. Neither ciprofloxacin nor any other fluoroquinolone should be given to children or pregnant women because of interference with cartilage formation and possible teratogenic effects. Ceftriaxone may be given in a dose of 2 gm intravenously once a day and cefoperazone as 2 gm intravenously twice a day, both for 14 days. Ampicillin and trimethoprim-sulfamethoxazole, parenterally and orally, are satisfactory and less costly alternatives when the infecting strain is known to be sensitive. Corticosteroid therapy with dexamethasone is beneficial as adjunctive therapy in severe typhoid fever.

Typhoid vaccine affords some protection against acquisition of S. typhi infection, but is no substitute for caution (see Advice for Travelers). Parenteral heat-phenol-inactivated vaccine has been available for many years. It is administered in two doses, 4 weeks apart with a booster every 3 years. A more recently developed oral, live-attenuated vaccine of the Ty21a strain of S. typhi also has efficacy. The oral vaccine is given with cool liquids, 1 hour before meals, every other day, for four doses.

The best preventive measures for typhoid are good sanitation, good personal hygiene, identification of carriers, and careful follow-up of cases.

[edit] Systemic Bacterial Diseases (Including Plague)

Many bacterial diseases have a higher prevalence in tropical regions. Diseases such as cholera, typhoid fever, and meningococcal, staphylococcal, and streptococcal infections are discussed elsewhere in the text. Certain febrile diseases caused by bacteria have particular geographic distributions and are associated with tropical and semitropical areas. The following discussion is limited to bacterial diseases that cause systemic, febrile illness and that are not discussed in sections dealing with particular organ systems.

[edit] Brucellosis.

Brucellosis is a disease of worldwide distribution, but is especially prevalent along the Mediterranean Sea (where it is known as Mediterranean fever) and in Mexico and South America. The disease is primarily a zoonosis affecting many domestic and wild animals. Four species of gram-negative bacilli of the genus Brucella infecting humans have been described: B. abortus (usually from a bovine source), B. melitensis (goats), B. suis (swine), and B. canis (dogs). People acquire disease through close exposure to infected animals, meat, and dairy products. Most cases in the United States are related to occupational exposures (e.g., meat packing and farming).

The spectrum of the disease can range from mild inapparent infection, to localized abscess formation, to severe systemic disease. Onset of disease is usually insidious with nonspecific symptoms of fatigue, sweats, chills, myalgia, arthralgia, and headache. Fever ranges from hectic to intermittent to absent. Axillary and cervical lymphadenopathy may occur, and splenomegaly has been observed in about 50% of patients with bacteremia. Fatality is rare with brucellosis, but some patients develop chronic infection with persistent malaise, anorexia, depression, and visceral or skeletal abscesses. The course of brucellosis may be complicated by mycotic aneurysm, encephalitis, meningitis, endocarditis, pneumonia, renal disease, and osteomyelitis.

Diagnosis of brucellosis is made by isolating the organism from blood or tissues or serodiagnosis, usually using agglutination tests. Treatment is with tetracycline for 3 to 4 weeks, combined with streptomycin for severe disease. Relapses after therapy are common.

[edit] Bartonellosis.

Bartonella bacilliformis is a gram- negative bacillus that is the causative agent of bartonellosis, or Oroya fever, and the skin disease verruga peruana. The organism is transmitted from person to person through the bites of sandflies of the genus Phlebotomus. The disease occurs naturally in only one part of the world, the Andean mountain valleys of Peru, Ecuador, and Colombia. Asymptomatic carrier rates approach 5% in this area.

The bacilli are capable of invading endothelial cells and erythrocytes. Hemolytic anemia results from destruction of parasitized erythrocytes. The clinical disease is associated with irregular fever, anemia, headache, myalgia, arthralgia, bone pain, and lymphadenopathy. Fatality rates in untreated cases approach 40%, and patients with bartonellosis have a peculiar susceptibility to invasive salmonellosis that commonly complicates the disease. Survivors of Oroya fever may go on to develop the cutaneous phase of the disease, verruga peruana, which consists of pathognomonic skin lesions and nodular hemangiomas.

The diagnosis is made on clinical grounds by the association of fever and hemolytic anemia in a person exposed to the endemic area. The organism may be isolated in blood cultures or demonstrated on the surface of erythrocytes on a blood smear. The drug of choice for treatment is chloramphenicol.

[edit] Plague.

