32 - Infectious Diseases: Viral Rickettsial

Editors: McPhee, Stephen J.; Papadakis, Maxine A.; Tierney, Lawrence M.

Title: Current Medical Diagnosis & Treatment, 46th Edition

Copyright ©2007 McGraw-Hill

> Table of Contents > 35 - Infectious Diseases: Protozoal & Helminthic

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Infectious Diseases: Protozoal & Helminthic

Robert S. Goldsmith MD, MPH, DTM&H

Protozoal Infections

African Trypanosomiasis (Sleeping Sickness)

Essentials of Diagnosis

  • History of exposure to tsetse flies, with subsequent bite lesion.

Hemolymphatic Stage:

  • Irregular fevers, headaches, joint pains, malaise, pruritus, papular skin rash, edemas.

  • Posterior cervical or generalized lymphadenopathy; hepatosplenomegaly.

  • Anemia, weight loss.

  • Trypanosomes in blood or lymph node aspirates; positive serology.

Meningoencephalitic Stage:

  • Insomnia, motor and sensory disorders, abnormal reflexes, somnolence to coma.

  • Trypanosomes and increased white cells and protein in cerebrospinal fluid.

General Considerations

African trypanosomiasis is caused by Trypanosoma brucei rhodesiense and Trypanosoma brucei gambiense, both hemoflagellates. The organisms are transmitted by bites of tsetse flies (Glossina species), which inhabit shaded areas along streams and rivers. Trypanosomes ingested in a blood meal undergo a developmental period of 18–35 days in the fly; when the fly feeds again on a new mammalian host, the infective stage is injected. Human disease occurs locally (but strictly in rural areas) throughout tropical Africa from south of the Sahara to about 20 degrees south latitude. T b gambiense infections are in the moist sub-Saharan savanna and riverine forests of west and central Africa up to the eastern Rift Valley. T b rhodesiense infections occur to the east of the Rift Valley in the savannah of east and southeast Africa and along the shores of Lake Victoria (up to 18% in some areas of Uganda).

T b rhodesiense infection is primarily a zoonosis of game animals but also infects cattle; humans are infected sporadically. Humans are the principal mammalian host for T b gambiense; it is uncertain whether there is an animal reservoir, but domestic animals can be infected. A third trypanosome, Trypanosoma brucei brucei, infects only wild and domestic animals.

Although African trypanosomiasis was largely controlled through the 1960s, the disease has reemerged as an increasing threat in west, central, and east Africa. Yearly, an estimated 30,000 new cases occur that result in a total prevalence of 300,000–500,000 infections (local prevalence in some foci exceeds 5%) and 100,000 deaths (most due to T b gambiense infection). Among visitors to the East African game parks, infections are rare, with about one case a year appearing in the United States.

Clinical Findings

A. Symptoms and Signs

Infections go through three stages: chancre, hemolymphatic, and encephalitic. The hemolymphatic period, which usually begins within 3–10 days after appearance of the chancre, is diagnosed by detecting the circulating parasite. Rhodesian trypanosomiasis is much more virulent, and untreated patients die within weeks to months. Gambian trypanosomiasis, however, usually goes through a long asymptomatic period in which a chancre is rare, the hemolytic stage may be absent or go unnoticed, and parasites are much more difficult to find. When Gambian symptoms do become manifest in weeks to months, they are often initially mild and nonspecific and are ignored by the patient; unless treated, however, death occurs within months to several years. There have been some reports of variations in severity.

1. The Trypanosomal Chancre

In T b rhodesiense infections, this is a local pruritic, painful inflammatory


reaction (3–10 cm) with regional lymphadenopathy that appears about 48 hours after the tsetse fly bite and lasts 2–4 weeks.

2. The Hemolymphatic (Early) Stage

High fever, severe headache, joint pains, and malaise recur at irregular intervals corresponding to waves of parasitemia. Between febrile episodes there are symptom-free periods that last up to 2 weeks. Transient rashes may appear, often pruritic and papular or circinate. Examination reveals mild enlargement of the liver and spleen, and edema (peripheral, pleural, ascites, etc). Enlarged, rubbery, and painless lymph nodes occur in 75% of patients. In Gambian trypanosomiasis, there may be lymphadenopathy, particularly of the posterior cervical group (Winterbottom's sign). With progression of the disease, there is weight loss and debilitation. Myocardial involvement may appear early in Rhodesian trypanosomiasis, and the patient may die of myocarditis before meningoencephalitic signs appear.

3. The Meningoencephalitic (Late) Stage

This stage appears within a few weeks or months of onset of Rhodesian trypanosomiasis, but in Gambian trypanosomiasis, sleeping sickness develops more insidiously, starting 6 months to several years after onset. Insomnia, anorexia, personality changes, apathy, and headaches are the early findings. A variety of motor or tonus disorders may develop, including tremors; seizures; and disturbances of speech, gait, and reflexes. Sensory involvement includes hyperesthesia and pruritus. Somnolence appears late. The patient becomes severely emaciated and, finally, comatose. Death often results from secondary infection.

B. Laboratory Findings

Definitive diagnosis requires finding the organism. Detection in the blood is usually possible in Rhodesian trypanosomiasis but is very difficult in Gambian trypanosomiasis. The diagnosis of early-stage Gambian trypanosomiasis is by screening with a field-adapted card agglutination test (CATT) (sensitivity about 96%, specificity high), which is then followed by confirmatory microscopy to detect the parasite in the blood, cerebrospinal fluid, or other tissues. Circulating IgM antibody, which becomes positive about 12 days after infection, is sometimes useful; its titers may fluctuate or be undetectable during brief periods of antigen excess, and a negative test does not rule out infection. Several other antibody tests are used epidemiologically for Gambian trypanosomiasis. In late central nervous system disease, though both circulating antibody and parasitemia may fall below detectable levels, serologic tests of the cerebrospinal fluid (especially IgM) may prove useful. Polymerase chain reaction (PCR) testing is highly sensitive but is not commercially available.

Motile parasites are found in wet films and after Giemsa or Wright's staining of thin and thick blood films; of aspirates of bite lesions, lymph nodes, or bone marrow; or of cerebrospinal fluid. The two species, morphologically identical, are differentiated by molecular techniques. Because the number of trypanosomes in blood fluctuates (they may be undetectable 3 out of 5 days but are more common during febrile periods), multiple anticoagulated specimens should be examined daily for as many as 15 days using 10–15 mL for centrifugation; the trypanosomes are concentrated in the buffy coat. Other diagnostic tests with blood are intraperitoneal inoculation of rodents (sensitive but only effective for T b rhodesiense), culture, Millipore filtration, and DEAE-cellulose anion exchange centrifugation. Only soft lymph nodes should be selected for aspiration (25-gauge needle); after the node is gently kneaded, the aspirate is examined immediately for motile organisms.

Cerebrospinal fluid is clear and shows an increase in pressure, lymphocytes (≥ 5 cells/mcL), and protein (> 35 mg/dL). Large eosinophilic plasma cells (Mott cells) are rarely seen but are considered pathognomonic by some experts. With progression of the disease, the parasite is more likely to be found in cerebrospinal fluid than in blood or lymph nodes. To detect the organism, the fluid should be examined within 20 minutes (to avoid parasitic lysis) and centrifuged twice (doubles sensitivity), inoculated into an experimental animal, and cultured.

Anemia, increased sedimentation rate, thrombocytopenia, and increased globulin are common. Eosinophilia is not seen. Electroencephalograms, MRI, and CT scans are nonspecific.

Differential Diagnosis

Trypanosomiasis may be mistaken for a variety of other diseases, including malaria, influenza, pneumonia, tuberculosis, infectious mononucleosis, leukemia, lymphoma, HIV infection, the arbovirus encephalitides, and psychosis. Serologic tests for syphilis may be falsely positive in trypanosomiasis.


Because all of the drugs used are toxic, specific detection of the organism is a prerequisite for treatment; immunoassays are insufficient to make the diagnosis. A key issue in choice of drugs is to distinguish early- from late-stage disease. Treatment is also complicated by drug resistance (pentamidine and melarsoprol) and by the need for prolonged follow-up.

Suramin and pentamidine do not adequately cross the blood-brain barrier and cannot be used when the central nervous system is involved; melarsoprol and eflornithine, however, do pass the barrier. Melarsoprol causes a reactive encephalopathy in 5–10% of patients (corticosteroids are partially protective) and the mortality rate from that complication is 50% or higher. Side effects of pentamidine, although usually well-tolerated, can include hypotension, dizziness, vomiting, and sterile abscess; those of suramin include gastrointestinal symptoms and rarely nephrotoxicity, hypotension, and pancytopenia. Eflornithine, used only for T b gambiense infections, has side effects that include


pancytopenia, diarrhea, hallucinations, and seizures. The drug is expensive and its continued availability (from the World Health Organization [WHO]) is uncertain. Suramin side effects, which may be severe, include vomiting, pruritus, paresthesias, and peripheral neuropathy. Suramin and melarsoprol are available only from the CDC Drug Service, Centers for Disease Control and Prevention, Atlanta, GA 30333. Telephone: 404–639-3670. Nifurtimox use continues to be under evaluation.

