Parasitic Diseases During Pregnancy

Although parasitic infections are common throughout the world, most clinicians are inexperienced in the diagnosis and treatment of these diseases. Clinicians increasingly are confronted with parasitic infections, such as malaria, schistosomiasis, and trypanosomiasis, because of the increase in international travel and the recent immigration of persons from Southeast Asia, the Caribbean, and Central and South America. Many parasitic infections may be encountered in tropical areas, and the effect of these diseases on less developed countries is staggering. Malaria, schistosomiasis, and filariasis affect 600 million people.¹ With an average of 5 million trips abroad each year, the probability that an American traveler may contract a parasitic infection is high. If infection occurs before or during pregnancy, the effect on maternal health and the developing fetus is dependent on the type of parasitic infection, the patient's natural immunity to that infection, and the parasite load. Diagnosis of these infections is based entirely on a high index of suspicion due to travel to or from an endemic area and the presence of certain infections endemic within the local community (e.g., giardiasis).

Physician's should have knowledge of the biology, life cycle, and clinical manifestations of each parasite. The decision to treat a parasitic infection during pregnancy is a difficult risk-benefit calculation based on knowledge of the associated morbidity and mortality, and the toxic effects of the antiparasitic drug. Because no definitive data are available on the safety of most antiparasitic drugs in pregnancy, drug therapy is indicated only in life-threatening situations or when the benefits of the drug clearly exceed the risks. The pregnant woman should be informed of the risks of treating a parasitic disease during pregnancy. Withholding treatment is appropriate when the infection does not pose an immediate threat to the mother or fetus.

This chapter summarizes the clinical aspects, treatment, and potential toxicity of treatment for common parasitic infections that might be encountered during pregnancy. Textbooks on tropical medicine and parasitology provide more definitive information on these and other parasitic infections.^{2, 3, 4} A frequently updated monograph from the Centers for Disease Control⁵ provides current information on the risks of parasitic infection, vaccine requirements, and chemoprophylaxis. This knowledge is important for both the physician and the prospective traveler.

Malaria is one of the most prevalent and serious infectious disease problems throughout the tropical and subtropical areas of the world. The disease infects more than 150 million inhabitants of more than 104 countries throughout Africa, Latin America, South America, Asia, and Oceana.¹ There are at least 1 million deaths annually due to malaria, primarily in children. Even in the United States, where endemic malaria was eradicated in the 1950s, the number of imported cases of malaria increased dramatically during the Vietnam War, and has increased more recently because of the increase in international travel and the recent influx of refugees.⁶ Familiarity with the diagnosis, complications, and treatment of malaria is essential because it is a potentially fatal infection for which prophylaxis and treatment are readily available.

The organism and its transmission

Malaria is caused by obligate intracellular protozoa of the genus Plasmodium. The four species known to infect humans are P. vivax, P. ovale, P. malariae, and P. falciparum. The disease is transmitted by the bite of an infected anopheline mosquito, through transfusions, by blood contamination as a result of needle abuse, or congenitally. The infection in humans is initiated after the inoculation of sporozoites from an infected mosquito. Within minutes, the sporozoites invade hepatocytes and undergo asexual multiplication to form between 2000 and 4000 daughter merozoites. The 2–6-week period of multiplication is called the exoerythrocytic phase and is not associated with symptoms or hepatic dysfunction. In P. falciparum and P. malariae infection, the hepatic phase terminates with rupture of hepatocytes, release of merozoites, and invasion of erythrocytes. In P. vivax and P. ovale infection, latent hepatic infection may persist for 2–5 years and result in repeated clinical infections known as relapses. Once the parasites enter the erythrocytic stage, they never reinvade the liver. Therefore, blood-induced infection (transfusion or congenital malaria) has no exoerythrocytic phase, and hence does not require specific therapy (primaquine) for eradication of the latent hepatic form.

The erythrocytic or clinical phase of malaria is initiated with the attachment of merozoites to a specific receptor site on the red blood cell, with subsequent invagination into the red cell.⁷ Once within the erythrocyte, the parasite enlarges from a small ring form to a trophozoite that has irregular or ameboid cytoplasm. Nuclear division occurs and results in the development of a multinucleated schizont with 6–24 daughter merozoites. Forty-eight hours after invasion of the red cell (72 hours in the case of P. malariae), the erythrocyte ruptures, releasing merozoites; these reinvade other red cells, continuing the erythrocytic cycle. A small number of parasitized erythrocytes undergo a different maturation cycle to form sexual gametocytes, which are infectious only to anopheline mosquitoes. If ingested by the mosquito, fertilization of the gametocytes occurs, leading to the encystment of the ookinete on the outer surface of the stomach of the mosquito. Daughter sporozoites are produced within the ookinete. At maturation, they migrate to the salivary glands of the mosquito, where they can be injected into a human at the next feeding, completing the life cycle.

Epidemiology

Malaria is endemic in areas of the world in which the anopheline mosquito exists and the infected human population remains above a critical density required for sustained transmission. In 1956, a dramatic effort to eradicate malaria was undertaken by the World Health Organization. This effort resulted in a marked decline in the number of cases worldwide. However, because of financial constraints, insecticide resistance, drug resistance in P. falciparum infection, and a number of other administrative and socioeconomic problems, the incidence of malaria has increased dramatically in many developing countries. As a consequence of the immigration of refugees from malaria-endemic countries to the United States and the increase in international travel of United States citizens, physicians in the United States are increasingly likely to see cases of malaria. In 1989, 1277 cases of malaria were reported to the Centers for Disease Control.⁸ From 1984 to 1991 the number of American travelers who acquired P. falciparum infection doubled.⁹

Clinical manifestations of maternal infection

The clinical presentation of malaria in most persons is dependent on host immunity and the infecting parasite. In malaria-endemic areas, pregnancy is associated with a significant decrease in the level of acquired immunity against malaria, which is evidenced by the greater frequency of clinical symptoms and a higher degree of parasitemia.^{10, 11} This effect is particularly apparent during the second half of pregnancy, but the factors responsible for potentiation of parasitemia remain unclear. In many endemic areas, malaria is a leading cause of maternal mortality.^{10, 11}

Although symptoms may be variable, chills, fever, headache, muscle pain, and arthralgia are common. Malarial febrile paroxysms may occur daily (P. falciparum), on alternate days (P. falciparum, P. vivax, and P. ovale), or every third day (P. malariae). These febrile paroxysms are characterized by a shaking rigor followed by a febrile period of approximately 6 hours. The temperature may be as high as 41°C during this period. Subsequently, profuse diaphoresis occurs. Physical findings are variable, but include splenomegaly and hepatomegaly in many cases. Jaundice, petechial rash, and conjunctival suffusion are present less frequently. Lymphadenopathy does not occur in malaria, and its presence suggests other possibilities. Symptoms of malaria in pregnancy may be nonspecific, and the condition often is misdiagnosed.^{12, 13}

The anemia of pregnancy is potentiated during malarial infection secondary to hypersplenism, direct lysis of parasitized erythrocytes, and autoimmune hemolysis.¹⁴ This rapid turnover of blood cells can produce serious folic acid deficiency and a general hypochromic microcytic iron deficiency anemia. In addition, placental pathology often is so altered in heavy malarial infections that circulation, nutrients, and oxygen transport to the fetus are markedly diminished.^{15, 16} Multiple studies have shown a direct correlation between maternal malarial infection and second-trimester human abortion, intrauterine death with macerated stillbirths, and fresh stillbirths due to intrapartum asphyxia.^{17, 18} The anemia produced by P. falciparum infection usually is seen after 20 weeks of pregnancy, and may induce congestive heart failure because of the reduced red cell mass.

The high fever associated with malaria also has been shown to cause premature labor and delivery, and if infection is acquired before the 16th week, abortion may result. This pyrexia can be confused with eclampsia because convulsion, coma, and death may occur. The effects of endemic malaria on the reproductive wastage of indigenous populations vary inversely with the degree of tolerance to the disease possessed by the community.^{9, 19} Thus, there appears to be an age-related susceptibility and an increased risk of severity in primiparas living in malaria-endemic countries. Among nonimmune women, malaria infection, if not treated immediately, frequently results in death of the fetus and occasionally of the mother.

The syndrome of acute renal insufficiency is a complication of P. falciparum malaria that can be superimposed on other diseases, such as toxemia of pregnancy. When associated with pregnancy, the cerebral form of malaria that is caused by P. falciparum may be mistaken for eclampsia, especially if the patient is comatose.

Malaria is a leading cause of maternal mortality in Thailand. Disseminated intravascular coagulation, acute respiratory distress syndrome, and renal failure have been described.^{9, 10, 13} Patients with changes in mental status should be evaluated for the hypoglycemia that may occur with quinine administration and be misdiagnosed as cerebral malaria.^{11, 13, 20, 21} The syndrome of cerebral malaria is potentially present in every acute case of P. falciparum malaria, and coma primarily is the result of hemostasis and thrombosis in cerebral vessels. This latter complication may be heralded by an acute change in mentation, stupor, or coma, and is associated with a high mortality rate.

Congenital infection

Intrauterine transmission of malaria from mother to fetus frequently occurs, although the mechanism of transplacental passage of the parasite is unknown. Most investigators agree that the placenta acts as a major barrier to the malaria parasite and that its efficacy in blocking transmission is dependent on the mother's immune status.^{9, 19} The incidence of placental malaria in indigenous areas is approximately 30%. However, only 10% of these mothers are symptomatic.²² The incidence of congenital malaria in infants of immune mothers is estimated to be 0.3%, but it may be as high as 10% in infants of nonimmune mothers.²³

In a recent study from Zaire, 21% of maternal blood, 33% of placentas, 9% of cord blood, and 7% of neonatal blood were positive for P. falciparum.²⁴ It is difficult to demonstrate malaria parasites in cord blood in immune mothers who have evidence of placental malaria.²⁴

In recent studies, placental sampling was more sensitive than maternal blood for detecting maternal infection, and more accurate in predicting fetal morbidity.²⁴ Direct penetration through chorionic villi, premature separation of the placenta, and the possible physiologic transfusion of maternal red blood cells to the fetal circulation in utero or at the time of delivery have been postulated as mechanisms of transmission of congenital malaria. Other factors that directly affect the occurrence of congenital malaria include passively transferred immune immunoglobulin G, which has been postulated to be protected in utero and during the first few months of life. The onset of symptoms in congenital malaria typically occurs at 2–4 weeks of age, which is the estimated half-life of maternal immunoglobulin G in the infant. Absence of antibody also would explain the higher incidence of congenital malaria in infants of nonimmune mothers. Other factors that may protect the infant initially include fetal hemoglobin, abnormal hemoglobins that are resistant to malarial infection, the secretion of lymphokines or macrophage-derived toxic substances across the placenta to fetal circulation, and partial malaria chemotherapy during pregnancy.