Plague is an ancient disease of enormous historical significance that still warrants fear and concern. The etiologic agent is the gram-negative bacillus, Yersinia pestis. Sylvatic plague is a zoonosis of wild rodents that is prevalent in large parts of the world including South America, South and Central Africa, Central Asia, the Near East, and the southwestern United States. The disease is maintained in wild, burrowing rodents as a relatively mild illness. Sylvatic plague may be passed to people by the bite of a flea from an infected wild rodent, and sporadic cases of human plague occur in endemic areas. The great plague epidemics resulted from a domestic cycle of infection involving rats and their fleas. Domestic rats with plague usually die and their fleas go to other rats or people, thereby spreading the epizootic and epidemic.

Plague occurs in several forms in humans. Bubonic plague is usually the result of flea-transmitted infection. The incubation period is 2 to 7 days. Bubonic plague begins as a febrile illness associated with the development of painful, swollen lymph nodes, or buboes. After evolution of the lymphadenitis, a secondary septicemia occurs with severe toxicity, prostration, and shock. Pestis minor is a clinical variant of bubonic plague characterized by the presence of a bubo with less severe systemic signs. Primary septicemic plague without evident localized infection occurs in few cases during epidemics. Approximately 5% of patients with plague develop pneumonia, usually as a preterminal event. Primary pneumonic plague results from person-to-person transmission of plague via droplets or as the result of inhalation of other material contaminated by plague bacilli. Pneumonic plague may be maintained in a cycle of person-to-person transmission.

Patients with plague often develop hemodynamic instability, staggering gait, confusion, and delirium. The course of plague may be complicated by meningitis, pneumonia, and disseminated intravascular coagulation. The fatality rate of untreated bubonic plague is 50% and higher, and pneumonic and primary septicemic plague are almost always fatal.

Diagnosis of plague is made by demonstrating organisms in smears of bubo aspirates, blood, or spinal fluid. It is confirmed by culture.

Treatment must begin before culture results are known, since delays result in failure of clinical cure despite bacteriologic response, and the patient may die of irreversible toxic effects of infection. The drug of choice is streptomycin, and it is often combined with chloramphenicol or tetracycline. Persons closely exposed to wild rodents in plague-endemic areas or who have potential laboratory exposure to plague should receive plague vaccine. Case contacts are handled by defleaing, surveillance, quarantine, and chemoprophylaxis.

In the American Southwest, sporadic cases of human plague occur as the result of exposure to prairie dogs, squirrels, chipmunks, and other burrowing rodents. The disease frequently is seen in hunters. Because the plague bacillus is endemic in most of the Southwest United States, it must always be considered in the diagnosis of severe febrile illness or lymphadenopathy in that area, be diagnosed as rapidly as possible, and be treated early. Proper isolation precautions must be taken to prevent spread.

[edit] Tularemia.

Tularemia is an infection of rodents and rabbits caused by the gram-negative bacillus Francisella tularensis, which is transmitted to people by exposure to infected tissues, by inhalation of contaminated material, and by biting arthropods. The disease occurs only in the northern temperate zones.

Tularemia in humans appears as several clinical syndromes that might be confused with plague. Ulceroglandular tularemia is characterized by an ulcerative skin lesion with regional lymphadenitis. Glandular tularemia refers to the presence of bubolike lymphadenitis without a skin lesion. Oculoglandular disease results from conjunctival inoculation and involves the periorbital tissues and lymph nodes of the head and neck. Septicemic tularemia is similar to primary septicemic plague in that localized lymph node or skin involvement may not be apparent. Ingestion tularemia is characterized by gastrointestinal symptoms with or without pharyngitis. Pulmonary tularemia may be primary, but more commonly occurs as a complication of septicemic disease.

Tularemia in the United States occurs primarily as the result of occupational exposure to animal materials (e.g., pelts) or in hunters similarly exposed. Fleas are important vectors. An epidemic of tularemia pneumonia occurred in New England that was related to inhalation of drafts from a chimney containing a dead animal. Tularemia should be suspected in any case of relatively severe systemic disease (especially with skin lesions) or pneumonia in an individual exposed to wild animals.

Diagnosis of tularemia is confirmed by culture or serology. Streptomycin is the drug of choice for therapy; however gentamicin, tetracycline, and chloramphenicol are also effective.

[edit] Rat-Bite Fever.