A. Early Disease, the Hemolymphatic Stage

The drug of choice for Gambian trypanosomiasis is pentamidine (4 mg/kg intramuscularly every day or every other day for 7–10 days; cure rare 93%). An alternate drug is intravenous eflornithine (400 mg/kg/d in four divided doses for 14 days). The treatment of Rhodesian trypanosomiasis is with intravenous suramin (100–200 mg [test dose], then 20 mg/kg [maximum 1 g] every 7 days for seven doses).

B. Late Disease with Central Nervous System Involvement

Drugs of choice for both parasitic infections are intravenous melarsoprol, 2–3.6 mg/kg/d for 3 days; after 1 week, 3.6 mg/kg/d for 3 days; repeat after 10–21 days. Relapse rates for Gambian trypanosomiasis, formerly low (5–8%), have markedly increased as melarsoprol drug resistance has risen sharply in some areas of Africa, where failure rates approach 30%. A new shortened melarsoprol treatment schedule (2.2 mg/kg/d for 10 days by slow intravenous injection plus coadministration of a corticosteroid) has been evaluated in a multinational study and is now advocated for treatment of T b gambiense infections only. An alternative treatment only against T b gambiense is eflornithine (as above).

Proper follow-up to ensure detection of the encephalitic stage requires initial cerebrospinal fluid examination, repeat studies at intervals during treatment, 3 months after treatment, and then at 6-month intervals for 2 years.


Individual prevention in endemic areas should include wearing long sleeves and trousers, avoiding dark-colored clothing, and using mosquito nets while sleeping. Repellents have no effect. Chemoprophylaxis with pentamidine is no longer in use. For T b gambiense infection, performing serologic tests every 6 months during exposure and for 3 years afterward is the safest method for detecting the disease at an early stage. Gambian control depends on detecting and treating the largely asymptomatic human reservoir.


Most patients—even those with advanced disease—recover following treatment. Relapses are uncommon (about 2%). If untreated or if therapy is started late, irreversible brain damage or death follows.

Burchmore RJ et al: Chemotherapy of human African trypanosomiasis. Curr Pharm Des 2002;8:256.

Chappuis F et al: Options for field diagnosis of human Africa trypanosomiasis. Clin Microbiol Rev 2005;18:133.

Kennedy PG: Human African trypanosomiasis of the CNS: current issues and challenges. J Clin Invest 2004;113:496.

Lejon V et al: Review Article: cerebrospinal fluid in human African trypanosomiasis: a key to diagnosis, therapeutic decision and post-treatment follow-up. Trop Med Int Health 2005;10:395.

Schmid C et al: Effectiveness of a 10-day melarsoprol schedule for the treatment of late-stage human African trypanosomiasis: confirmation from a multinational study (IMPAMEL II). J Infect Dis 2005;191:1922.

Stich A et al: Human African trypanosomiasis. BMJ 2002;325:203.

American Trypanosomiasis (Chagas' Disease)

Essentials of Diagnosis

Acute stage:

  • Inflammatory lesion at site of inoculation; prolonged fever, tachycardia, hepatosplenomegaly, lymphadenopathy, signs of myocarditis.

  • Parasites in peripheral blood, positive serologic tests.

Chronic Stage:

  • Heart failure with cardiac arrhythmias; decreased intensity of heart sounds; episodes of thromboembolism.

  • In some regions, dysphagia, severe constipation, and radiologic evidence of megaesophagus or megacolon.

  • Positive xenodiagnosis or hemoculture, positive serologic tests; abnormal ECG.

General Considerations

Chagas' disease is caused by Trypanosoma cruzi, a protozoan parasite of humans and wild and domestic animals. T cruzi occurs only in the Americas; it is found in wild animals and to a lesser extent in humans from southern South America to southern United States. An estimated 13 million people are infected, mostly in rural areas, resulting in about 45,000 deaths yearly due to cardiac disease. The disease is often acquired in childhood; the proportion of infected persons increases with age. In many countries in South America, Chagas' disease is the most important cause of heart disease. In southern United States, although the organism has been found in triatomine bugs and wild and domestic animals, only a few confirmed instances of local transmission


have been reported. In the United States, a large number of immigrants from endemic areas of Latin America (particularly Central America) are infected (estimated 50,000–100,000); a handful of infections following blood transfusion have been reported.

T cruzi is transmitted by reduviid (triatomine) bugs infected by ingesting blood from animals or humans who have circulating trypanosomes. Multiplication occurs in the digestive tract of the bug; infective forms are eliminated in feces. Infection in humans occurs through “contamination” with bug feces; the parasite penetrates the skin (generally through the bite wound), mucous membranes, or the conjunctiva. Transmission can also occur by blood transfusion or in utero.

The trypanosomes first multiply close to the point of entry. They then enter the bloodstream as trypanosomes and later invade cells and assume the leishmanial form. The organism has a predilection for myocardium, smooth muscle, and central nervous system glial cells. Multiplication causes cellular destruction, inflammation, and fibrosis.

In South America, a major eradication program based on improved housing, use of residual pyrethroid insecticides and pyrethroid-impregnated bed curtains (under evaluation), and screening of blood donors has achieved striking reductions in new infections; Uruguay, Chile, and parts of Brazil and Argentina are now free of transmission.

Clinical Findings

A. Symptoms and Signs

Although infection continues for many years—probably for life—as many as 70% of persons remain asymptomatic. The acute stage, seen principally in children, lasts 2–4 months and leads to death in up to 10% of cases. The earliest findings are at the site of inoculation either in the eye—Romaña's sign (unilateral bipalpebral edema, conjunctivitis, local lymphadenopathy)—or in the skin—a chagoma (furuncle-like lesion with local lymphadenopathy). Subsequent findings include fever, malaise, headache, hepatomegaly, mild splenomegaly, and generalized lymphadenopathy. Acute myocarditis may lead to biventricular failure, but arrhythmias are rare. Meningoencephalitis is limited to young children and is often fatal.

A latent period (indeterminate phase) may last from 10 to 30 years in which the patient is without symptoms and signs of the disease but in which serologic tests and sometimes parasitologic examination confirm the presence of the infection.

The chronic stage is usually manifested by cardiac disease in the third and fourth decades of life, characterized by arrhythmias, congestive heart failure (often with prominent right-sided findings), ventricular aneurysms, and systemic or pulmonary embolization originating from mural thrombi. Valvular lesions are absent. Sudden cardiac arrest in young persons may occur and is attributed to ventricular fibrillation. Megacolon and megaesophagus, caused by damage to nerve plexuses in the bowel or esophageal wall, occur in some areas of Chile, Argentina, and Brazil; findings include dysphagia, regurgitation, constipation, sigmoid volvulus, bacterial overgrowth in the small intestine, and parotid gland hypertrophy. Megasyndromes can also affect the urinary tract.

In immunosuppressed persons—including infrequently in AIDS patients and transplant recipients—latent Chagas' disease may reactivate. Common findings are cardiomyopathy and brain lesions indistinguishable from cerebral toxoplasmosis.

B. Laboratory Findings

Diagnosis is by parasitologic and serologic methods. Trypanosomes can be detected in most acute and congenital cases and in up to 40% of chronic infections. In the acute stage, the organism may be found (1) as motile trypanosomes in anticoagulated blood, (2) as Giemsa-stained trypanosomes in anticoagulated blood used to prepare thin and thick or buffy coat films, or (3) by blood culture or animal inoculation. Occasionally, amastigotes can be found in tissue aspirates or biopsies of chagomas or lymph nodes by direct examination, staining, or culture. In the chronic stage, however, the organism is rarely found directly but may be detected by culture, animal inoculation, or xenodiagnosis. The latter consists of permitting uninfected laboratory-reared bugs of the local major vector to feed on the patients and then examining their intestinal contents for trypanosomes. Culture in appropriate media is kept for 30 days; animal inoculation is in 3-day-old to 10-day-old laboratory mice or rats. Trypanosoma rangeli, a nonpathogenic blood trypanosome also found in humans in Central America and northern South America, must not be mistaken for T cruzi trypomastigotes.

Several highly sensitive IgG serologic tests (hemagglutination inhibition, complement fixation, enzyme-linked immunosorbent assay [ELISA], immunofluorescence, Western blot, others) are routinely used and are of presumptive value when positive. However, two or three of these tests should be done because both false-negative (including some cases of depressed immune response) and false-positive tests are common. The latter may occur in other infections—including leishmaniasis, malaria, syphilis, and T rangeli infection—and in autoimmune diseases. For the ELISA and immunofluorescence tests, sensitivity is 93–98% and specificity (excluding leishmaniasis) is 99%. Antibodies of the IgM class are elevated early in the acute stage but are replaced by IgG antibodies as the disease progresses. Maximum titers are reached in 3–4 months; thereafter, titers can remain positive at a low level for life. In chronic infections, when serologic tests are negative, PCR and DNA methods sometimes make the diagnosis. These tests may also prove useful in assessing effectiveness of therapy (clearance of parasites), whereas serologic tests do not. Immunoassays are being evaluated to detect urine and blood antigens. The most important electrocardiographic abnormalities are right bundle branch block and arrhythmias. In certain regions of South America,


radiologic examination may show megaesophagus, megacolon, or cardiac enlargement with characteristic apical aneurysms.