Most cases of congenital malaria are misdiagnosed initially because of the lack of specific symptoms and a general lack of awareness of this uncommon disease.²⁵ Usually, there is a history of maternal exposure to malaria, which may be apparent or obscured by parental emigration from an endemic area many years previously. The onset of symptoms usually occurs 2–4 weeks after birth, but in rare cases, it may be as late as 15 months. Fever is uniformly present, and although activity, birth weight, and feeding pattern initially may be normal, the child may become irritable, lethargic, and anorexic as the disease progresses. Seizures may occur secondary to fever or as a consequence of cerebral malaria. Hepatomegaly or splenomegaly may not be present during the first few days of symptoms, but will develop rapidly, particularly in P. vivax and P. falciparum malaria.

Diagnosis

Diagnosis is based on clinical suspicion and confirmed by the finding of malaria parasites in thick and thin blood smears. The diagnosis must be considered in any febrile patient who has resided in or traveled to the Caribbean, Latin America, Asia, Oceana, or Africa within the previous 12–24 months. A history of malaria, typical malaria paroxysms, blood transfusions, or narcotic injections in an addict suggest the disease. In a woman who has emigrated from a malaria-endemic area within the last 3 years, pregnancy may cause a relapse, particularly with P. vivax or P. ovale infection.

The diagnosis of malaria essentially rests on the finding of parasites in stained peripheral blood smears. Although a higher density of parasites appears in circulation during the paroxysms as schizonts burst and release merozoites, timing in obtaining smears is less important than obtaining the smears several times daily for several days. Giemsa stain is preferred for speciation, which is necessary for treatment protocols, but routine Wright's stain is adequate for identification of the parasites. Thick smears may be used for concentrating the parasites in persons with low parasitemia. However, artifacts are numerous, and correct interpretation of these tests requires experience. Once parasites are detected, Giemsa-stained thin blood smears should be examined to determine which species is present. Because most physicians are not experienced in the morphologic differentiation of Plasmodium species, an expert opinion should be sought as soon as possible because therapy varies from species to species. The most important distinction is to determine whether P. falciparum is present because drug resistance is known with this species, and it is associated with an increased mortality rate. Several rapid diagnostic tests (RDTs) have been developed recently avoiding the need for light microscopy in remote settings and potentially improving fever management in resource limited settings.(119)

Quantification of parasitemia may be performed and then followed over the subsequent days of treatment to determine the effectiveness of therapy. General textbooks on parasitology explain the morphologic differentiation of the four human species of Plasmodium.^{2, 3, 4} Malaria infection should be differentiated from bacterial sepsis and other transplacentally acquired infections, such as syphilis, toxoplasmosis, cytomegalovirus, rubella, and herpes simplex virus infection.

Treatment

After the diagnosis and speciation of malaria, treatment should be instituted immediately (Table 1).

Table 1. Treatment and chemoprophylaxis of malaria infections

*All doses are listed in the salt preparation.

Because of the high prevalence of this disease, all patients with P. falciparum infection should be assumed to be infected with a chloroquine-resistant organism. The current recommendation for the treatment of uncomplicated P. falciparum malaria in pregnancy includes quinine sulfate 650 mg salt/542 mg base orally three times/day plus clindamycin 20 mg/kg/day divided three times/day for 7 days. For complicated malaria the current recommendation is quinidine gluconate 10 mg salt/kg (maximum dose, 600 mg) infused in normal saline over 1 hour followed by continuous infusion of 0.02 mg salt/kg/minute by infusion pump for up to 72 hours plus clindamycin 20 mg/kg/day divided three times/day for 7 days. Quinidine is cardiotoxic and may cause cardiac arrhythmias; therefore, electrocardiogram and blood pressure monitoring should be performed throughout the infusion period.²⁶P. falciparum in the nonimmune host is a life-threatening infection, and despite the risks of therapy for the fetus, inadequate treatment can result in severe morbidity, neurologic sequelae, and death. Alternatives to quinidine include mefloquine 15 mg/kg orally followed by 10 mg/kg orally 6–12 hours later or a single oral dose of 1250 mg. Mefloquine is not recommended in pregnancy due to the teratogenic effects, and it should not be given with quinidine or quinine. For severe cases of cerebral malaria, quinidine plus clindamycin IV or doxycycline IV should be used. The toxic effect of doxycycline on bone formation also would make this drug less optimal in pregnant patients.

For treatment of P. vivax, P. ovale, or P. malariae, initial therapy with chloroquine phosphate 1 g orally followed by 500 mg at 6 hours, 24 hours, and 48 hours is recommended. Chloroquine apparently is well tolerated during pregnancy at these doses. For radical cure of P. vivax and P. ovale infection, primaquine phosphate usually is recommended at 26.3 mg/day orally for 14 days. This drug is effective in eradicating latent hepatic infection for these two species, and hence is not necessary for the treatment of P. malariae or P. falciparum infection because there is no hepatic phase. Primaquine is not necessary for the treatment of congenital malaria because it is a form of transfusion malaria and does not have an exoerythrocytic (liver) phase. Because primaquine is potentially teratogenic, it should not be used during pregnancy. Chloraquin resistant P. vivax infections (mostly from Papau New Guinea and Indonesia) should be treated with quinine sulfate 650 mg salt orally three times/day for 7 days.

In addition, patients with glucose-6-phosphate dehydrogenase deficiency may experience hemolytic anemia from primaquine. Relapses can be treated with chloroquine during pregnancy, and primaquine can be administered to the mother after delivery. Whenever radical cure with primaquine is indicated during pregnancy, chloroquine can be given once a week until delivery, at which time primaquine can be given.

Although the antimalarial drugs are potentially toxic during pregnancy, the risk of not treating the infection in the pregnant mother is far greater. Chloroquine has not been found to have a harmful effect on the fetus when used in the recommended doses for malaria prophylaxis or treatment. Blindness, auditory nerve injury, and central nervous system (CNS) disturbances have been noted with prolonged high doses of chloroquine. Hart and Naugton²⁷ described a patient who took excessive amounts of chloroquine for lupus erythematosus during four of her seven pregnancies. The patient had one miscarriage at 4 months, two children with evidence of eighth nerve damage, and a third child with neonatal convulsions, hemihypertrophy of the body, and later development of a Wilms' tumor on that side. Occasionally, gastrointestinal discomfort and temporary blurring of vision have been described.

In large doses, quinidine may cause tinnitus, dizziness and, occasionally, nausea and vomiting. However, side effects are unlikely with therapeutic doses for malaria. Other drugs, including pyrimethamine, trimethoprim, sulfa compounds, tetracycline, and primaquine, generally are contraindicated during pregnancy. Pyrimethamine can cause inhibition of leukopoiesis and megaloblastic changes in the bone marrow when administered in higher than therapeutic doses. Trimethoprim, which is closely related to pyrimethamine, also interferes with folic acid metabolism and is teratogenic at high doses in animals. Neither drug should be prescribed during the first trimester of pregnancy, despite the lack of evidence that either drug is teratogenic in humans in the doses used for malaria. Sulfonamides, dapsone, and primaquine produce hemolysis in patients with glucose-6-dehydrogenase deficiency, and sulfonamides given at the end of pregnancy may increase the risk of kernicterus; therefore, they should not be used in the last week of pregnancy. Tetracycline also is not recommended during pregnancy because it is a known potential teratogen, particularly if it is administered during the period of organogenesis (25–40th day of gestation) or during the second trimester, when it inhibits bone growth and produces hypoplasia of deciduous teeth.

Prevention

In areas of the world where malaria is endemic, the use of limited residual insecticides and chemoprophylaxis for pregnant women and children is recommended. Mosquito contact should be minimized with the use of house screens, insecticide-treated bed nets, insect repellent, and insecticides. Residents living in chloroquin sensitive holoendemic areas who become pregnant should take prophylactic antimalarials starting with an initial therapeutic dose to clear any preexisting parasitemia (e.g., chloroquine 1 g) followed by regular prophylaxis, which should be continued for 6 weeks after delivery. Visitors to endemic areas should take prophylactic medication, such as chloroquine phosphate 500 mg orally, once a week for the duration of their stay and for 6 weeks after returning or for the duration of pregnancy, whichever is longer, because delayed attacks of P. vivax or P. ovale malaria may occur.²⁸ After delivery, primaquine may be administered for radical cure of these infections.

Areas of chloroquine sensitive P. falciparum malaria continue to shrink. Mefloquine is the currently recommended prophylactic agent for pregnant women traveling to chloroquin resistant areas, 250 mg orally/week beginning 1 week before travel and continuing 4 weeks after return. It is now recommended that all pregnant women living in areas of high or intermittent (stable) P. falciparum transmission should receive intermittent presumptive treatment (IPT) after quickening during antenatal visits. Ideally this involves two and possibly three IPT doses with sulphadoxine-pyrimethamine (500 mg/25 mg orally). This strategy is not recommended for areas of low or unstable transmission.

Ten per cent of the world population, including 2–5% in the United States and up to 80% in some tropical countries, is infected with the intestinal protozoan Entamoeba histolytica.²⁹ The primary habitat of the parasite is the ileum and colon. Although amebiasis frequently may be seen in an asymptomatic carrier state, E. histolytica also may induce disease ranging from chronic mild diarrhea to fulminant dysentery. Occasionally, extraintestinal complications, such as hepatic abscess, occur.

The organism and its transmission

Of the seven species of ameba that naturally parasitize the human mouth and intestine, only E. histolytica has been associated with gastrointestinal disease. Debate has centered on the possibility of there being two subspecies of E. histolytica. One being invasive (pathogenic), the trophozoites being typically large, up to 50 μm in diameter, and characterized by the ingestion of erythrocytes and invasion of tissue. The second subspecies being noninvasive, limited in size to between 10 and 20 μm in diameter, and nonerythrophagocytic. Their pathogenicity, difference in size, and tendency to ingest host tissue also may be determined by complex environmental factors that include viruses or plasmids that encode for virulence.

E. histolytica exists in two forms: the motile trophozoite and the cyst. The trophozoite dwells in the lumen or wall of the colon and divides by binary fission; in the presence of rapid transit, it may be passed unchanged in liquid stool. It prefers anaerobic conditions and requires either bacteria or tissue substrates to satisfy nutritional requirements. In the absence of diarrhea, the trophozoite usually will encyst and be passed in the stool. Cysts contain a single nucleus, glycogen vacuoles, and sausage-shaped chromatoid bodies. As the cyst matures, it absorbs its cytoplasmic vacuoles and becomes quadrinucleate. In general, the cysts are highly resistant to environmental changes, chlorine concentrations found in water purification systems, and gastric acid.