The term rat-bite fever is used to describe two diseases. Rat-bite fevers occur in areas of crowding and poor socioeconomic conditions where close exposure to rats leads to bites or other contacts. One rat-bite disease is caused by the gram-negative rod Streptobacillus moniliformis and is called Haverhill fever. The disease is characterized by edema, ulceration, and abscess formation at the rat-bite site, which is associated with intermittent fever paroxysms, a maculopapular to petechial rash, and polyarthritis. The rash frequently involves the palms and soles. Diagnosis is made by the clinical history and the course of the disease, by serologic studies, or by animal inoculation.

The other disease, sodoku, is caused by Spirillum minus, a gram-negative organism that is transmitted primarily by rat bite. The disease is characterized by inflammation at the bite site, lymphadenitis, paroxysmal fever, and a dark red, macular rash. Arthritis is absent. The diagnosis is made by darkfield examination of exudates or animal inoculation.

Haverhill fever has been described primarily in the United States, whereas sodoku is the prevalent rat-bite fever in Japan and Asia. A fatality rate of 10% is reported in untreated cases of both diseases. The treatment of choice for both is penicillin, with tetracycline and streptomycin as alternatives.

[edit] Rickettsial Diseases

Rickettsiae are obligate, intracellular bacteria that infect a variety of mammals and arthropod vectors. The organisms invade endothelial cells and cause vasculitis. Most diseases caused by rickettsiae can be categorized into two groups: the spotted fevers and the typhus group. Other rickettsial diseases are Q fever, trench fever, and ehrlichiosis.

Among the rickettsial spotted fevers are Rocky Mountain spotted fever (caused by Rickettsia richettsii); boutonneuse fever, South African tick bite fever, and Indian and Kenyan tick typhus (all caused by R. conorii); Queensland tick typhus (R. australis); and North Asian tick typhus (R. sibirica). All of these diseases are transmitted by ticks and have wild rodent and other animal reservoirs.

The spotted fevers are characterized by an acute febrile illness with chills and headache, followed in several days by the eruption of a maculopapular rash often involving the palms and soles. The rash may become petechial to purpuric. A primary ulcerative lesion with an eschar at the site of the tick bite usually occurs with R. conorii and R. sibirica infections, occasionally in Queensland tick typhus, but never in Rocky Mountain spotted fever. Rocky Mountain spotted fever occurs in North and South America. Boutonneuse fever and the other R. conorii infections occur along the Mediterranean Sea and in Africa and India. The geographic distribution of the other rickettsial spotted fevers are indicated by their name.

Rickettsialpox is another member of the spotted fever group and is caused by R. akari, which has the house mouse as reservoir and a mite as vector. The course is usually mild. This disease is characterized by a primary papule followed by a febrile illness and a maculopapular rash that becomes vesicular. The primary papule becomes vesicular and then evolves into an eschar. Rickettsialpox has been described primarily in the United States and Russia in urban settings, but sporadic cases from tropical areas also have been reported.

Rocky Mountain spotted fever is the most important of the rickettsial spotted fevers in the United States. The name of the disease derives from where it was first studied. Most cases now occur along the East Coast of the United States, especially in suburban areas of Virginia and Maryland, and places such as Cape Cod. The disease occurs in any area in which the tick vector, usually of the genus Dermacentor, is prevalent. The most important preventive measure is avoidance of ticks.

Rocky Mountain spotted fever should be suspected in any patient who has a febrile illness with severe headache that progresses in association with the development of a petechial or purpuric rash. In Rocky Mountain spotted fever, prodromal symptoms usually occur for several days before the rash, whereas in meningococcal disease the rash usually appears shortly after the onset of illness. Obviously the differential diagnosis of these two diseases is critical. Treatment must be prompt in either case.

The typhus group of rickettsial diseases includes epidemic typhus (R. prowazekii). Epidemic typhus appears to have humans as its only reservoir, although flying squirrels have been implicated; it is transmitted by the body louse. Epidemic typhus may occur anywhere in the world under situations of deprivation, crowding, and pediculosis. Recurrent typhus, known as Brill-Zinsser disease, may occur many years after initial infection and may appear in immigrants to areas where practitioners are unfamiliar with epidemic typhus. Murine typhus occurs worldwide in domestic cycles involving rats and their fleas. Scrub typhus, which occurs in the South Pacific and Asia, is transmitted by chigger bites from a natural reservoir in small mammals.