Treatment of Chagas' disease is inadequate because the two drugs used, nifurtimox and benznidazole, often cause severe side effects, must be used for long periods, and are ineffective against chronic infection. In acute disease and congenital infections, the drugs are effective in reducing the duration and severity of infection, but cure is achieved in only about 70% of patients. In the chronic phase, although parasitemia may disappear in up to 70% of patients, treatment does not alter the serologic reaction, cardiac function, or progression of the disease. Nevertheless, most experts concur that treatment should be attempted in all T cruzi-infected persons regardless of clinical status or time since infection.

Nifurtimox is given orally in daily doses of 8–10 mg/kg in four divided doses after meals for 90–120 days. It generally produces gastrointestinal complaints, weight loss, tremors, and peripheral neuropathy. Hallucinations, pulmonary infiltrates, and convulsions are rare. In the United States, nifurtimox is available only from the Parasitic Disease Drug Service, Centers for Disease Control and Prevention, Atlanta, GA 30333 (404–639-3670). Benznidazole—usually available only in Brazil—is given at a dosage of 5 mg/kg/d in divided doses for 60 days. Its side effects include granulocytopenia, rash, and peripheral neuropathy. The drug is better tolerated by children.

In the chronic stage, digoxin is not well tolerated and is used as a last resort. The most effective antiarrhythmic drug is amiodarone. Cardiac pacemakers are used for atrioventricular block. Amiodarone and angiotensin-converting enzyme inhibitors may result in better survival in selected patients. Surgery is important in the treatment of megaesophagus and megacolon. In endemic areas, blood should not be used for transfusion unless at least two serologic tests are negative; otherwise, blood can be treated with gentian violet to kill the parasites. Immigrants from endemic areas should be tested for the infection.


Acute infections in infants and young children are often fatal, particularly when the central nervous system is involved. Adults with chronic heart disease also may ultimately die of the disease.

Andrade AL et al: Short report: benznidazole efficacy among Trypanosoma cruzi-infected a six-year follow-up. Am J Trop Med Hyg 2004;71:594.

Lury KM et al: Chagas' disease involving the brain and spinal cord: MRI findings. AJR Am J Roentgenol 2005;185:550.

Meneghelli UG: Chagasic enteropathy. Rev Soc Bras Med Trop 2004;37:252.

Paulinoa M et al: The chemotherapy of Chagas' disease: an overview. Mini Rev Med Chem 2005;5:499.

Salomone OA et al: Trypanosoma cruzi in persons without serologic evidence of disease, Argentina. Emerg Infect Dis 2003;9:1558.


Essentials of Diagnosis

  • Mild to moderate colitis: recurrent diarrhea and abdominal cramps, sometimes alternating with constipation; mucus may be present; blood is usually absent.

  • Severe colitis: semiformed to liquid stools streaked with blood and mucus, fever, colic, prostration; ileus, perforation with peritonitis, and hemorrhage occur.

  • Hepatic amebiasis: fever, hepatomegaly, pain, localized tenderness.

  • Laboratory findings: amebas or antigen in stools or in abscess aspirate followed by differentiation, when possible, of Entamoeba histolytica from Entamoeba dispar; positive serologic tests with severe colitis or hepatic abscess; ultrasound or CT scan showing hepatic abscess.

General Considerations

Though the causative protozoan parasite Entamoeba histolytica was once considered a single species with varying virulence, it is now recognized that the Entamoeba complex contains two morphologically identical species: (1) Entamoeba dispar (about 90% of the complex), which remains in the colon as a stable commensal that is avirulent and produces an asymptomatic carrier state; and (2) E histolytica, which shows varying degrees of virulence ranging from a commensal state in the colon—in which it does not cause disease, yet is potentially invasive—to being invasive of the intestinal wall, resulting in acute diarrhea or dysentery or chronic diarrhea. E histolytica may also be carried by the blood to the liver where it may produce hepatic abscess. Rarely, the lungs, brain, other organs, or perianal skin may be infected. About 10% of asymptomatic carriers of E histolytica develop invasive disease; the others clear the infection within 1 year.

Both E histolytica and E dispar exist as two forms in the lumen and mucosal crypts of the large bowel: identical-appearing cysts (10–14 mcm) and motile trophozoites (12–50 mcm). In the absence of diarrhea, trophozoites encyst in the large bowel. Trophozoites passed into the environment die rapidly, but cysts remain viable in soil and water for several weeks to months at appropriate temperature and humidity.

The infections are present worldwide but are most prevalent and severe in subtropical and tropical areas under conditions of crowding, poor sanitation, and poor


nutrition. Using the new taxonomy, prevalence estimates have changed. Of 500 million persons worldwide infected with entamoeba, most are infected with E dispar and an estimated 10% (50 million) with E histolytica. Invasive E histolytica may constitute 5 million cases, with mortality in the range of 100,000 per year. In the United States, infections are most common in immigrants from—and travelers to—developing countries.

Humans are the only established host and are universally susceptible. Only cysts are infectious, since after ingestion they survive gastric acidity, which destroys trophozoites. Transmission occurs through ingestion of cysts from fecally contaminated food or water. Flies and other arthropods also serve as mechanical vectors; to an undetermined degree, transmission results from contamination of food by the hands of food handlers. Where human excrement is used as fertilizer, it is often a source of food and water contamination. Person-to-person contact is also important in transmission; therefore, all household members as well as an infected person's sexual partner should have their stools examined. In communal settings such as mental hospitals, prevalence rates as high as 50% have been reported. Amebiasis is rarely epidemic, but urban outbreaks have occurred because of common-source water contamination. Although entamoeba infections occur frequently among homosexuals, in the developed countries these infections are usually due to the E dispar and do not require treatment. In AIDS, E histolytica infection does not become an opportunistic infection, except for reports from Taiwan.

Fulminant infections may occur in pregnancy and in young children. Corticosteroids and other immunosuppressive drugs given in error for inflammatory bowel disease may convert a commensal infection into an invasive one.

The characteristic intestinal lesion is the amebic ulcer, which can occur anywhere in the large bowel (including the appendix) and sometimes in the terminal ileum but predominates in the cecum, descending colon, and the rectosigmoid colon—areas of greatest fecal stasis. Trophozoites invade the colonic mucosa by means of their ameboid movement and proteolytic secretions and induce necrosis to form the characteristic flask-shaped ulcers. Ulcers are usually limited to the muscularis, but if penetration to the serous layer occurs, bowel perforation, local abscess, or generalized peritonitis may result. In fulminating cases, ulceration may be extensive, and the bowel becomes thin and friable. Hepatic abscesses range from a few millimeters to 15 cm or larger, usually are single, occur more often in the right lobe (particularly the upper portion), and are more common in men.

Clinical Findings

A. Symptoms and Signs

Amebiasis is classified into intestinal and extraintestinal disease and further subdivided into the clinical syndromes described below. Some patients have an acute onset of severe diarrhea as early as 8 days (commonly 2–4 weeks) after infection. Others may be asymptomatic or have mild intestinal infection for months to several years before either intestinal symptoms or liver abscess appears. Transition may occur from one type of intestinal infection to another, and each may give rise to hepatic abscess, or the intestinal infection may clear spontaneously.

1. Intestinal Amebiasis

a. Asymptomatic infection

In most infected persons, the organism lives as a commensal, and the carrier is without symptoms.

b. Mild to moderate colitis (nondysenteric colitis)

A few stools a day are passed that are semiformed and have no blood. There may be abdominal cramps, flatulence, fatigue, and weight loss; fever is uncommon. Periods of remission and recurrence may last days to weeks or longer; during remissions, the patient may have constipation. Abdominal examination may show distention, hyperperistalsis, and tenderness. In some patients with chronic infection, the colon is thick and palpable, particularly over the cecum and descending colon. Toxic products released as a result of the bowel infection may induce periportal inflammation, mild hepatomegaly, and low-grade liver enzyme abnormalities but without demonstrable trophozoites in the liver.

c. Severe colitis (dysenteric colitis)

As the severity of intestinal infection increases, the number of stools increases, and they change from semiformed to liquid with streaks of blood beginning to appear. With larger numbers of stools, 10–20 or more, little fecal material is present, but blood (fresh or dark) and bits of necrotic tissue become increasingly evident. With increasing severity, the patient may become prostrate and toxic, with fever up to 40.5°C, and have colic, tenesmus, vomiting, generalized abdominal tenderness, and nonspecific hepatic enlargement and tenderness. Rare complications include appendicitis, bowel perforation, fulminating colitis, massive mucosal sloughing, and hemorrhage. Death may follow.

d. Localized ulcerative lesions of the colon

Bowel ulcerations limited to the rectal area may result in passage of formed stools with bloody exudate. Ulcerations limited to the cecum may induce mild diarrhea and simulate appendicitis. Amebic appendicitis, in which the appendix is extensively involved but not the remainder of the large bowel, is rare.

e. Localized granulomatous lesions of the colon (ameboma)

This occurs as a result of excessive production of granulation tissue in response to amebic infection, either in the course of dysentery or slowly in chronic intestinal infection. These masses may present as an irregular tumor (single or multiple) projecting into the bowel or as an annular constricting mass up to several centimeters in length. Clinical findings (pain, obstructive symptoms, and hemorrhage) and x-ray findings may simulate colonic carcinoma, tuberculosis, or lymphogranuloma venereum. At endoscopy,


the mass is deep red and bleeds easily, and biopsy specimens show granulation tissue and E histolytica; the number of organisms may be relatively few. Antiamebic drugs are usually adequate treatment; surgical removal of the lesion without prior or immediate postoperative drug therapy is likely to result in death from disseminated disease.