The disease typically is transmitted by ingestion of the cyst forms due to fecal contamination of food or water. Excystment occurs during transit through the stomach and small intestine, with release of eight trophozoites, which migrate to the colon, where they undergo binary fission every 8 hours in the trophozoite stage. Encystment of these organisms occurs when environmental conditions become unfavorable for continued trophozoite multiplication.

Epidemiology

E. histolytica is present throughout the world at a prevalence parallel to the level of sanitation and personal hygiene within the community.³⁰ Rates as high as 50–80% may occur in tropical areas where levels of sanitation are low. In the United States, the overall prevalence is estimated to be 3–5%, except in communities of homosexual men, institutions for the mentally retarded, Native American reservations, and migrant labor camps, where the prevalence may be as high as 40%.^{31, 32} Epidemics have occurred in any part of the world that is known for a high prevalence of infection, and more severe disease is seen in certain parts of Central and South America, the West Coast of Africa, and Southeast Asia. Reasons for the enhanced severity of disease in these areas are not clear.

Clinical manifestations

Symptoms associated with intestinal infection with E. histolytica vary dramatically from person to person and from area to area. Perhaps the most common illness associated with amebic disease is colonic irritation characterized by colicky lower abdominal pain, with or without diarrhea. The stool may be loose, and mucus and blood may be present. On physical examination, abdominal tenderness may be present. During pregnancy, amebic disease appears to be more frequently associated with acute exacerbations of the disease and with more prominent symptoms.^{33, 34, 35} Infected pregnant women may have bloody, dysenteric stools with moderate abdominal pain and tenderness. The diarrhea is marked, and secondary signs include fluid loss and electrolyte imbalance, which may adversely effect the outcome of pregnancy.³⁶ There is no documentation of placental involvement or transmission of the parasite to the fetus. Fulminating attacks of amebic dysentery may be precipitated by pregnancy or the administration of corticosteroids.³⁷ Sigmoidoscopy may show extensive rectosigmoid ulceration and, in rare cases, extensive destruction of the colonic mucosa and submucosa, with massive hemorrhage or perforation of the bowel wall. Repeated severe attacks of intestinal amebiasis may lead to ulcerative postdysenteric colitis. In rare cases, an ameboma may be documented in the cecum radiologically, and may be misdiagnosed as adenocarcinoma of the cecum.³⁸

A severe complication of amebiasis is the development of hepatic abscess secondary to migration of E. histolytica. Hepatic amebiasis does not appear to be a frequent complication of amebiasis in pregnancy. On the contrary, hepatic abscess appears to be more common in asymptomatic infection of the colon than in symptomatic intestinal disease. The abscess may develop insidiously, with fever, sweating, weight loss, and tender hepatomegaly. The abscess usually occurs singly, and is located in the posterior portion of the right lobe of the liver. Occasionally, abscesses enlarge upward, producing a bulge in the diaphragmatic dome with sympathetic pleural effusions. Other abscesses rupture through the diaphragm, producing an amebic pleural abscess. A more serious complication of hepatic amebiasis includes rupture into the pericardium and peritonenum. The clinical signs associated with these occurrences are those of a moribund patient with signs of pleural effusion, pericardial tamponade, or acute abdomen, depending on the site of rupture. Brain abscesses also have been described as a complication of extraintestinal amebiasis. They may manifest as seizures or coma.

Diagnosis

The diagnosis of intestinal amebiasis is based on identifying E. histolytica in the stool or a biopsy specimen. Examination of multiple stools is necessary because cysts and trophozoites may be excreted variably. Liquid or semiformed stools should be examined immediately in a saline wet-mount preparation for the presence of motile trophozoites. Additional stools should be placed in polyvinyl alcohol (PVA) or formalin and later concentrated by centrifugation in formalin-ether, which is effective in the identification of cysts. In symptomatic patients, a specimen should be obtained during sigmoidoscopy and examined immediately by direct mount in saline on a warm microscope stage for motile erythrocyte-containing amebas.

The diagnosis of amebic liver abscess is based primarily on suspicion, and it must be distinguished from a mass lesion in the liver caused by pyogenic abscess or neoplasm. Radioisotopic scanning, computed tomography, and ultrasonography of the liver are helpful in diagnosing amebic abscess, which will appear as a single defect in the right lobe. Results of stool examination for amebas are usually negative, and frequently, the diagnosis is based on a positive serologic finding in conjunction with a characteristic hepatic scan. The indirect hemagglutination test result is considered positive if antibody is present in a dilution of 1:128 or greater. A diagnostic aspiration of liver at the point of localized tenderness may be performed that will yield an odorless, brownish liquid (anchovy paste) characteristic of amebic abscess. This liquid typically is devoid of amebas because the parasite is localized more frequently to the capsule of the abscess. Invasive procedures should be avoided, and an empiric trial of metronidazole should be used in difficult diagnostic cases.

Treatment

Therapy for amebiasis should be aimed at relief of symptoms; replacement of fluid, electrolytes, and blood; and eradication of the organism. Many of the drugs recommended as amebicides may be toxic during pregnancy, and drug therapy during pregnancy should be tailored to the severity of symptoms. Asymptomatic women who are known passers of E. histolytica cysts should have treatment delayed until after 14 weeks of gestation or until after delivery. Metronidazole 750 mg three times a day orally for 5–10 days may then be given.³⁹ An alternative drug is paromomycin 25–30 mg/kg/day in three divided doses for 7 days.⁴⁰ In patients with prominent symptomatic amebiasis of the intestine, metronidazole plus paromomycin should be given at the same doses.

An alternative drug for asymptomatic infection is iodoquinol 650 mg three times a day for 20 days. However, there is no information about the safety of iodoquinol in pregnancy.

The use of metronidazole alone for symptomatic intestinal disease will cure about 90% of patients. The addition of one of the luminal amebicides, such as paromomycin, will raise the cure rate to 100%. Amebic liver abscess has occurred in a few patients who were treated for dysentery with metronidazole alone.^{39, 40, 41, 42, 43} This complication probably results from a failure of metronidazole to eliminate luminal organisms in a small number of cases.

In extraintestinal amebiasis, including hepatic abscess, metronidazole for 10 days is the drug of choice. In patients who are severely ill, needle aspiration may be helpful, but in general, repeated use of needle aspiration of the liver is unnecessary. Similarly, surgical attempts to correct amebic bowel perforation or peritonitis should be avoided.⁴⁴ Maintaining drainage of the peritoneum in addition to the use of appropriate antimicrobial therapy is the most effective treatment. Dehydroemetine has been recommended for nonpregnant patients, but is contraindicated in pregnancy.

Metronidazole is mutagenic in bacteria,⁴⁵ and it has caused lung tumors in mice, but not in hamsters.⁴⁶ These effects have not been seen in humans, and it has never been shown to be a teratogen in pregnant women or carcinogenic in humans.^{47, 48, 49} However, the use of the drug for non-life-threatening situations is attended with some controversy, and many clinicians prefer not to use it in pregnancy, particularly during the first trimester. If a patient is treated with metronidazole, she should avoid alcoholic beverages because a disulfiram (Antabuse)-like effect has been reported. In addition, urine discoloration, vertigo, nausea, and diarrhea have been noted as side effects. Due to this concern, metronidazole is not recommended during the first trimester of pregnancy. Dehydroemetine and iodoquinol are appropriate for use in a nonpregnant patient, but are contraindicated during pregnancy. Paromomycin, an effective luminal amebicide, is considered safe to use in pregnancy because it is poorly absorbed from the gastrointestinal tract. Another drug similar in effectiveness to paromomycin is diloxanide furoate, given as 500 mg three times a day for 10 days. This drug is a luminal amebicide, and because absorption from the gastrointestinal tract is low, it is believed to be safe for use during pregnancy. However, no data concerning possible teratogenic effects are available.

Giardia lamblia is the leading protozoan cause of diarrhea in travelers and in waterborne outbreaks in the United States.^{50, 51} Like amebiasis, giardiasis is found throughout the world, with an average incidence of 7% worldwide and 4–7% in the United States. Giardiasis frequently is marked by persistent diarrhea and malabsorption and frequently is found in areas of poor sanitation and among populations that cannot maintain adequate personal hygiene.

The organism and its transmission

G. lamblia is a multiflagellated protozoan with a trophozoite and a cyst stage. Infection in humans is initiated after ingestion of the cyst form. Excystation occurs within the stomach and upper gastrointestinal tract. The organism remains in the duodenum and upper jejunum, where the alkaline pH is favorable. Giardia multiplies by longitudinal fission, and the trophozoites attach firmly to the intestinal epithelial surface by means of a powerful sucking disk. Under a microscope, its two nuclei and central parabasal body give the organism the appearance of a face with two large eyes. As the trophozoites pass into the colon, encystation occurs, and the cysts are excreted from the body. Cysts may remain viable and infectious in water for longer than 3 months, and they may be infective after storage in tap water for 16 days. Infection is transmitted to another person through ingestion of fecally contaminated water containing Giardia cysts.

Epidemiology

Giardiasis is found worldwide, with high prevalence rates in areas of poor sanitation. In the United States, G. lamblia is isolated in 3.8% of examined stools, making it the single most frequently identified intestinal parasite.⁵² Children are three times more likely to be involved than adults, and probably have more clinical manifestations. Gastrectomy, decreased gastric acidity, and chronic pancreatitis in adults may increase susceptibility. In addition, giardiasis frequently has been reported in patients with immunoglobulin deficiency, particularly those with a deficiency in intestinal immunoglobulin A. Certain high-risk populations have a high prevalence rate, such as homosexually active men; travelers to Eastern Europe and the Soviet Republic; hikers; and residents of towns where occasional epidemics from contaminated water supplies have occurred.^{53, 54, 55} Sporadic outbreaks have been concentrated in the Rocky and Cascade Mountains in the USA. Wild animals may serve as alternate hosts. Beavers were implicated in an outbreak in Camas, Washington.⁵¹ The highly resistant cyst form of Giardia has been responsible for many of these waterborne outbreaks, and direct fecal-oral transmission has been implicated among homosexual men, where the incidence may be as high as 30%. Similar outbreaks have been described among homes for the retarded and child day-care centers.

Clinical manifestations

Similar to E. histolytica, symptomatic disease varies widely in patients infected with G. lamblia. Symptomatic disease usually occurs 1–2 weeks after infection and is characterized by the sudden onset of watery, foul diarrhea, abdominal distension, flatulence, nausea, anorexia, and abdominal cramps. The stools often are malodorous, loose, and mixed with mucus. Blood and fecal leukocytes rarely are present. This acute stage may last for 3–4 days; if not treated, it may progress to a chronic infection, which is associated with steatorrhea and malabsorption. For unknown reasons, in many patients the infection resolves completely without treatment. Other persons who are infected have no symptoms, and the parasite load detectable in these patients may be far less than that detected in symptomatic patients.