Epidemic typhus and murine typhus are characterized by fever, headache, myalgia, and a macular rash. Murine typhus is a milder disease than epidemic typhus, with the fatality rate among untreated cases being 2% in the former and 10% to 40% in the latter. Brill-Zinsser disease is typically milder than primary disease, and the rash may be absent. Scrub typhus is associated with an ulcer that has an eschar at the site of the chigger bite, febrile illness, a maculopapular rash, lymphadenopathy, and often pulmonary signs and symptoms.

Coxiella burnetii, a rickettsial organism, is the etiologic agent of Q fever. C. burnetti differs from organisms of the genus Rickettsia in several ways, including the ability to invade a wider variety of cells and a relative resistance to desiccation and heat. The organism has a number of wild and domestic animal reservoirs and has been found in several varieties of tick. It occurs worldwide. The usual transmission to humans is through the air via dusts contaminated by animal tissues, placental material, and birth fluids. Outbreaks in the United States have been associated with the handling of cattle, abattoirs, and aerosolized material emanating from slaughterhouses. Cases also have occurred in laboratory workers handling the organism.

The disease is characterized by a sudden onset of febrile illness with chills, myalgia, and prominent headache that lasts 1 to 2 weeks and occasionally longer. Multiple areas of pneumonitis may be apparent on chest radiograph, and the patient may complain of nonproductive cough and pleuritic chest pain. Abnormal liver function tests are frequent, but clinical jaundice is unusual. Rash and lymphadenopathy are absent. C. burnetti also can cause a chronic syndrome that is essentially Q fever endocarditis. Q fever endocarditis should be suspected in patients with “culture-negative” endocarditis with possible environmental exposure to C. burnetii and associated active liver disease.

Trench fever is caused by Rochalimaea quintana and is transmitted by lice. The reservoir is human and the disease occurs under conditions of crowding and pediculosis. It is usually a mild systemic febrile illness, frequently with characteristic shin pain. Occasionally, chronic or relapsing infections occur.

Ehrlichia sennetsu is the etiologic agent of sennetsu fever. The organism was formerly assigned to the genus Rickettsia. The mode of transmission has not been clearly established, but ticks are suspected. Sennetsu fever is a systemic febrile illness associated with lymphadenopathy and hepatosplenomegaly that occurs in Japan and other parts of Asia. In the 1980s, human ehrlichiosis was recognized in the United States. The organism is now identified as E. chaffeensis, closely related to the dog pathogen E. canis. The vector of human disease has not been established, but canine ehrlichiosis is transmitted by ticks. Human ehrlichiosis is generally a mild, nondescript systemic illness that, in some instances, is associated with macular or petechial rash. Severe illness is complicated by shock and multisystem organ failure and, in some cases, a toxic shock–like syndrome.

The diagnosis of rickettsial disease depends on the recognition of acute febrile illness associated with rash. Important diagnostic clues derive from the epidemiology of the diseases, geographic distribution, history of arthropod bites, and animal exposures. The character of the rash, or its absence, and the presence or absence of an eschar also help make the diagnosis.

The Weil-Felix reaction, which is based on the agglutination of three strains of Proteus vulgaris (Ox-19, Ox-2, Ox-K) by serum from patients with various rickettsial diseases, is the classic serologic test for infection due to rickettsiae. Agglutinin titers against Ox-19 and Ox-2 typically rise in all the diseases of the spotted fever group, except rickettsialpox. Agglutinin to Ox-19 usually rises in epidemic and murine typhus, whereas the antibody response to Ox-2 is variable in these. The Ox-K, but not the Ox-19 and Ox-2, agglutinins are elevated in scrub typhus. None of the agglutinins rise in rickettsialpox or Q fever, and titers may not change in Brill-Zinsser disease.

The Weil-Felix reactions generally have been supplanted by specific serologic tests for confirmation of diagnosis. All of the serologic tests show titer changes late in disease and usually are not useful for acute diagnosis. Serologic tests for various Q fever antigens can help in the diagnosis of Q fever endocarditis. Demonstration of rickettsia in skin biopsies from patients with rashes can be accomplished by direct immunofluorescent staining. In vitro isolation of rickettsiae and in vivo isolation by injection of patient material into laboratory animals are occasionally performed, but the techniques required are available only in special research laboratories, and such isolations are dangerous to laboratory personnel. The differential diagnosis of rickettsial diseases is summarized in Table 30-5.

Table 30-5 Epidemiologic, Clinical, and Laboratory Characteristics of Diseases Caused by Rickettsia