2. Extraintestinal amebiasis

a. Hepatic amebiasis

Amebic liver abscess, although a relatively infrequent (3–9%) consequence of intestinal amebiasis, is not uncommon given the large number of intestinal infections. A large proportion of patients with liver abscess do not have concurrent intestinal symptoms, nor can they recall having had chronic intestinal symptoms. The onset of symptoms can be sudden or gradual, ranging from a few days to many months. Cardinal manifestations are fever (often high), pain (continuous, stabbing, or pleuritic, and sometimes severe), and an enlarged and tender liver. Patients may also experience malaise or prostration, sweating, chills, anorexia, and weight loss. The liver enlargement may present subcostally, in the epigastrium, as a localized bulging of the rib cage, or, as a result of enlargement against the dome of the diaphragm, it may produce coughing and findings at the right lung base (dullness to percussion, rales, and diminished breath sounds). Intercostal tenderness is common. Localizing signs on the skin may be an area of edema or a point of maximum tenderness. Without prompt treatment, the abscess may rupture into the pleural, peritoneal, or pericardial space or other contiguous organs, and death may follow.

b. Other extraintestinal infections

Skin infections may develop in the perianal area. Metastatic infection may rarely occur throughout the body, particularly the lungs, brain, and genitalia.

B. Laboratory Findings

Diagnosis is by finding E histolytica or its antigen or by serologic tests. However, each method has limitations.

1. Intestinal amebiasis

A standard approach is to examine three stool specimens microscopically (preserved or fresh) and to test one for antigen. In microscopic examinations, trophozoites and cysts of E histolytica and E dispar cannot be distinguished from each other but can be distinguished from the other intestinal protozoa. Methods to differentiate between E histolytica and E dispar continue under evaluation. A sensitive and specific ELISA method is available to detect E histolytica-specific antigen in stool. The techLab Entamoeba test (sensitivity 93%, specificity 97%) is considered able to differentiate the organisms, but requires fresh or frozen stool specimens; preserved stool cannot be used.

Microscopic examination of stools. Microscopic examination is relatively insensitive and does not differentiate the two Entamoeba species or the free-living ameba, Entamoeba moshkovskii, which is now recognized in stool with an undetermined frequency. Testing three specimens obtained under optimal conditions followed by concentration and staining methods will generally detect only 80% of entamoeba complex infections; three additional tests will raise the diagnostic rate to 90%. Trophozoites predominate in liquid stools, cysts in formed stools. A standard procedure is to collect three specimens at 2-day intervals or longer, with one of the three obtained after a laxative such as (1) sodium sulfate or phosphate (Fleet's Phospho-Soda), 30–60 g in a glass of water; or (2) bisacodyl 5–15 mL. Oil laxatives should not be used. Because trophozoites rapidly autolyze, stools should be examined within 30 minutes or immediately mixed with a preservative. If the patient has received specific therapy, antibiotics, antimalarials, antidiarrheal preparations (containing bismuth, kaolin, or magnesium hydroxide), barium, or mineral oil, specimen collection should be delayed.

Bowel examination. Colonoscopy is preferred over sigmoidoscopy. The bowel should not be cleansed by laxative or enema as this washes exudate from the ulcers and destroys trophozoites. Typically, there are no findings in mild intestinal disease; in severe disease, ulcers may be found that are 1 mm to 2 cm across, with intact intervening mucosa. If present, exudate should be collected with a glass pipette (not with cotton, to which trophozoites may adhere) or by scraping with a metal curette and examined immediately for motile trophozoites and for E histolytica antigen. In some centers, rectal biopsy (from the edge of the ulcer) has enhanced diagnosis; biopsy specimens are best examined by immunofluorescence methods.

Serology. Serologic tests for antibody are positive only in the case of E histolytica infection. Testing is usually not recommended in mild to moderate intestinal infection as it lacks sensitivity and does not differentiate present from past infection. The indirect hemagglutination and immunofluorescent tests have been replaced by the ELISA and enzyme immunoassays, which are positive in about 70% of patients with active intestinal disease (the frequency is lower in mild colitis, higher in dysentery) and in about 10% of asymptomatic E histolytica cyst passers; false-positive results are rare. The tests remain positive for months to 10 years after successful treatment, varying by the test used. The agar gel immunodiffusion test, though less sensitive, is rapidly conducted and may detect current infection because it becomes negative 3–6 months after eradication of the organism.

Other tests. Detection of trophozoites that contain ingested red blood cells is nearly diagnostic for invasive E histolytica but may be confused with the occasional E dispar or macrophage that also contains the red blood cells. Many patients with amebic colitis test positive for occult blood, whereas findings for fecal leukocytes are noncontributory. The white blood cell count can reach 20,000/mcL or higher in amebic dysentery but is not elevated in mild colitis. A low-grade eosinophilia is occasionally present.

2. Hepatic abscess

Elevation of the right dome of the diaphragm and the size and location of the abscess


can be determined by ultrasonography (usually round or oval nonhomogeneous lesions, abrupt transition from normal liver to the lesion, hypoechoic center with diffuse echoes throughout the abscess), CT (well-defined, round, low-density lesions with an internal, nonhomogeneous structure), MRI, and radioisotope scanning. After intravenous injection of contrast material, CT may show a hyperdense halo around the periphery of the abscess. Gallium scans, only infrequently useful, show a cold spot (sometimes with a bright rim) as opposed to the increased gallium uptake in the center of pyogenic abscesses. More than one abscess may be present. Serologic tests are almost always positive (except early in the infection). Examination of stools for antigen and the organism is frequently negative. The white count ranges from 15,000 to 25,000/mcL. Eosinophilia is not present. Liver function test abnormalities, when present, are usually minimal. As CT, MRI, and sonography do not distinguish amebic and pyogenic abscesses, percutaneous aspiration may be indicated; this is best done by an image-guided needle (risks described below). The aspirate is divided into serial 30- to 50-mL aliquots, but only the last sample is examined for amebas, as the organisms are found at the edge of the cyst. Detection of amebic antigen in aspirate appears to be very sensitive; studies are under way to evaluate tests for circulating antigen.

Differential Diagnosis

Amebiasis should be considered in patients with acute or chronic diarrhea (including cases associated with only mild changes in bowel habits; in patients who have an exposure history, including travel or household or sexual exposure); liver abscess; and annular lesions of the colon. All patients with presumed inflammatory bowel disease should be tested for antibodies, by multiple stool examinations for antigen and the organism, and by colonoscopy with biopsy because of the risk of overwhelming amebic disease if corticosteroid therapy were to be given in the presence of amebiasis. The differential diagnosis of amebic liver abscess includes pyogenic abscess, echinococcal cyst, benign cyst, and hepatocellular carcinoma.


The decision to treat is based on a composite of data including (1) finding Entamoeba cysts or trophozoites, (2) differentiating E histolytica from E dispar; (3) testing for E histolytica antigen in stool or hepatic abscess aspirate; and (4) testing for serum antibody, which, if positive, could represent old infection. Asymptomatic infections should generally not be treated if differentiation between E histolytica and E dispar has not achieved; whereas, cases with a definitive diagnosis of E histolytica should be treated whether symptomatic or not.

The choice of drug depends on the clinical presentation and the site of drug action. Treatment may require the concurrent or sequential use of several drugs. Table 35-1 outlines a preferred and an alternative method of treatment for each clinical type of amebiasis.

Table 35-1. Treatment of amebiasis.

Clinical Presentation Drug(s) of Choice Alternative Drug(s)
Asymptomatic intestinal infection Diloxanide furoate1,2 Iodoquinol (diiodohydroxyquin)3 or paromomycin4
Mild to moderate intestinal disease (nondysenteric colitis) (1) Tinidazole5 or metronidazole5
(2) Diloxanide furoate,1,2 iodoquinol,3 or paromomycin4
(1) Diloxanide furoate1,2 or iodoquinol3
(2) A tetracycline6
    followed by
(3) Chloroquine7
(1) Paromomycin4
    followed by
(2) Chloroquine7
Severe intestinal disease (dysentery) (1) Tinidazole5 or metronidazole5
(2) Diloxanide furoate1,2 or iodoquinol3
    or, if parenteral therapy is needed initially:
(1) Intravenous metronidazole8 until oral therapy can be started;
(2) Then give oral metronidazole5 plus diloxanide furoate1,2 or iodoquinol3
(1) A tetracycline6
(2) Diloxanide furoate1,2 or iodoquinol3
    followed by
(3) Chloroquine9
    or, if parenteral therapy is needed initially:
(1) Dehydroemetine11 or emetine1,10
    followed by
(2) A tetracycline6 plus diloxanide furoate1,2 or iodoquinol3
    followed by
(3) Chloroquine9
Hepatic abscess (1) Tinidazole5 or metronidazole5,8,
(2) Diloxanide furoate1,2 or iodoquinol3
    followed by
(3) Chloroquine9
(1) Dehydroemetine11 or emetine1,11
    followed by
(2) Chloroquine12
(3) Diloxanide furoate1,2 or iodoquinol3
Ameboma or extra-intestinal disease As for hepatic abscess, but not including chloroquine As for hepatic abscess, but not including chloroquine
1Not available in the United States.
2Diloxanide furoate, 500 mg orally three times daily with meals for 10 days.
3Iodoquinol (diiodohydroxyquin), 650 mg orally three times daily for 21 days. Available in the United States by calling 800-247-9767.
4Paromomycin, 25–35 mg/kg (base) (maximum 3 g) orally in three divided doses after meals daily for 7 days.
5Although tinidazole and metronidazole are equally effective, tinidazole is given in a shorter course and is better tolerated. The tinidazole dosage in asymptomatic and mild intestinal infection is 2 g orally daily for 3 days; in severe intestinal infection and hepatic abscess, the dosage is 2 g once daily for 5 days. The metronidazole dosage is 750 mg orally three times daily for 10 days. The drugs should be taken with food.
6Tetracycline, 250 mg orally four times daily for 10 days; in severe dysentery, give 500 mg four times daily for the first 5 days, then 250 mg four times daily for 5 days. Tetracycline should not be used during pregnancy.
7Chloroquine, 500 mg (salt) orally daily for 7 days.
8An intravenous metronidazole formulation is available; change to oral medication as soon as possible. See manufacturer's recommendation for dosage and cautions.
9Chloroquine, 500 mg (salt) daily for 14 days.
10Dehydroemetine or emetine, 1 mg/kg subcutaneously (preferred) or intramuscularly daily for the least number of days necessary to control severe symptoms (usually 3–5 days) (maximum daily dose for dehydroemetine is 90 mg; for emetine, 65 mg). Both drugs can be severely toxic.
11Use dosage recommended in footnote 10 for 8–10 days.
12Chloroquine, 500 mg (salt) orally twice daily for 2 days and then 500 mg orally daily for 19 days.