If the disease progresses to a chronic infection, there may be periodic, brief episodes of loose, foul stools, which may be yellow and frothy and accompanied by increased abdominal distention and flatus. Cramps are unusual in chronic infection, but anorexia, nausea, and midepigastric discomfort are frequent complaints. Findings of malabsorption studies may be abnormal. A postgiardial lactose intolerance may develop in patients from ethnic groups with a predisposition to lactase deficiency after apparent eradication of parasites with specific therapy.⁵⁶

The adverse effects of Giardia infection on pregnancy are related to the associated diarrhea, fluid and electrolyte loss, and malabsorption, which may contribute adversely to the ultimate outcome of the pregnancy. Maternal-to-fetal transmission has not been documented. If a pregnant woman has associated dysgammaglobulinemia, giardiasis may be severe and more resistant to therapy. Pathogenesis of these abnormalities is poorly understood. Mechanical blockage of microvilli, deconjugation of bile salts, altered motility, and mucosal invasion have been suggested as possible mechanisms. Patients with giardiasis and severe malabsorption have jejunal colonization with enterobacteria, suggesting that the bacteria may potentiate the mucosal lesion and be responsible for the development of malabsorption. Jejunal biopsy of patients infected with Giardia sometimes shows flattening of microvilli in an inflammatory infiltrate.

Diagnosis

The diagnosis of giardiasis, which is based primarily on stool examination, often is difficult to document because of variable cyst and trophozoite excretion. In the acute stage of the disease, stools frequently are watery and loose, and may contain the more labile trophozoites because of rapid bowel transit. A direct saline smear or preservation of the stool in formalin or PVA may aid in the identification of this organism. Semiformed or formed stool should be fixed in formalin, and a formalin-ether concentration used for identification of the cyst. Some investigators claim that only 50% of cases can be confirmed by stool diagnosis, but others have shown that at least 90% of proved Giardia infections can be identified by two stool examinations on different days using the formalin-ether concentration. Frequently, when stool examinations repeatedly have negative results, duodenal intubation with aspiration of duodenal contents and duodenal biopsy may be useful in confirmation of the diagnosis. The Enterotest is a gelatin capsule containing a string that can be used to sample the duodenal contents for Giardia trophozoites, thereby avoiding duodenal intubation and biopsy.⁵⁷ When used properly, this test may be as sensitive as duodenal aspiration. Another diagnostic test is an enzyme-linked immunosorbent assay for Giardia antigen in stool. It is equally sensitive and specific for Giardia diagnosis as the other tests, and is more applicable for larger epidemiologic studies.⁵⁸

Treatment

Therapy for giardiasis in nonpregnant patients consists of treatment with either quinacrine hydrochloride 100 mg three times a day for 5 days or metronidazole 250 mg three times a day for 5 days. Either drug will result in the elimination of the organism in 70–90% of cases. Pregnant women should receive therapy only if they are severely symptomatic because the infection may be self-limited in many persons. For pregnancy, a trial with paromomycin 10 mg/kg three times a day for 1 week is recommended. If symptoms persist or are severe, metronidazole may be used with the same reservations mentioned in the previous section. Other drugs effective against Giardia include furazolidone and tinidazole, the latter of which is not licensed in the United States. Furazolidone is not recommended by the Food and Drug Administration for use in pregnancy because it has induced mammary tumors in rats.

Trichomonas vaginalis is a pathogenic protozoan commonly found in the human genitourinary tract. Transmitted primarily by sexual intercourse, this organism causes vaginitis in women and nongonococcal urethritis in men. It is estimated that more than 200 million people worldwide are infected with this parasite annually.⁵⁹ In the developed countries, T. vaginalis is perhaps the most common pathogenic protozoan of humans, with estimates of 3–4 million cases annually in the United States and more than 1.5 million cases in Great Britain.⁶⁰

The organism and its life cycle

T. vaginalis is a flagellated eukaryotic protozoan that exists only in a trophozoite stage. The size and shape of the trophozoite are variable, depending on culture conditions, and it averages 15 μm long and 7 μm wide (the size of a leukocyte). Trichomonads are known for their characteristic twitching, erratic motility due to four anterior flagella, which originate in an anterior kinetosomal complex. A fifth flagellum is attached by a membrane that also originates from the kinetosomal complex. Within the organism, there is an anterior nucleus containing five chromosomes, a parabasal apparatus, a Golgi complex, and an axostyle, which runs through the center of the cell to form a posterior tail. Large chromatic granules called hydrogenosomes are present within the cytoplasm, parallel to the axostyle. Reproduction is by mitotic division and longitudinal fission, which occurs every 8–12 hours under optimal conditions.

T. vaginalis is a facultative anaerobe, and growth is inhibited at high oxygen tensions because of its deficiency of catalase. The pH is a critical growth-limiting factor because more robust and smaller organisms are observed in high pH ranges, and less motile, enlarged organisms are encountered at pH levels that are lower or higher than the optimum pH, 5.5. The vaginal pH in trichomonal vaginitis usually is 5.5–7.0.⁶¹

Epidemiology

The prevalence of trichomoniasis varies according to the type of population studied and the diagnostic techniques used for identification of the organism. The incidence ranges from 5% to 10% in healthy women to as high as 50–70% in prostitutes and female prison inmates. An increased risk of infection has been found in persons with multiple sex partners, poor personal hygiene, and low socioeconomic status. Several investigators have shown a greater prevalence of trichomoniasis in blacks, multiparous women, women married at an early age, and pregnant women. The peak incidence of trichomonal infection usually is 16–35 years of age. Seventy per cent of men who have had sexual contact with an infected woman within the previous 48 hours will harbor T. vaginalis in the urethra.⁶² Further, there appears to be an increased cure rate with metronidazole when both partners are treated simultaneously. Anecdotal data have suggested nonvenereal transmission, such as fomites, but it is believed that this mode of transmission is uncommon.⁶³

Clinical manifestations

In women, T. vaginalis primarily infects the vaginal epithelium and less commonly, the endocervix.⁶¹ The urethra, Bartholin's gland, and Skene's gland are other common sites of infection. There have been rare reports of extravaginal infection involving the fallopian tube, perinephric abscess, and cerebrospinal fluid. In men, the urethra is most commonly infected, but T. vaginalis also has been isolated from epididymal aspirates, prostatic secretions, and seminal vesicles.⁶⁴

The clinical manifestations of vaginal trichomonal infection range from asymptomatic carriage to severe vaginitis. During pregnancy, infection with T. vaginalis commonly induces a prominent vaginal discharge. There is some evidence that growth of the parasite is enhanced in vitro by estrogens, and this finding may explain the severity of symptoms and tenacity of infection in colonized women during pregnancy or in those taking exogenous estrogens. Although infection during pregnancy has not been studied carefully, other investigations have suggested that the presence of T. vaginalis correlates poorly with symptoms and physical examination in nonpregnant women.^{65, 66} Unfortunately, most of these studies have not carefully differentiated between patients with cervicitis and those with vaginitis or considered the effect of coinfection with other pathogens. In symptomatic disease, the patient may complain of malodorous discharge, dyspareunia, and dysuria. The patient may report postcoital bleeding, which may be due to cervicitis caused by T. vaginalis or other pathogens. Abdominal pain and regional lymphadenopathy also may be present in a small number of patients with trichomoniasis.

On physical examination, a purulent discharge may be present at the introitus and within the vagina; it may be characterized as a yellow-green homogeneous or frothy discharge. This finding contrasts with the characteristic white floccular discharge of candidal vaginitis and the white homogeneous discharge of bacterial vaginosis. The vulva may be erythematous and edematous, and excoriations may be present. The vagina and cervix also may be erythematous, and small punctate hemorrhages may be present on the cervix (strawberry cervix).

There is conflicting information about the association of trichomonal vaginitis and puerperal fever and neonatal infection. There is little evidence that T. vaginalis is an invasive organism or that it produces amnionitis or endometritis. It is unlikely that intrauterine infection occurs, although this possibility has never been disproved, and several studies have documented neonatal infection. Between 2% and 17% of female infants born to infected mothers will have vaginal infection.⁶⁷ Neonatal vaginal epithelium is relatively mature as a result of the influence of maternal estrogen and is thus susceptible to T. vaginalis infection. Typically, these infections are asymptomatic, although a vaginal discharge may develop. Maternal estrogen is metabolized by 3–4 weeks of age, and vaginal epithelium returns to a prepubescent state that is relatively resistant to T. vaginalis. It is not clear whether a latent or asymptomatic state of T. vaginalis carriage can exist through childhood.

In men, T. vaginalis infections usually are asymptomatic and appear to be self-limited. In some men, T. vaginalis has been associated with urethritis characterized by the presence of a small scanty discharge, dysuria and, rarely, superficial penile ulcerations.⁶⁸ In developed countries, T. vaginalis has been isolated from less than 15% of men with nongonococcal urethritis, and usually from less than 5%.⁶⁴ In some developing countries where the presence of T. vaginalis remains high, some researchers believe that a higher proportion of nongonococcal urethritis (>50%) is caused by this agent. Reported complications in men include epididymitis, prostatitis, and balanoposthitis.⁶⁹

Diagnosis

The diagnosis of trichomonal infection is independent on the identification of T. vaginalis by wet-mount preparations, cultures, Papanicolaou smears, or special stains. The saline wet-mount preparations are reliable, simple, and inexpensive, and treatment can be instituted immediately. Although wet-mount preparation is less sensitive in asymptomatic patients who have a low concentration of T. vaginalis in vaginal secretions, it is 80–90% sensitive in symptomatic patients.⁷⁰ Cultures for T. vaginalis are far more sensitive and specific in identification of T. vaginalis, particularly in women who are asymptomatic. The combination of both tests should increase the sensitivity of detecting trichomoniasis to 98%. Giemsa- and Papanicolaou-stained smears also have been useful in detecting T. vaginalis in asymptomatic women.⁷⁰

Treatment

Metronidazole and other 5-nitroimidazoles, such as tinidazole and nimorazole, are recommended as standard therapy for trichomoniasis. More than 98% of T. vaginalis strains are exquisitely sensitive to metronidazole, but several strains have demonstrated in vitro and in vivo high levels of resistance to the drug.⁷¹ Investigations are examining the extent of drug resistance and its mechanisms. The recommended dosage of metronidazole for initial treatment of trichomonal infection is 2 g orally as a single dose.⁷² Cure rates of 95% are reported when sexual partners are treated simultaneously because the asymptomatic male partner is a major source of reinfection and of alleged treatment failure.⁷² The side effects of metronidazole are mild, and include a metallic taste and nausea in a few patients. Metronidazole blocks the metabolism of alcohol, and nausea, vomiting, and flushing may be exhibited when alcohol is taken simultaneously or soon after metronidazole administration. Metronidazole is mutagenic for bacteria and capable of producing lung tumors in mice after prolonged administration, so many clinicians avoid the use of the drug during the first trimester of pregnancy. However, extended follow-up studies of women who have taken metronidazole have not demonstrated an increased risk of cancer or teratogenicity.

The organism and its life cycle

Trypanosomes are minute, actively motile, fusiform protozoa characterized by the presence of one flagellum originating from an extranuclear, terminally located organelle containing deoxyribonucleic acid (DNA), the kinetoplast. This flagellum runs alongside the body of the protozoan and forms an undulating membrane. Both the undulating membrane and the free flagellum confer considerable motility to the protozoan. Reproduction takes place by binary longitudinal fission. Morphologic characteristics of many varieties of trypanosomes are so nearly identical that they are distinguishable only by their pathogenicity for certain animals, differences in biochemical requirements, and ability to multiply in insects. Three species are pathogenic in man; these include Trypanosoma gambiense (West African trypanosomiasis), T. rhodesiense (East African trypanosomiasis), and T. cruzi (Chagas' disease). They are found primarily in South America. The life cycle of these trypanosomes differs from species to species, including vectors and reservoir host other than man. African trypanosomiasis is transmitted by Glossina species (tsetse fly), and Chagas' disease is transmitted by reduviid bugs (Triatoma species). Reservoir hosts for each of the species include hogs, goats, and cattle for T. gambiense; wild game animals and cattle for T. rhodesiense; and dogs, cats, armadillos, and small wild mammals for T. cruzi.^{73, 74}

In general, after the bite of the vector, trypanosomes are inoculated into the subcutaneous tissue, where they multiply to produce a local chancre. After the appearance of this lesion, the trypanosome spreads through the tissue spaces into the lymphatics, eventually spilling into the general circulation, where they continue to multiply by longitudinal fission. The parasitemia is of low intensity, and at some time during the stage of dissemination, trypanosomes localize in the tissue of the reticuloendothelial system or the CNS. After invading tissue cells, the trypanosome loses its undulating membrane and flagellum and assumes a leishmanial form, dividing by binary fission. Eventually, new flagellated forms are produced, which re-enter the general circulation to initiate another cycle if ingested by the vector. All trypanosomes have the potential for transplacental transmission, with resulting intrauterine infection of the fetus during parasitemia. Infective T. cruzi may be found in breast milk and may infect the infant by direct inoculation or through the gastrointestinal tract.⁷³ African trypanosomiasis usually results in infertility, and may cause abortion, stillbirth, and premature labor when active or acquired during pregnancy. South American trypanosomiasis apparently has fewer adverse effects on fertility and pregnancy.⁷³

Clinical manifestations

WEST AFRICAN TRYPANOSOMIASIS (T. GAMBIENSE)

Five to 10 days after the bite of the tsetse fly, a local lesion of trypanoma may develop that eventually will ulcerate over the ensuing weeks. Enlargement of lymph glands may develop several months later, particularly in the posterior cervical triangle. This condition is known as Winterbottom's sign. The acute disease lasts a year and is characterized by irregular fever, headache, joint and muscle pain, and rash. Kerandel's sign, which consists of severe pain after pressure of the palms or over the ulner nerve, may be present. Gradually, the chronic phase of the disease ensues, with development of characteristic CNS changes. Diffuse meningoencephalitis and meningomyelitis develop. The fever and headache become pronounced, and the patient may have lethargy, melancholic attitude, mental retardation, low and tremulous speech, tremors of the tongue and limbs, and altered reflexes. Death results from the disease or intercurrent infection, such as malaria, dysentery, or pneumonia.^{74, 75}

EAST AFRICAN TRYPANOSOMIASIS (T. RHODESIENSE)

Onset of symptoms usually occurs a few days after the person has been bitten by the tsetse fly, but incubation periods of up to 3 weeks have been observed. Rhodesian trypanosomiasis runs a more rapid and fatal course than does Gambian disease. The pathologic changes in acute disease are similar, but the febrile paroxysms are more frequent and severe, with less pronounced glandular enlargement.⁷⁶ Edema, mild carditis, weakness, and emaciation are more prominent. Chronic lesions in the CNS are less frequently encountered, but mental disturbances may develop, indicating the presence of CNS complications.⁷⁷

CHAGAS' DISEASE (T. CRUZI)

After an incubation period of 1–2 weeks, there is an abrupt onset of daily fever. Erythematous rash and adenitis of the cervical, axillary, and iliac glands usually are observed. Infection of the orbital region may lead to unilateral conjunctivitis and edema of the eyelids, referred to as Romaña's sign. This acute form of the disease most often is seen in children. Hepatosplenomegaly is typical, and involvement of the myocardium may result in congestive heart failure. The untreated disease lasts for several weeks to months, with a mortality rate of 5–10%. Chronic Chagas' disease develops more slowly and insidiously in persons who have no history of previous acute disease.⁷⁸ Cardiomyopathies may be seen in 20–40% of the patients with chronic disease,⁷⁹ and gastrointestinal manifestations, mostly related to megoesophagus or megacolon, may be seen in 20–30%.⁸⁰

Diagnosis

Diagnosis of trypanosomiasis depends on demonstration of the organism in the peripheral blood, in tissue, or on serologic tests. All three species of trypanosomes may be demonstrated in the peripheral blood in the early phases of infection. However, in chronic disease, circulating trypanosomes are found less frequently, and elevated IgM and specific trypanosome antibody levels lead to definitive diagnosis.^{81, 82}

Treatment

For African trypanosomiasis, suramin is the most effective agent for non-CNS disease.⁸³ After a 100–200-mg test dose, 1 g is given intravenously on the 1st, 3rd, 7th, 14th, and 21st days, for a total of 5 g. If CNS involvement is detected, an effective agent is melarsoprol (Mel B). Simultaneous treatment with steroids has been recommended to prevent the CNS toxicity associated with melarsoprol.

There is no satisfactory treatment for Chagas' disease, although nifurtimox 10 mg/kg/day for 3–4 months shows promise as an effective agent.⁸⁴ Eflornithine, benznidazole, and γ-interferon have been used. These drugs are believed to be toxic during pregnancy, but usually trypanosomiasis is associated with infertility and abortion and, in severe cases, death of the patient. Thus, treatment with these drugs may be warranted. There are no drugs available for chemoprophylaxis that are safe for use during pregnancy.⁸⁵ Therefore, pregnant women traveling to endemic areas should exercise due caution in exposing themselves to the bite of the vectors.

The organism and its life cycle

Leishmania are obligate intracellular protozoa of which four species are known to infect humans. L. donovani primarily infects the reticuloendothelial cells throughout the body. It causes the disease known as kala-azar, and is widely distributed throughout Asia, Europe, Africa, India, and the Western Hemisphere in parts of Central and South America. The major vector is the sandfly (Phlebotomus), and a variety of small animals are important reservoirs of the infection. L. tropica (Oriental sore) represents the classic form of cutaneous leishmaniasis. L. braziliensis and L. mexicana (New World leishmaniasis) induce a disease in which the patient has ulcers of the oral or nasal mucosa, often after a primary skin ulcer has healed.⁸⁶ These mucosal lesions tend to progress to involve extensive nose destruction.

The various species of Leishmania are transmitted by the bite of sandflies belonging to the genus Phlebotomus. Sandflies acquire the protozoan directly from infected skin or by ingesting parasites circulating in the blood of the reservoir host. In the sandfly, Leishmania transforms into a flagellate (promastigote) that is infective to humans. After inoculation of the promastigote into a human host, the organism enters macrophages of the reticuloendothelial system (L. donovani) or into histiocytes that are present in dermal tissue (cutaneous leishmaniasis), where they are transformed into amastigote forms and divide by binary fission. After multiplication, daughter amastigotes reinvade neighboring histiocytes or, in the case of visceral leishmaniasis, disseminate throughout the reticuloendothelial system.

Clinical manifestations

VISCERAL LEISHMANIASIS

The visceral form of the disease has a prolonged incubation period that may vary from 2 weeks to 18 months. Fever, which often consists of two daily spikes, may be abrupt or gradual in onset. It persists for 1–6 weeks, and then disappears, only to reappear at irregular intervals during the course of the disease. Physical findings may include splenomegaly, lymphadenopathy, and hepatomegaly, with signs of portal hypotension and edema. Anemia and thrombocytopenia with hypergammaglobulin frequently are present and often are associated with bleeding. As the disease advances, the skin becomes gray, and hyperpigmentation is noted in light-skinned persons. Most patients with visceral leishmaniasis are severely debilitated and infertile, although this form of leishmaniasis carries a potential risk of intrauterine fetal infection if pregnancy occurs during the early phase of the disease.^{87, 88} Congenital infection with leishmania has been described. Increased fetal wastage almost always is associated with L. donovoni infection.

CUTANEOUS LEISHMANIASIS

The clinical manifestations of cutaneous leishmaniasis are similar for L. tropica, L. braziliensis, and L. mexicana. The disease starts as a pruritic red papule at the site of inoculation. The lesion grows to an average diameter of 2 cm or more and tends to ulcerate 2–6 months after the bite of the vector. These lesions tend to heal over a 1-year period. However, destructive mucocutaneous lesions may develop years after healing of the primary lesion in L. mexicana and L. braziliensis infection.

Diagnosis

Diagnosis of visceral leishmaniasis is made by finding leishmanial organisms in stained preparations of the blood, bone marrow, lymph nodes, or material obtained by splenic puncture. Serologic tests are not specific, and the leishmanin skin test finding usually is negative in patients with kala-azar. Diagnosis of cutaneous leishmaniasis is based on suspicion and demonstration of the organism in scrapings or by culture. The leishmanin skin test result usually is positive during the primary lesion period, but may revert to negative in rare cases of disseminated cutaneous leishmaniasis.⁸⁹  Newer diagnostic modalities which utilize polymerase chain reaction (PCR) based technology are also being developed for the diagnosis of leishmaniasis.⁹⁰

Treatment

Cutaneous leishmaniasis is not known to carry serious risk to the mother or fetus, so treatment during pregnancy should be avoided and postponed until after delivery. However, patients with visceral leishmaniasis must be treated immediately regardless of pregnancy. Sodium antimonylgluconate (Pentostam) is the drug of choice for all forms of leishmaniasis. For visceral leishmaniasis, the adult dose is 20 mg/kg/day intravenously or intramuscularly for 30 days. For cutaneous leishmaniasis, the dose is 0.6 g intramuscularly for 10 days. Patients who do not respond to antimonials should be treated with amphotericin B, 0.25–1 mg/kg intravenously daily or every other day for up to 8 weeks.⁹¹ The toxicity of antimonials during pregnancy is unclear.