The tissue amebicides dehydroemetine and emetine act on organisms in the bowel wall and in other tissues but not on amebas in the bowel lumen. Chloroquine is active principally against amebas in the liver. The luminal amebicides diloxanide furoate (not available in the United States), iodoquinol, and paromomycin act on organisms in the bowel lumen but are ineffective against amebas in the bowel wall or other tissues. Oral tetracycline inhibits the bacterial associates of E histolytica and thus has an indirect effect on amebas in the bowel lumen and bowel wall but not in other tissues; parenteral antibiotics have little efficacy at any site. Tinidazole and metronidazole are unique in that they are effective both in the bowel lumen and in the bowel wall and other tissues, including the central nervous system. Although, the two drugs are equally effective, tinidazole has a shorter course and may be better tolerated but is more expensive than metronidazole. When the drugs are used alone, they often fail to eradicate luminal organisms.

A. Asymptomatic Intestinal Infection

In asymptomatic cyst-passers, if stool antigen and serum antibody tests are negative, it can be presumed that the patient has an E dispar infection, which should not be treated. Nevertheless, an unrecognized commensal E histolytica infection could be present. Documented E histolytica infections should be treated. Cure rates for E histolytica infection with a single course of diloxanide furoate or iodoquinol are 80–85%. Within endemic areas, asymptomatic carriers generally are not treated because of the frequency of reinfection.

B. Mild to Moderate Intestinal Disease

In patients with intestinal symptoms and entamoeba in the stool in whom E dispar and E histolytica cannot be differentiated, if both stool antigen and serum antibody tests are negative it is possible that the latter tests are false negatives and that an E histolytica infection is present. In such cases, it is often best to proceed with anti-E histolytica treatment. Tinidazole or metronidazole plus a luminal amebicide is the treatment of choice. Alternatives are set forth in Table 35-1. The minimum dose of chloroquine needed to destroy trophozoites carried to the liver or to eradicate an undetected early-stage liver abscess is not established.

C. Severe Intestinal Disease

Fluid and electrolyte therapy and opioids to control bowel motility are necessary adjuncts. Opioids are used cautiously because of the risk of toxic megacolon. In fulminant disease, it may be prudent to add broad-spectrum antibiotics to treat intestinal bacteria that enter the peritoneum.

D. Hepatic Abscess

There is no clinical evidence of tinidazole or metronidazole-resistant E histolytica, though it can be induced experimentally. Chloroquine has been included in treatment to



avoid rare long-term failures, although many sources do not include its use. Regarding rare short-term drug failures, if a satisfactory clinical response does not occur in 3–5 days, the abscess should be drained for therapeutic purposes and to exclude pyogenic abscess. Continued failure to achieve an adequate clinical response requires changing to the potentially toxic alternative drug dehydroemetine (or emetine) plus chloroquine. Treatment also requires a luminal amebicide (diloxanide furoate or iodoquinol), whether or not the organism is found in the stool. Antibiotics are added for concomitant bacterial liver abscess, although metronidazole itself is highly effective against anaerobic bacteria, a major cause of bacterial liver abscesses. Imaging defects in the liver disappear slowly (range: 3–13 months) after treatment; some calcify.

Most patients treated with tinidazole or metronidazole for an amebic liver cyst do not require therapeutic percutaneous drainage; when needed, the catheter method is preferred using image guiding. Indications are a large abscess (> 5–10 cm); threatening rupture; the presence of a left lobe abscess (due to the risk of perforation into the peritoneum); and the absence of medical response after 3–5 days of metronidazole therapy. The risks of aspiration or catheter drainage are bacterial superinfection, bleeding, peritoneal spillage, and inadvertent puncture of an infected hydatid cyst. In the absence of a rapid response to treatment, it is prudent to add antibiotics for the infrequent bacterial coinfection.

E. Adverse Drug Reactions

Metronidazole often induces transient nausea, vomiting, epigastric discomfort, headache, or a metallic taste in the mouth; if alcohol is taken during or shortly after treatment, a disulfiram-like reaction may occur. Drug interactions with some commonly used drugs (cimetidine, some anticoagulants, phenytoin, phenobarbital, cholestyramine, fluorouracil, cyclosporine, lithium) have been reported. Metronidazole increases the rate of naturally occurring tumors in mice but not in nonrodent species. Prudence dictates that metronidazole be given to pregnant or nursing mothers only if other drugs cannot be used. Probably, the same precautions for usage and drug interactions apply to tinidazole.

Dehydroemetine and emetine cause nausea, vomiting, and pain at the injection site. They are also cardiotoxic, with a narrow range between therapeutic and toxic effects; dehydroemetine may be the safer of the two drugs. The tetracyclines should not be used in pregnancy; erythromycin stearate and paromomycin are alternatives. Paromomycin may cause mild gastrointestinal symptoms, infrequently intense diarrhea, and rarely overgrowth of nonsusceptible organisms. Paromomycin should be used with caution in ulcerated bowel conditions and is not used in the presence of significant renal disease. Iodoquinol produces a mild, transient diarrhea. It should be taken with meals; used with caution in patients with optic neuropathy, renal, or thyroid disease; and discontinued in the event of iodine toxicity (dermatitis, fever). The neurotoxicity seen with extended treatment does not occur at the standard 3-week dosage. Diloxanide usage commonly results in flatulence.

Follow-Up Care

In follow-up, examine at least three stools at 2- to 3-day intervals, starting 2–4 weeks after the end of treatment. For some patients, colonoscopy and reexamination of stools within 3 months may be indicated.

Postdysenteric colitis is an uncommon sequela of severe amebic colitis. Following adequate treatment, diarrhea continues and the mucosa may be reddened and edematous, but no ulcers or organisms are found. Most such cases are self-limited, with permanent remission in weeks to months. Uncommonly, severe and unremitting diarrhea may represent ulcerative colitis triggered by the amebic infection.

Prevention & Control

Prevention requires safe water supplies, sanitary disposal of human feces, adequate cooking of foods, protection of foods from fly contamination, washing hands after defecation and before preparing or eating foods and, in endemic areas, avoidance of foods that cannot be cooked or peeled. Water supplies can be boiled (briefly) or treated with iodine (0.5 mL tincture of iodine per liter for 20 minutes, or longer if the water is cold); cysts are resistant to standard concentrations of chlorine. Filters are also available to purify drinking water. Disinfection dips for fruits and vegetables are not advised, and no drug is safe or effective in prophylaxis.


The mortality rate from untreated amebic dysentery, hepatic abscess, or ameboma may be high. With chemotherapy instituted early in the course of the disease, the prognosis is good.

Haque R et al: Amebiasis. N Engl J Med 2003;348:1565.

Lebbad M et al: PCR differentiation of Entamoeba histolytica and Entamoeba dispar from patients with amoeba infection initially diagnosed by microscopy. Scand J Infect Dis 2005;37:680.

Moran P et al: Infection by human immunodeficiency virus-1 is not a risk factor for amebiasis. Am J Trop Med Hyg 2005;73:296.

Stanley SL Jr: Amoebiasis. Lancet 2003;361:1025.

Tinidazole (Tindamax)—a new anti-protozoal drug. Med Lett Drugs Ther 2004;46:70.

Infections with Pathogenic Free-Living Amebas

Essentials of Diagnosis

  • Meningoencephalitis.

  • Granulomatous encephalitis and other granulomatous lesions.

  • Keratitis.


The free-living amebas that cause disease in humans are mainly of these genera: Acanthamoeba, Naegleria, and Balamuthia. The organisms are widely distributed in soil and fresh and brackish water. Acanthamoeba and Naegleria species have been found to harbor Legionella, Vibrio cholerae, and other endosymbiotic bacteria and may serve as a reservoir for these organisms.

1. Primary Amebic Meningoencephalitis

Primary amebic meningoencephalitis is a fulminating, hemorrhagic, necrotizing meningoencephalitis that occurs in healthy children and young adults and is rapidly fatal. It is caused by free-living amebas, most commonly by Naegleria fowleri. Other causes are Balamuthia mandrillaris and the Acanthamoeba species (see below).

N fowleri is a thermophilic organism found in fresh and polluted warm lake water, domestic water supplies, swimming pools, thermal water, and sewers. Most patients give a history of exposure to fresh water; dust is also a possible source. The organism apparently invades along the olfactory nerve to enter the central nervous system. Nasal and throat swabs have shown a carrier state, and serologic surveys suggest that inapparent infections occur.

Clinical Findings

A. Symptoms and Signs

The incubation period varies from 2 to 15 days. Early symptoms include headache, fever, and lethargy, often associated with rhinitis and pharyngitis. Vomiting, disorientation, and other signs of meningoencephalitis develop within 1 or 2 days, followed by coma and then death within 7–10 days. No distinctive clinical features distinguish the infection from acute bacterial meningoencephalitis. At autopsy, some victims have a nonspecific myocarditis.

B. Laboratory Tests

Lumbar or ventricular cerebrospinal fluid contains several hundred to 25,000 leukocytes/mcL (50–100% neutrophils) and erythrocytes (up to several thousand per microliter). Protein is usually somewhat elevated, and glucose is normal or moderately reduced. If conventional examinations for bacteria and fungi are negative, the fluid is examined for free-living amebas. Phase contrast is preferred. A wet mount examined by an ordinary optical microscope with the aperture restricted or condenser down will enhance contrast and refractility; a warm stage is not needed. The fluid should not be centrifuged at speeds over 150 × g (5 minutes) or refrigerated, as this tends to immobilize the amebas (7–14 mcm). Their brisk motility and lack of a large granular nucleus distinguishes them from leukocytes of various types, which they closely resemble. Staining, culture, and mouse inoculation should be performed. Serologic testing is only useful epidemiologically; patients die before antibodies are detectable.

Precise species identification is based on morphology, demonstration of flagellate transformation (Naegleria only), and various immunologic methods.


Seven well-documented survivors of N fowleri infection have been reported based on treatment with intravenous and intrathecal amphotericin B, intravenous miconazole, and oral rifampin.

B mandrillaris meningoencephalitis occurs in both immunocompetent and immunocompromised persons and runs a subacute course that can last months to 2 years. Multiple hypodense lesions are seen with imaging studies. Diagnosis is based on brain biopsy; culture is not effective. Several cases have been successfully treated with combination therapy using flucytosine, pentamidine, fluconazole, sulfadiazine, and azithromycin.

2. Acanthamoeba Infections

Granulomatous Lesions

Free-living amebas of the genus Acanthamoeba are ubiquitous, being found in soil and in fresh, brackish, thermal water, and chlorinated swimming pools as trophozoites (15–35 mcm) or cysts (10–15 mcm). Several species, including Acanthamoeba culbertsoni, cause a number of poorly defined syndromes, especially in debilitated or immunosuppressed patients, including those with AIDS: (1) subacute and chronic multifocal granulomatous necrotizing encephalitis leading to death in weeks to months, (2) skin lesions (ulcers or hard nodules in which ameba may be detected), (3) granulomatous dissemination to many tissues, and (4) keratitis. Portals of entry may include the skin, eyes, or respiratory tract. A commensal nasal carrier state occurs. Eighty percent of immunocompetent persons have antibodies against Acanthamoeba antigens.

The encephalitis presents with mental status abnormalities, meningismus, and neurologic features of a space-occupying lesion. Focal consolidation on chest films and cerebrospinal fluid lymphocytosis may be present. Antemortem diagnosis has been made by culture, brain biopsy, or cerebrospinal fluid wet mounts and by using specific fluorescent stains. PCR and DNA analysis are also used where available. No treatment has been effective, but ketoconazole, miconazole, itraconazole, sulfonamides, clotrimazole, pentamidine, paromomycin, propamidine, neomycin, amphotericin B, alkylphosphocholine, cotrimoxazole, or flucytosine can be tried.


Hundreds of cases of acanthamoeba keratitis and some of uveitis have been documented; most were associated with


wearing contact lenses, others with penetrating corneal trauma or exposure to contaminated water. Suggestive features include (1) a waxing and waning clinical course over several months with severe ocular pain, photophobia, tearing, blurred vision, and conjunctival injection; (2) partial or 360-degree paracentral stromal ring infiltrate on ophthalmologic examination; (3) recurrent corneal epithelial breakdown; and (4) a corneal lesion refractory to the usual medications. Typically, the keratitis progresses slowly over months and can lead to blindness. The diagnosis can be confirmed by vigorously scraping the cornea with a swab or platinum-tipped spatula. The material is microscopically examined (1) as a wet preparation for cysts and motile trophozoites, (2) after staining, (3) by immunofluorescent techniques, and (4) after being cultured using various media. Isolates can be identified by isoenzyme analysis and DNA profiles. Because of variable drug sensitivities, each isolate should be tested for its drug susceptibility. Serologic tests have not been shown to be useful. Many cases of acanthamoeba keratitis are misdiagnosed as viral keratitis.

With early treatment, many patients can expect cure and a good visual result. Topical propamidine isethionate (0.1%) with either chlorhexidine digluconate (0.02%), polyhexamethylene biguanide, or neomycin-polymyxin B-gramicidin has been used successfully. Topical miconazole has also been used. Oral itraconazole or ketoconazole can be added for deep keratitis. Drug resistance has been reported. Use of corticosteroid therapy is controversial. In spite of medical treatment, penetrating keratoplasty is often necessary to excise diseased tissue; corneal grafting can be done after the amebic infection has been eradicated.

Prevention requires immersion of contact lenses in disinfectant solutions or by heat sterilization. The lens should not be cleaned in homemade saline solutions nor worn while swimming.

Bloch KC et al: Inability to make a premortem diagnosis of Acanthoamoeba species infection in a patient with fatal granulomatous amebic encephalitis. J Clin Microbiol 2005;43:3003.

Driebe WT Jr: Present status of contact lens-induced corneal infections. Ophthalmol Clin North Am 2003;16:485.

Marciano-Cabral F et al: Acanthamoeba spp. as agents of disease in humans. Clin Microbiol Rev 2003;16:273.

Paltiel M et al: Disseminated cutaneous acanthamebiasis: a case report and review of the literature. Cutis 2004;73:241.

Vargas-Zepeda J et al: Successful treatment of Naegleria fowleri meningoencephalitis by using intravenous amphotericin B, fluconazole and rifampicin. Arch Med Res 2005;36:83.


Essentials of Diagnosis

  • History of tick bite or exposure to ticks.

  • Fever, other flu-like symptoms, anemia.

  • Small intraerythrocytic protozoa on Giemsa-stained blood smears.

  • Positive serologic tests.

General Considerations

Babesiae are tick-borne protozoal parasites of wild and domestic animals worldwide. Babesiosis in humans is an uncommon intraerythrocytic infection caused mainly by two Babesia species. In Europe, infection is caused by Babesia divergens, and more than 30 cases have been reported. In the United States, infection is caused by Babesia microti, and hundreds of cases have been reported from coastal and island areas of northeastern and mid-Atlantic states as well as from Wisconsin, Minnesota, Missouri, Washington, and California. Antibody prevalence of 3–8% in serosurveys indicates a high level of subclinical infection. New Babesia species or strains (WA1 and others) have been described in humans in California, Washington, Georgia, and Kentucky. Gene sequencing of these isolates suggests that three are similar to B divergens. Serosurveys and limited confirmation of isolates suggest infection with B microti or other species in Taiwan, China, Japan, Egypt, South Africa, Mexico, Switzerland, and South America.

Natural hosts for B microti are various wild and domestic animals, particularly the white-footed mouse and white-tailed deer. With extension of the deer's habitat, the range of human infection is increasing as well. Humans are infected as a result of Ixodes scapularis (also called Ixodes dammini) tick bites (mainly nymphal) but also by blood transfusion and perinatally. Severe infections are most common in the elderly and immunosuppressed and in persons lacking a spleen. Coinfections with Lyme disease and ehrlichiosis occur because of cotransmission from the same tick. Without passing through an exoerythrocytic stage, B microti enters the red blood cell and multiplies, resulting in cell rupture followed by infection of other red blood cells.

Clinical Findings

A. Symptoms and Signs

The incubation period is 1 week to several months; parasitemia is evident in 2–4 weeks. Patients usually do not recall the tick bite. The flu-like illness is characterized by irregular fever, chills, headache, diaphoresis, cough, arthralgia, myalgia, and fatigue but is without malaria-like periodicity of symptoms. Other findings may include nausea, vomiting, jaundice, arthralgia, emotional lability, and splenomegaly. Although parasitemia may continue for months to years, with or without symptoms, the disease is usually self-limited; after several weeks to months (rarely to 18 months),


most patients recover without sequelae. Severe complications, including acute respiratory, cardiac, and renal failure, are most likely to occur in older or splenectomized persons; mortality can reach 5–9% among those hospitalized.

All B divergens infections (in Europe, transmitted by Ixodes ricinus) have been in splenectomized patients. These infections progress rapidly with high fever, severe hemolytic anemia, jaundice, hemoglobinuria, and renal failure; death rates are over 40%.