Intestinal nematodes often are thought to be unimportant or novel causes of infection in humans. Yet, in many low-income, rural communities in the southeast United States, half of the population may have infection with Ascaris lumbricoides, Trichuris trichiura, or both; in urban areas, immigrants from tropical countries constitute a substantial population with a high prevalence of intestinal infection. In 1972, Warren⁹² estimated that 4 million persons in the United States were infected with Ascaris, 2.2 million with Trichuris, 42 million with pinworm, 700,000 with hookworm, and 400,000 with Strongyloides. Maternal infection with these intestinal roundworms usually is benign, except when there is a heavy worm burden. Diagnosis is important in symptomatic gastrointestinal disease, but treatment often can be avoided until after pregnancy because roundworm infection rarely is associated with severe complications of pregnancy or adverse fetal outcome. Infection with more than one parasite is common, and the clinician should evaluate the patient thoroughly for other intestinal nematodes and protozoan parasites that can be transmitted by the fecal-oral route.

Ascaris lumbricoides

THE ORGANISM AND ITS LIFE CYCLE

A. lumbricoides is known as the giant roundworm of humans, and is the largest of the intestinal nematodes. Ascaris is the most common helminthic infection of man, with an estimated prevalence of 1 billion infections, 4 million of which are in the United States.⁹³ Adult worms inhabit the lumen of the small intestine and have a short life span of approximately 10–24 months. The adults, which are 15–40 cm long, may pass up to 200,000 eggs per day. The eggs are excreted with the stool and embryonate for 3 weeks or more in a moist environment. After full maturation and ingestion of the eggs, larvae hatch within the duodenum and pass into the venous circulation, where they migrate to the lungs and across the pulmonary capillary beds. The larvae migrate up the respiratory bronchi, and are swallowed. They then reach their final destination within the jejunum. The nematodes mature into full adults over the ensuing 3 months.

The prevalence of ascariasis is highest in children between the ages of 1 and 12 years. The infection is transmitted by ingestion of the embryonated eggs that have contaminated raw fruits or vegetables or through geophagia. Direct human-to-human transmission without embryonation in the soil does not occur.

CLINICAL MANIFESTATIONS

During the migratory phase of the larvae, the nematodes may cause pneumonia characterized by marked eosinophilia. This condition may be associated with fever, cough, wheezing, and migratory pulmonary infiltrates (Loeffler's syndrome). The severity of these symptoms may be related to the intensity of infection or to prior sensitization. Ascariasis also is a major cause of asthma in many endemic areas.⁹⁴ Intestinal symptoms vary according to the worm burden. In heavy infections of between 500 and 2000 worms, serious complications may occur, including obstruction of pancreatic and bile ducts, appendicitis, intussusception, volvulus, intestinal perforation, and intestinal obstruction.^{95, 96} Occasionally, worms may be vomited or passed whole with the stool. Ascaris infection can cause a modest degree of malabsorption of fat, protein, and carbohydrate.⁹⁷ In some persons, secondary to other infection, fever, starvation, or antibiotic therapy, Ascaris may migrate outside of the gastrointestinal tract. Adult worms have been reported to invade the female genital tract and cause tubo-ovarian abscess, pelvic pain, and menorrhagia.

DIAGNOSIS AND TREATMENT

Diagnosis depends on the identification of characteristic eggs in the stool. Because of the enormous daily output of eggs by gravid ascarids, direct smear examination of the stool is sufficient for diagnosis. Commonly, the recovery of an adult worm or identification of larvae in sputum or gastric aspirates may confirm the diagnosis. Treatment of ascariasis should be withheld during pregnancy until after delivery because these infections usually are not associated with a significant risk to the mother or fetus. The drug of choice for treatment of intestinal infection in nonpregnant women is mebendazole 100 mg twice a day for 3 days.

Albendazole 400 mg as a single dose is an alternative therapy. Antitubulin agents such as albendazole, mebendazole, and thiobendazole should be considered teratogenic in light of recent animal studies.^{98, 99} Alternative therapy includes pyrantel pamoate 11 mg/kg/day orally for 3 days.

Hookworm

THE ORGANISM AND ITS LIFE CYCLE

Human infection with two species of hookworm, Ancylostoma duodenale and Necator americanus, is estimated to affect approximately one quarter of the world's population. Adult hookworms are small, cylindrical, 1 cm-long gray-white nematodes. Hookworms reside predominantly in the upper small intestine, attached to the mucosa by their strong buccal capsule. The average daily blood loss for N. americanus is approximately 0.03 ml, and for A. duodenale, it is 0.2 ml. Human hookworms have a mean life span of approximately 5 years, and an adult may lay an average of 7000 eggs daily. After the eggs reach the soil, they will embryonate for 1–2 weeks, releasing rhabditiform larvae. These larvae are free living, but within several days, they molt to the filariform stage, which is infectious and penetrates the skin on contact of the host. Often, a severely pruritic cutaneous eruption (ground itch) appears after penetration. The larvae follow a migratory pattern similar to that of Ascaris and may cause eosinophilic pneumonia. The adults mature approximately 5 weeks after infection, and may live for 2–10 years.¹⁰⁰

The larvae flourish in climates providing adequate rainfall and well-drained soil and in areas where a reservoir of human infection is maintained by fecal contamination of the soil. Although larvae require relatively little moisture, drying and direct sunlight are destructive. The superficial position of larvae on the topsoil provides easy access for the penetration of human skin. Major epidemiologic features of hookworm transmission concern methods of disposal of fecal waste and the habit of walking barefoot.

CLINICAL MANIFESTATIONS

The major manifestations of hookworm disease are dependent on the stage of infection and the number of invading parasites. Invasion of the skin by infective larvae may result in the development of an erythematous maculopapular skin rash. Edema with pruritus may appear primarily around the feet and between the toes. Migration of the larvae from the lung to the gastrointestinal tract may cause wheezing, cough, fever, and migratory pneumonitis. Within the intestine, the clinical manifestations are directly proportional to the number of worms and related to the degree of tissue destruction and blood loss. The distinction between asymptomatic infection with relatively few worms and disease produced by a sizable worm burden is clinically important, and can be quantitated roughly by fecal egg counts.¹⁰⁰

Abdominal pain, diarrhea, and weight loss usually are noticed only in heavy infection with hookworm. The chronic manifestations of hookworm disease include iron deficiency anemia and hypoalbuminemia. Malabsorption also has been reported in children, but less commonly in adults. During pregnancy, the main concern is iron deficiency anemia. For example, in a light infection, the daily blood loss may be 10 ml/day or less. However, in heavy infection with 300 worms or more, the patient may have blood loss of 50 ml or more. If blood loss continues, potentiating the anemia of pregnancy, complications such as cardiac insufficiency and anasarca may develop. Therefore, a decision to treat a patient during pregnancy should be based on the degree of worm burden and the associated blood loss.

DIAGNOSIS AND TREATMENT

Direct fecal smear examination is adequate for diagnosis of clinically significant hookworm infection. For quantitative purposes, the modified Stoll method can be used to estimate the number of eggs per gram of feces. This method can be used to estimate the amount of daily blood loss on the basis of 2 ml/day/1000 eggs/g feces.¹⁰¹ Light to moderate worm infections during pregnancy can be managed with dietary and iron supplementation, and specific drug therapy can be withheld until after delivery. In pregnant women with a clinically high worm burden and significant anemia, therapy may be instituted with mebendazole, 100 mg orally twice a day for 3 days. Alternative therapy includes pyrantel pamoate 11 mg/kg orally as a single dose. As with many antihelmintic drugs, the safety of these medications has not been documented for use during pregnancy. Supportive therapy should be instituted, including replacement of iron, vitamins, and protein, and blood transfusion, if indicated.

Strongyloides stercoralis

THE ORGANISM AND ITS LIFE CYCLE

Strongyloides is a colorless, semitransparent nematode that is 2.2 mm long; it resides in the mucosa of the jejunum. Larvae typically hatch within the mucosa, bore through the epithelium to the intestinal lumen, and are passed in the feces. The larvae either molt and differentiate into adult males and females or metamorphose into filariform infective forms. The filariform larvae may autoinfect through penetration of the intestinal mucosa from an existing infection or penetration of skin that comes in contact with infected soil. The larvae are passed by the bloodstream to the lungs, where they migrate through the alveolar space and up the tracheobronchial tree, and subsequently are swallowed to their final habitat in the small intestine. Deposition of eggs begins approximately 28 days after initial infection.

CLINICAL MANIFESTATIONS

Migration through the skin and the pulmonary system is associated with clinical complications similar to those described for Ascaris and hookworm. Within the gastrointestinal tract, Strongyloides infection usually is asymptomatic, but may be associated with abdominal pain and tenderness. In heavy infections, epigastric pain, tenderness, nausea, flatulence, vomiting, and diarrhea may be observed.¹⁰² Burning or abdominal pain, often epigastric, occurs in association with diarrhea and passage of mucus in severe disease. Some patients complain of nausea, vomiting, and weight loss, with evidence of malabsorption or protein-losing enteropathy.¹⁰³ Eosinophilia is a prominent feature of this infection. In debilitated immunosuppressed or steroid-treated patients, massive autoinfection with widespread dissemination of larvae to extraintestinal organs, including the CNS, may occur.¹⁰⁴ This hyperinfection often is associated with severe enterocolitis and gram-negative bacteremia, which may lead to death.¹⁰⁵ However, the immunosuppression frequently associated with pregnancy has not been complicated with disseminated Strongyloides.

DIAGNOSIS AND TREATMENT

Definitive diagnosis depends on the finding of S. stercoralis larvae in feces, duodenal fluid, or sputum. Frequently, repeated examinations may be necessary to exclude the diagnosis. Treatment consists of thiabendazole 50 mg/kg twice a day orally for 2 days. Albendazole 400 mg/day for 3 days and ivermectin 200 μg/kg/day for 2 days are reasonable alternatives.

Because of the potential for dissemination, pregnant women with Strongyloides infection should be monitored carefully and treated if any complications are suspected. Otherwise, asymptomatic disease treatment may be instituted after delivery.