B. Laboratory Findings

Diagnosis is established by identification of the intraerythrocytic parasite (2–3 mcm) on Giemsa-stained thick and thin blood smears; no gametocytes and no intracellular pigment are seen. A single red cell may contain different stages of the parasite, and parasitemia can exceed 10%. Repeated smears are often necessary because less than 1% of erythrocytes may be infected, especially early in infection. The organism must be differentiated from malarial parasites, particularly Plasmodium falciparum. As low-level Babesia parasitemia is easily missed, isolation can be attempted by intraperitoneal inoculation of blood into hamsters or gerbils. Antibody in humans is detectable within 2–4 weeks after onset of symptoms and persists for 6–12 months. Testing with specific antigens in the immunofluorescent test is relatively species-specific, with a titer of 1:1024 or greater considered diagnostic; antibody titers against Plasmodium are generally low or absent. An ELISA also has high sensitivity and specificity. The PCR method, where available, is more sensitive for low parasitemias but is of equal specificity. Immunoblot testing for IgM and IgG antibody is investigational; a positive IgM must be confirmed by a follow-up positive IgG. Other findings include hemolytic anemia, thrombocytopenia, low-grade leukocytosis or leukopenia, and abnormal liver and renal function tests. Imaging studies may detect morphologic changes in the spleen.


No drug treatment is fully satisfactory. Although B microti infections in patients with intact spleens are usually self-limiting and can be treated asymptomatically, it is now recommended that all patients—even those mildly ill—should be treated with a 7- to 10-day course of oral atovaquone (750 mg every 12 hours) plus azithromycin (600 mg orally once daily). The alternative treatment is a 7-day course of quinine (650 mg three times daily) plus clindamycin (600 mg orally three times daily orally or 1200 mg twice daily intravenously). Following treatment of chronically infected persons, parasitemia can continue for several months. Exchange transfusion plus the antibiotics has been successful in several severely ill asplenic patients and in patients with parasitemia greater than 10%. Management of B divergens infection can be attempted with exchange transfusion and clindamycin-quinine plus atovaquone therapy or trimethoprim-sulfamethoxazole (TMP-SMZ) plus pentamidine.

Della-Giustina D et al: Transfusion-acquired babesiosis in a nonendemic area. Mil Med 2005;170:295.

Froberg MK et al: Babesiosis and HIV. Lancet 2004;363:704.

Herwaldt BL et al: Babesia divergens-like infection, Washington State. Emerg Infect Dis 2004;10:622.

Kogut SJ et al: Babesia microti, upstate New York. Emerg Infect Dis 2005;11:476.


Balantidium coli is a large ciliated intestinal protozoan found worldwide, but particularly in the tropics. Pigs are considered the reservoir host, but the agent has been found in other animals and in insects. The disease is rare in humans, occurring as an acute or chronic infection resulting from ingestion of cysts passed in stools of humans or swine. Outbreaks have been reported. In the new host, the cyst wall dissolves and the trophozoite may invade the mucosa and submucosa of the terminal ileum, appendix, and large bowel, causing abscesses and irregularly rounded ulcerations. Many infections are asymptomatic and need not be treated. Chronic recurrent diarrhea, alternating with constipation, is most common, but mild to moderate diarrhea to severe dysentery with bloody mucoid stools, tenesmus, and colic may occur. Rare instances of infection in the lung, liver, and vagina have been reported in immunocompromised, including AIDS, patients.

Diagnosis is established by finding trophozoites in liquid stools, cysts in formed stools, or the trophozoite in scrapings or biopsy of ulcers of the large bowel. Specimens must be examined rapidly or placed in preservative.

The treatment of choice is tetracycline hydrochloride, 500 mg orally four times daily for 10 days. The alternative drug is iodoquinol (diiodohydroxyquin), 650 mg orally three times daily for 21 days. Occasional success has also been reported with metronidazole (750 mg orally three times daily for 5 days) or paromomycin (25–30 mg/kg [base] orally in three divided doses for 5–10 days).

In properly treated mild to moderate symptomatic cases, the prognosis is good, but in spite of treatment, fatalities have occurred in severe infections as a result of intestinal perforation or hemorrhage.

Ferry T et al: Severe peritonitis due to Balantidium coli acquired In France. Eur J Clin Microbiol Infect Dis 2004;23:393.

Vasilakopoulou A et al: Balantidium coli pneumonia in an immunocompromised patient. Scand J Infect Dis 2003;35: 144.

Coccidiosis (Cryptosporidiosis, Isosporiasis, Cyclosporiasis) & Microsporidiosis

Coccidiosis and microsporidiosis are intracellular infections of intestinal epithelial cells by spore-forming protozoa. The causes of coccidiosis are Cryptosporidium spp,


particularly Cryptosporidium parvum and Cryptosporidium hominis; Isospora belli; Cyclospora cayetanensis; and Sarcocystis bovihominis and Sarcocystis suihominis. Various species are the etiologic agents of microsporidiosis (see below). Many of these infections occur worldwide, particularly in the tropics and in regions where hygiene is poor. They are causes of traveler's diarrhea; endemic childhood gastroenteritis (particularly in malnourished children in developing countries); institutional and community outbreaks of diarrhea; and acute and chronic diarrhea in immunosuppressed patients, including those with AIDS, in whom infection can be life-threatening. Clustering occurs in households, day care centers, and among sexual partners. Diarrhea in non-AIDS patients—sporadic, epidemic, and traveler's—is more likely to be due to cryptosporidia and less often to cyclospora or microsporidia. Diarrhea in AIDS is more commonly due to the microsporidia, Enterocytozoon bieneusi, and Encephalitozoon (formerly Septata) intestinalis, but Cryptosporidium, Isospora, and Cyclospora are also important causes.

The infectious agents are oocysts (spores) transmitted directly from person to person or by contaminated drinking or swimming water or food. Ingested oocysts release sporozoites that invade and multiply in enterocytes, primarily in the small bowel. Liberated merozoites reinvade other cells in the process of asexual intracellular multiplication. Eventually, sexual stages are released; following fertilization, immature oocysts form which are then shed in feces. The oocysts mature on exposure to air and can remain viable in a moist environment for months to years. All but the Sarcocystis species complete their life cycle in a single host.

The Isospora and Cyclospora species found in humans appear to be distinct to humans only. Cryptosporidiosis is a zoonosis in which infections in farm animals (cattle, goats, turkeys, and others) can be transmitted to humans; however, most human infections are acquired from humans. Cyclospora and probably Isospora require time outside the host to sporulate and become infectious. The oocysts of cryptosporidiosis, however, are infectious on excretion, thus permitting immediate human fecal-oral transmission.

Although the small bowel is the usual location of infection, other sites can be involved. Colon infection is common in cryptosporidiosis and has been reported with microsporidiosis. In AIDS patients, biliary tract infections may occur in cryptosporidiosis, cyclosporiasis, microsporidiosis, and isosporiasis and may result in either a sclerosing, cholangitis-like syndrome or an acalculous cholecystitis. Disseminated disease and corneal infections occur with several microsporidial species.

The pathogenesis of these diarrheas is not well understood. No enterotoxin has been identified. Voluminous secretory or malabsorption diarrhea (including vitamin B12, D-xylose, and fat absorption dysfunction) can result. Although histologic examination of the small bowel can be normal, with intense infection there may be dense inflammatory infiltration accompanied by blunting to atrophy of the villi and crypt hyperplasia. The infections are nonulcerative and noninvasive except for E intestinalis, which can be invasive.

Clinical Findings

A. Symptoms and Signs

Generally, the forms of diarrhea caused by the coccidial and microsporidial organisms are clinically indistinguishable from each other. In immunocompetent persons, infection varies from no symptoms, to a mild diarrhea with flatulence and bloating, to severe and frequent watery diarrhea in which the onset may be explosive. Mucus may be present in stools but no microscopic or gross blood. Other findings may include low-grade fever, malaise, anorexia, abdominal cramps, vomiting, dehydration, and myalgia. These symptoms are generally self-limited, lasting a few days to several weeks (sometimes longer for isosporiasis). Weight loss can be marked. Parasitologic clearance, however, may take several months.

In immunologically deficient patients, the diarrhea can be profuse (up to 15 L daily has been reported), with cholera-like watery movements, accompanied by severe malabsorption, electrolyte imbalance, and marked weight loss; fever is uncommon. Mucus is seen in the stools, but blood and leukocytes are seldom present. The diarrhea may recur or persist, and passage of organisms continues for months to indefinitely.

B. Laboratory Findings

In diagnosis, three stool specimens should be obtained fresh and in preservative over 5–7 days and processed by a variety of flotation or concentration methods to detect the distinctive oocysts (differences are based on size and intracellular location). A modified acid-fast stain is used for cryptosporidia, cyclospora, and isospora; in microsporidiosis, a modified trichrome or Weber stain is used. Clinicians should realize when ordering ova and parasite examinations that laboratories—unless specifically requested to do so—do not normally include the specialized tests needed to detect coccidia and microsporidia. The organisms can sometimes also be detected by duodenal aspiration or biopsy. For diagnosis of biliary disease, ultrasonography is used initially followed by endoscopic retrograde cholangiopancreatography when necessary.