Enterobius vermicularis

THE ORGANISM AND ITS LIFE CYCLE

Pinworm infection is one of the most common of all intestinal infections of humans in the United States, with an estimated 42 million cases. Pinworm infection is particularly common among children and is not associated with any specific socioeconomic level. Enterobiasis is most prevalent in institutional groups and among members of the same family. E. vermicularis is a 1-cm, white, thread-like worm inhabiting the cecum, appendix, and colon. Adult female worms migrate to the anal canal at night, deposit approximately 10,000 eggs on the perianal skin, and subsequently die. Each egg contains an embryo that develops into an infective larvae within a few hours. After an egg is ingested, the larvae are released within the small intestine and migrate down the bowel lumen to the cecum. The adult matures in approximately 1 month. Occasionally, autoinfection occurs when the egg hatches in the perianal area and the larvae migrate into the bowel to mature. The eggs are highly resistant to desiccation and will contaminate nightclothes and bed linen.

CLINICAL MANIFESTATIONS

Pinworm infections are primarily asymptomatic and rarely cause complications in pregnancy. The major clinical manifestation of pinworm disease is itching, pruritus ani, and pruritus vulvae. Occasionally, the migration of the parasite produces ectopic disease, such as appendicitis, chronic salpingitis, vaginitis, or ulcerative lesions of the small and large bowel.^{106, 107, 108}

DIAGNOSIS AND TREATMENT

Diagnosis of pinworm is readily made by examination of an adhesive cellophane tape pressed against the perianal region early in the morning. A single examination may detect 50% of infections, three will detect 90%, and five will detect 99%.¹⁰¹ Therapy for pinworm infection during pregnancy should be postponed until after delivery. Treatment consists of a single dose of mebendazole 100 mg orally that is repeated 2 weeks later. Alternative therapy includes pyrantel pamoate 11 mg/kg or albendazole, 400 mg orally in a single dose which also should be repeated 2 weeks later.

Trichuris trichiura

THE ORGANISM AND ITS LIFE CYCLE

Approximately half a billion trichuriasis cases occur worldwide in warm, moist regions. Approximately 2.2 million persons in the United States are infected with Trichuris trichiura, primarily in the rural southeast. The adult worm is approximately 40 mm long and is characterized by an attenuated whiplike anterior part, which has resulted in the characteristic name given to this nematode, whipworm. The head or anterior part of the worm penetrates and anchors itself into the intestinal mucosa of the large intestine, and adults produce approximately 5000 eggs daily. The eggs must incubate for at least 3 weeks in the soil before they become infective. After ingestion, the eggs hatch in the small intestine, and the larvae become embedded in the intestinal villi. After several days, they migrate to the large intestine, where they mature in 3 months. The adult worms may live for as long as 8 years.

CLINICAL MANIFESTATIONS

Most infections with T. trichiura are asymptomatic, but occasionally, nausea, abdominal pain, and diarrhea have been associated with heavier infections. In severe infections with 800 or more worms, mild anemia or rectal prolapse may develop, often associated with secondary infection. Bleeding from heavy infections may be sufficient to produce iron deficiency anemia;¹⁰⁹ otherwise, whipworm infection poses little risk to pregnant women.

DIAGNOSIS AND TREATMENT

Diagnosis is based on identification of ova on stool examination. A simple smear technique usually is sufficient because the level of egg output is so high (approximately 200 eggs/g feces/worm). Therapy during pregnancy should be withheld until after delivery, at which time the patient may be treated with mebendazole 100 mg orally twice a day for 3 days. This drug is associated with a cure rate of 70–90% and a reduction in egg output of 90–99%.

Tissue-dwelling nematodes are geographically widespread, particularly in the tropics, where they infect millions of people. The life cycle of these organisms usually is complex, involving arthropod intermediate hosts (except forTrichinella). Intermediate hosts other than humans frequently are involved. The relative pathogenicity of adult worms versus the larval form varies according to the species, worm load, and frequency of exposure to the infective forms. In general, these infections do not pose specific risks to pregnant patients except in the sense of altering general maternal health.

Trichinosis

THE ORGANISM AND ITS LIFE CYCLE

Humans are infected by Trichinella spiralis organisms when they eat raw or inadequately cooked meat containing viable larvae. The larvae are freed from the cyst wall after digestion in the stomach, and they subsequently attach to the mucosa of the jejunum and develop into adult worms. Fertilized female worms release approximately 500 larvae over a 2-week period. In heavy infections, large numbers of larvae circulate in the blood, and many of these burrow into individual muscle fibers, where they encyst and become capable of infecting another host if ingested. Important reservoirs for T. spiralis are hogs, bears, and other wild animals, such as rats.

CLINICAL MANIFESTATIONS

Within the first week of infection, diarrhea, abdominal discomfort, and vomiting may become manifest. In patients with heavy worm burdens, fulminate enteritis may be documented. During the second week of infection, systemic symptoms such as fever, periorbital edema, subconjunctival hemorrhage, chemosis, myositis with pain and swelling, and weakness are common. Occasionally, a macular or petechial rash is observed, and some patients complain of headache, cough, shortness of breath, and hoarseness. Systemic symptoms usually subside after 3 weeks, but malaise and weakness may persist.¹¹⁰ There is no evidence that pregnancy exacerbates the clinical symptoms of trichinosis or that the infection has an adverse effect on pregnancy. Except for two possible cases of intrauterine infection,¹¹¹ transplacental infection appears unlikely.

DIAGNOSIS AND TREATMENT

Diagnosis of trichinosis should be suspected in patients who have a history of recent consumption of poorly cooked meat, including pork products, and the clinical features of periorbital edema, myositis, fever, and eosinophilia. Definitive diagnosis is based on the finding of encysted larvae in a muscle biopsy specimen. In lieu of muscle biopsy, diagnosis often is based on serologic findings, which may not be positive until 3–4 weeks after infection.

Treatment consists of mebendazole, 200–400 mg three times a day for 3 days, then 400–500 mg three times a day for 10 days. Steroids also have been recommended for severe symptoms.

Few data are available on the use of mebendazole during pregnancy, but there is no reason to avoid its use for the treatment of symptomatic trichinosis during pregnancy.

Filariasis

THE ORGANISM AND ITS LIFE CYCLE

Bancroftian and Malayan filariasis are similar clinical conditions that result from transmission of the filiarial nematodes Wuchereria bancrofti and Brugia malayi by mosquitoes. Onchocerca volvulus and Loa loa are other filarial infections transmitted to humans by arthropod vectors. These infections may have adverse effects on maternal health, but in general do not have a specific effect on pregnancy or the neonate. After the bite of an infected arthropod, infective larvae pass into the lymphatics and lymph nodes, where they mature over the next 6 months into white thread-like adult worms. In the case of W. bancrofti and B. malayi, the adults will live for many years, and fertilized female worms discharge microfilariae by way of the lymphatics into the bloodstream. Nocturnal periodicity characterized by a surge of microfilariae in the blood has been documented primarily with B. malayi. The cycle is completed by feeding of the mosquito, which ingests the circulating microfilariae. In L. loa infection, the adult worms continually migrate through connective tissue and discharge sheathed microfilariae into the blood, primarily during the daytime. Onchocerca adult worms often are found tangled together in nodules of fibrous tissue, where they similarly discharge unsheathed microfilariae, which migrate through the skin in connective tissue. The life cycle is continued when these microfilariae are ingested by female black flies.

CLINICAL MANIFESTATIONS

W. bancrofti and B. malayi infections frequently are asymptomatic despite the presence of microfilariae. Symptomatic disease usually is due to either acute inflammation or chronic lymphatic obstruction. Intermittent attacks of lymphangitis or lymphadenitis with fever, headache, backache, and nausea occasionally occur. In chronic infections, lymphedema may develop, with associated elephantiasis.¹¹² In female patients, this process may affect the breast, vulva, and pelvic organs, thereby having an adverse effect on fertility and lactation. Elephantiasis of the vulva may obstruct labor and necessitate abdominal delivery. L. loa infection frequently is asymptomatic, but patients frequently have transient swelling or localized subcutaneous edema called Calabar swellings. Calabar swellings commonly are seen around joints such as the wrist or knee, and recur irregularly at the same site or at different sites. Occasionally, a worm is seen passing through the subconjunctiva of the eye. Onchocerciasis usually is associated with firm, nontender, freely mobile, fibrous nodules that may be several millimeters to several centimeters in size. In chronic disease, lymphadenopathy may become prominent, microfilariae may induce iridocyclitis, glaucoma, choroiditis, and optic atrophy.¹¹³

DIAGNOSIS AND TREATMENT

In filarial disease, diagnosis is dependent on the finding of the parasite. In bancroftian and Malayan filariasis, blood samples should be taken around midnight and concentrated for identification of microfilariae. In L. loa infection, the diagnosis is established by the finding of microfilariae in daytime blood. In onchocerciasis, the diagnosis is made by demonstration of microfilariae in skin snips or in the cornea or interior chamber of the eye on slit lamp examination.

Treatment of L. loa, W. bancrofti, and B. malayi infection is centered on the use of diethylcarbamazine citrate, which is effective against microfilariae, but has little effect on adult worms.

The recommended dosage is 50 mg orally on day 1, 50 mg three times a day on day 2, 100 mg three times a day on day 3, and 6 mg/kg/day in three doses on days 4 through 21. The recommended treatment for onchocerciasis is ivermectin 150 μg/kg orally once, repeated every 6–12 months. Preliminary studies suggest that ivermectin is well tolerated during pregnancy, with no major toxicities detected.¹¹⁴ Little is known about the toxic effects of diethylcarbamazine during pregnancy, and it is recommended that therapy be delayed until after delivery unless symptoms require immediate treatment.

Trematodes are parasitic flukes frequently found in humans and widely distributed throughout the world. These organisms have complex life cycles that involve aquatic snails as intermediate hosts. Sexual reproduction occurs among adult worms, with asexual multiplication in the larvae stages. With the exception of schistosomes, most flukes that infect humans are hermaphroditic. Schistosomiasis is discussed later because of its high rates of morbidity and mortality. Other flukes include Clonorchis, Opisthorchis, Fasciolopsis, Fasciola, and Paragonimus, which frequently infect the gastrointestinal tract or lung and often are associated with symptomatic disease. However, acute or chronic infections may impair maternal health, but do not appear to have a significant role in perinatal morbidity or mortality, and hence are not discussed here. Treatment for these infections should be withheld until after delivery (Table 2).

Table 2. Treatment of selected parasitic infections in pregnancy

Schistosomiasis

THE ORGANISM AND ITS LIFE CYCLE

Presently, three human blood flukes, Schistosoma mansoni, S. japonicum, and S. haematobium, infect more than 200 million people throughout the world. Geographically, these infections are distributed throughout Africa, South America, and Asia. Humans are the definitive hosts for Schistosoma, the adult organisms of which are 1–2 cm long and typically live in the venous system of the intestine or bladder. The adults exist as separate sexes and may live up to 30 years. Eggs are passed with stools in S. mansoni and S. japonicum infection and with urine in S. haematobium infection. The eggs hatch in fresh water, releasing ciliated motile miracidia that penetrate the body of a specific snail intermediate host. Within the snail, the miracidia multiply asexually, and in 4–6 weeks, hundreds of motile fork-tail cercariae are released. These infective forms are capable of penetrating human skin, after which they pass through a migratory phase in the lung and liver. Eventually, they reach their final habitat in the portal venous system (S. mansoni and S. japonicum) or in the urinary bladder venous plexus (S. haematobium). S. mansoni infection occurs in Arabia, Africa, South America, and the Caribbean; S. japonicum infection occurs in Japan, China, and the Philippines; S. haematobium infection occurs in Africa and the Middle East. The two major factors responsible for the endemic nature of schistosomiasis in specific geographic areas are dependent on the presence of specific snail intermediate hosts and the method of disposal of human waste.

CLINICAL MANIFESTATIONS

The clinical syndromes associated with schistosomiasis are related to the infecting species, the worm burden, the general health of the patient, and possibly genetic susceptibility.¹¹⁵ Symptoms also vary widely according to the duration of disease. Acute schistosomiasis frequently is associated with dermatitis or swimmers itch, which may be prominent 24 hours after penetration of the cercariae. This condition may be evident by the presence of a pruritic papular rash in the area of infection. The next clinical phase coincides with the beginning of oviposition 4–8 weeks after infection. Referred to as Katayama fever, infections with S. japonicum initially present with the acute onset of fever, chills, sweating, headache, and cough. On physical examination, hepatosplenomegaly and lymphadenopathy may be noted in a patient with eosinophilia in the range of 40%. Most of these symptoms and signs disappear within a few weeks, and this clinical response may represent a serum sickness-like syndrome initiated by massive antigenic challenge produced by the eggs.¹¹⁶ Similar presentations have been described with infections with S. mansoni, particularly in Puerto Rico.

Chronic schistosomiasis frequently is asymptomatic. In patients with a heavy worm burden, prominent symptoms consist of fatigue and abdominal pain associated with intermittent diarrhea or dysentery. In S. mansoni and S. japonicum infection, hepatomegaly and, subsequently, splenomegaly may develop secondary to a granulomatous response to Schistosoma eggs. This inflammation results in a presinusoidal block to portal blood flow and eventually in the development of portal hypertension and portal systemic collateral circulation. Intestinal schistosomiasis may manifest as chronic granulomatous lesions of the bowel wall, with multiple intestinal polyps. Sudden episodes of hematemesis from bleeding esophageal varices may occur. The terminal stage of hepatosplenic schistosomiasis usually is manifested by jaundice, ascites, and hepatic failure.

In S. haematobium infection, granulomatous reactions to the eggs located within the ureters and bladder may lead to obstruction of urinary flow or papillomatous irregularities of the bladder wall. Hematuria and dysuria frequently are noticed by the patient, and secondary complications include hydronephrosis, hydroureters, secondary infection, and uremia. In Egypt, an association has been demonstrated between S. haematobium infection and Salmonella urinary carrier state and bladder cancer.¹¹⁷

Eggs of both S. mansoni and S. haematobium worms often are found in the reproductive organs of infected females. Acute and chronic inflammation of the fallopian tubes often leads to the development of salpingitis, infertility, and ectopic pregnancies.^{118, 119} Similarly, lesions of the cervix, vagina, and vulva may impede intercourse, vaginal delivery, and fertility. Although schistosomiasis may adversely affect pregnancy, there is no evidence that pregnancy accelerates the development or increases the severity of schistosomal disease.

Other complications of schistosomiasis include pulmonary disease manifest by cor pulmonale caused by eggs trapped in the pulmonary capillaries. CNS schistosomiasis is a complication of S. japonicum infection, and it may manifest as a space-occupying lesion or generalized encephalopathy. In addition, granulomatous lesions have been noticed around ectopic eggs within the spinal cord, resulting in a transverse myelitis syndrome.

DIAGNOSIS AND TREATMENT

The definitive diagnosis of schistosomiasis can be made by the finding of schistosome eggs in feces, urine, or biopsy specimen of infected liver, rectum, or bladder tissue. Because assessing the intensity of infection is an essential part of the clinical evaluation, quantitative techniques for stool and urine examination are strongly recommended. Urine collection for the diagnosis of S. haematobium infection is best performed between noon and 2 pm. Tissue from rectal and bladder biopsy may be processed routinely for microscopic examination, and a rapid diagnosis may be made by low-magnification examination of a small piece of mucosa compressed between two glass slides. Serologic tests for the diagnosis of schistosomiasis are readily available, but do not differentiate between past exposure with no active disease and active infection with high worm burden.

In considering treatment of acute or chronic infection, it is important to remember that the associated complications of this disease become manifest after prolonged chronic infection. Hence, it would be advisable to withhold treatment in pregnant women until after delivery because of possible toxicity to the fetus. However, several new drugs have been developed that are effective and associated with low toxicity. For S. haematobium infection, praziquantel 20 mg/kg twice a day for 1 day is recommended. For S. japonicum infection, praziquantel 20 mg/kg three times a day for 1 day appears to be effective. For S. mansoni infection, praziquantel, 20 mg/kg twice a day for 1 day is effective. Oxamniquine 15 mg/kg as a single dose also is effective. As with most antiparasitic drugs, there are no data on the toxicity of these drugs to the human fetus, but praziquantel, which is effective against all three species, is safe in pregnant animals.

Tapeworms are highly prevalent in humans and are cosmopolitan in distribution. These parasites also have complex life cycles. They may cause illness in humans in either of two stages of their life cycle: the adult stage, which may cause signs and symptoms referable to the gastrointestinal tract, where the adult tapeworm resides, and the larval stage, which may cause signs and symptoms secondary to enlarging larval cysts in various tissues of the mammalian host. Four tapeworms primarily cause gastrointestinal infection: Taenia saginata, T. solium, Diphyllobothrium latum, and Hymenolepis nana. T. solium and H. nana also may infect a human as an intermediate host, with survival of a larval form in tissue outside of the gastrointestinal tract. A human also may serve as an intermediate host for the larval form of Echinococcus granulosus.

Biology and life cycle

Adult tapeworms are segmented worms with one major part, the head or scolex, designed for attachment. The other part, the proglottid, is designed for efficient hermaphroditic reproduction. Each parasitic tapeworm has particular morphologic differences that help to differentiate one from another. T. saginata has four muscular suction cups on the scolex, and T. solium maintains a group of hooks in the form of a rostellum. D. latum has two sucking grooves that give its head a distinctive appearance. Even the proglottids differ among species in terms of branching of the uterus and uterine size relative to the proglottid.

Ingestion of the eggs and development of larvae occur in susceptible intermediate hosts, which differ among the tapeworms. The larvae or oncospheres of T. saginata and T. solium occur in fluid-filled sacs called cysticerci within cattle (T. saginata), and pigs and humans (T. solium).

D. latum has two intermediate hosts, including crustaceans and fish. E. granulosus has an intermediate host of sheep or cattle, with a definitive host of dogs. Humans become involved only accidentally, by contact with contaminated dog feces.

Clinical manifestations

Symptoms of T. saginata infection are minimal and consist of mild abdominal cramps and hunger-like pains. Rarely, a large number of worms causes intestinal or appendiceal obstruction. The psychological effect of infection with tapeworms appears to be more severe than the associated symptoms.

Intestinal symptoms with T. solium infection are similar to those of T. saginata infection, or nonexistent. However, more prominent symptoms may be associated when humans are infected by worms in the larval stage known as cysticercosis. This form of disease is most common in Mexico and certain parts of Africa and South America, and may involve any tissue of the body. CNS involvement is common, and causes headache, papilledema, hemiparesis, decreased vision, and seizure.

Of the three tapeworms, D. latum has the greatest potential for causing severe effects on pregnancy. Large numbers of this worm can be present within the intestinal tract, and it is known for its ability to compete effectively for certain vitamins, such as vitamin B₁₂. The cestode will split the vitamin B₁₂ intrinsic factor complex, making vitamin B₁₂ unavailable by the host. Folate absorption by the host also may be diminished by the presence of this tapeworm, and the two deficiencies may potentiate anemia of pregnancy. Symptoms may involve mild gastrointestinal discomfort and typical symptoms of megaloblastic anemia, including pallor, glossitis, and loss of tongue papilli. Neurologic symptoms and signs include numbness, paresthesia, loss of vibration sense, weakness, and unsteady gait.

H. nana infection usually is asymptomatic, but may induce mucosal irritation. Some patients with heavy infection may have abdominal cramps, diarrhea, dizziness, and seizure.

E. granulosus is associated with the development of hydatid cysts, primarily in the right lobe of the liver. Symptoms are referable to the mass effect of the cyst, which occasionally ruptures into the bile tract, leading to cholangitis and intermittent ductal obstruction. Cysts also may rupture through the capsule of the liver into the peritoneal cavity or through the diaphragm into the pleural space, resulting in a pleural effusion and shortness of breath. Rupture into the peritoneal cavity leads to the formation of new daughter cysts throughout the peritoneum. Eventually, these cysts will enlarge and can compress and rupture adjacent abdominal viscera. However, most cysts remain intact for several years and may be outlined by a smooth rim of calcification.

Diagnosis and treatment

The diagnosis of infection with intestinal cestodes is made by demonstration of the eggs and proglottids in the feces. However, diagnosis of larval stages within human hosts is more difficult and based on clinical suspicion. Diagnosis of cysticercosis is made on the basis of the finding of small calcific densities on roentgenogram of the skull or extremities or identification of characteristic lesions by computed tomography (CT) or brain scan. Serologic tests for cysticercus antibodies have value in confirming the diagnosis. The best available test is the indirect hemagglutination test. Hydatid disease is suggested by the presence of a symmetric tumor mass detected by palpation on routine examination of the abdomen, sonography, or CT scan. The mass may be outlined by a smooth rim of calcification in chronic lesions, but may not be present in young, growing cysts. Indirect hemagglutination and latex agglutination antibody tests are useful in confirmation of the diagnosis.

Treatment of intestinal tapeworms, including T. saginata, T. solium, and D. latum, is praziquantel 10–20 mg/kg in a single dose. Treatment of H. nana also is a single dose of praziquantel 25 mg/kg. Alternative therapy is niclosamide 2 g chewed thoroughly, then 1 g/day (two tablets) for 6 days. Treatment of cysticercosis or hydatid disease is based on surgical removal of the intact cyst if it is inducing obstructive symptoms. Care should be exercised in preventing spillage of the cyst contents into the peritoneum. Several studies have suggested that high-dose mebendazole administration is effective in killing tapeworms in the larval stage. This treatment is useful for patients who cannot undergo surgery or as adjunctive therapy.