Specific Diseases

A. Cryptosporidiosis

The organism is found worldwide. Its fecal-oral mode of transmission is human-to-human (sometimes from asymptomatic persons) and animal-to-human from many vertebrate species, including chickens, birds, rodents, dogs, cats, sheep, and cattle. C hominus naturally infects humans; C parvum infects cattle (important reservoir) and humans. The organism is highly infectious (relatively few parasites can induce infection), is readily transmitted in day care settings and households, and can be transmitted by contaminated food and water.


The organism is the leading cause of recreational water-associated outbreaks of gastroenteritis. The incubation period appears to be 1–12 days. In immunocompetent persons, the illness is usually self-limited and lasts fewer than 30 days. Oocysts passed in stools are fully sporulated and infectious; therefore, hospitalized patients should be isolated and stool precautions strictly observed. The prevalence of asymptomatic human carriers in the United States is estimated to be about 1.5%. Outbreaks are of particular concern, as exemplified by the 1993 epidemic in Milwaukee in which 400,000 persons became ill. Since chlorine disinfection of water is not effective, adequate filtration is required. However, because of the oocysts' small size (2–5 mcm), filtration is difficult and unreliable (the < 1 mcm filters used frequently become obstructed).

Cryptosporidiosis develops in 10–20% of AIDS patients some time during their illness. Cryptosporidiosis may involve any part of the gastrointestinal tract, including the biliary tract (sclerosing cholangitis has been described); respiratory tract infection, hepatitis, pancreatitis, lymphadenopathy, and hepatosplenomegaly may occur, as well as multisystem involvement.

Diagnosis is by detecting the organism by the modified acid-fast and other staining methods; a minimum of two concentrated specimens should be tested. Using stool specimens, commercially available antigen detection kits improve on the diagnosis: direct fluorescent antibody methods have sensitivities and specificities of 99–100%; enzyme immunoassays have sensitivities and specificities of 93–100%. Immunochromatographic lateral-flow assays have also become available. Some of the kits can be used with both fresh and frozen specimens; others, however, can only be used if the specimen is fresh. Where available, the PCR test offers an alternative mode of diagnosis. Tests for serum antibody are useful epidemiologically but not for patient diagnosis.

Stools rarely show white or red blood cells. Blood leukocytosis and eosinophilia are uncommon. Radiologic changes have been reported in the stomach, intestines, and bile ducts in severe disease. Oocysts can be visualized in stained biopsy sections of intestinal mucosa. In AIDS patients with unexplained diarrhea, the organism should also be looked for in sputum and bronchoalveolar lavage fluid; specimens obtained from lung tissue have sometimes been positive.

B. Isosporiasis

I belli oocysts in feces are 20–30 × 10–20 mcm. Opinion differs about whether the oocyst can be transmitted directly from person to person by anal-oral sexual contact or if it must pass into the environment and mature to its infectious stage. Outbreaks have occurred in day care centers and mental institutions. The incubation period is 7–11 days. The watery diarrhea can last for weeks to months, but is usually self-limited in immunocompetent persons; in immunocompromised patients, the severity of diarrhea can resemble that in cryptosporidiosis. A hemorrhagic ulcerative colitis has been described.

Diagnosis by stool examination is often difficult, for the organisms may be scanty even in the presence of significant symptoms. Because of their buoyancy, oocysts must be looked for just beneath the coverslip using direct smears or concentrated specimens. Confirmation is by acid-fast staining. Frequently, diagnosis can be made only after duodenal aspiration or duodenal biopsy of multiple specimens. Serologic tests are available. Eosinophilia and eosinophils in stools are sometimes present.

C. Cyclosporiasis

C cayetanensis oocysts (8–10 mcm) must undergo a period of sporulation in the environment before they become infectious. Although humans appear to be the only species that are carriers of C cayetanensis, this is an unsettled question. Transmission is by fecally contaminated food and water, generally in tropical and subtropical areas; large outbreaks have occurred. In the United States, outbreaks have been attributed to imported fresh fruit and leafy vegetables. Children, HIV-AIDS patients, and travelers are the more commonly recognized hosts. Diarrhea begins after an incubation period of 2–11 days. The illness can be self-limited or persist with weight loss. Rarely, the organisms invade the biliary tree, and Reiter's syndrome has been attributed to the infection. Oocysts can be identified in concentrated stool specimens by examination of wet mounts under phase microscopy, by use of modified acid-fast stains (oocysts are variably acid-fast), by the modified safranin stain, or by autofluorescence with ultraviolet light microscopy. Antibodies have been detected, and titers increase during convalescence.

D. Microsporidiosis

Microsporidia are obligate intracellular protozoans (0.5–2 mcm × 1–4 mcm) that are pathogens of arthropods, fish, and vertebrates. Many human infections are of zoonotic origin from domestic and wild animals, but human-to-human transmission has been documented. Infection is mainly by ingestion of the spores but also by inhalation or finger contamination of the eyes. At least 14 species are known to infect humans; disease is seen mainly in immunocompromised persons, particularly those with AIDS. In chronic AIDS diarrhea, the two most common intestinal parasites are Enterocytozoon bieneusi and Encephalitozoon intestinalis. These parasites can also cause biliary infection (cholangitis, cholecystitis). In immunocompetent persons, the diarrhea due to these parasites (including traveler's diarrhea) is self-limited. E intestinalis, other Encephalitozoon species, Enterocytozoon cuniculi, Enterocytozoon hellem, Brachiola connori, and Vittaforma corneae can disseminate to many tissues, including the sinuses, lungs, liver, urinary tract, and brain. In E cuniculi infection, MRI has shown contrast-enhancing brain lesions. Most of the above parasites and others


have been found as a nonpathogenic carrier state or as a cause of keratoconjunctivitis. Pleistophora species and Trachipleistophora hominis cause a myositis associated with high elevations of creatine phosphokinase, lactate dehydrogenase, and myoglobin. Thus, microsporidia should be considered in infections in immunocompromised persons in whom no other infectious agent can be found.

Microsporidia are detected in feces, body fluids (including duodenal fluid), and tissue biopsies (intestinal epithelium, cornea, conjunctiva, bronchi, and others) by light microscopy using various staining methods, particularly trichrome and Weber's chromotrope-based stains, followed by confirmatory fluorescence staining. In conducting stool examinations, after concentration, slide preparations should be very thin, stained for 90 minutes, and examined at × 1000 (or higher) magnification. In specialized laboratories, culture, molecular assays, and electron microscopic confirmation of histologic findings may be available. Although specific antibodies have been detected for some species, serologic diagnosis is controversial and of limited use. PCR is a research method.


Most acute infections in immunocompetent persons are self-limited and do not require treatment. Supportive treatment for severe or chronic diarrhea includes fluid and electrolyte replacement and, in chronic cases, parenteral nutrition.

In isosporiasis, effective treatment in immunosuppressed persons has been described using (1) trimethoprim (160 mg) and sulfamethoxazole (800 mg) four times orally daily for 10 days and then twice daily for 3 weeks; or (2) sulfadiazine, 4 g orally, and pyrimethamine, 35–75 mg orally, in four divided doses daily, plus leucovorin calcium, 10–25 mg orally daily, for 3–7 weeks. In immunocompromised patients, it may be necessary to continue a maintenance dose indefinitely with TMP-SMZ three times weekly or Fansidar once weekly. Efficacy in primary infection has also been reported for furazolidone (400 mg/d orally for 10 days), roxithromycin, ciprofloxacin, nitrofurantoin, metronidazole, quinacrine, pyrimethamine, albendazole with ornidazole, and diclazuril.

In the treatment of cyclosporiasis, TMP (160 mg)-SMZ (800 mg) orally twice daily for 7 days is effective; in HIV infections, higher doses (four times daily for 10 days) and long-term maintenance (three times weekly) are needed. For patients intolerant of TMP-SMZ, ciprofloxacin (500 mg orally twice daily for 7 days) can be tried. In microsporidiosis, the Encephalitozoon species often respond to albendazole (400 mg two times daily for 3 weeks up to 3 months). In E bieneusi infection and in the various causes of disseminated disease, albendazole, octreotide, fumagillin (60 mg/d orally for 14 days), atovaquone, azithromycin, metronidazole, and nitazoxanide can be tried. For ocular lesions, some infections respond to oral albendazole plus fumagillin eyedrops.

No treatment has been successful for sarcocystosis or cryptosporidiosis. However, for cryptosporidiosis, nitazoxamide is approved in the United States for use in children; evaluation in adults (500 mg orally twice daily for 3 days) continues. In this disease, vigorous treatment of underlying AIDS may relieve the parasitic diarrhea; other drugs that have been tried are roxithromycin (300 mg orally twice daily for 4 weeks), spiramycin (1 g orally three times daily for 2 weeks or longer), paromomycin (25–35 mg/kg/d orally in three or four divided doses; duration uncertain), zidovudine (AZT), azithromycin (600 mg daily), octreotide, eflornithine, letrazuril, hyperimmune bovine colostrum, and lactobacillus.


Measures to reduce exposure to these organisms are recommended for immunocompromised patients. These include reduced exposure to swimming in fresh water and boiling of drinking water (1 minute) or use of a filter that removes particles over 1 mcm in size.

Didier ES: Microsporidiosis: an emerging and opportunistic infection in humans and animals. Acta Trop 2005;94:61.

Johnston SP et al: Evaluation of three commercial assays for detection of Giardia and Cryptosporidium organisms in fecal specimens. J Clin Microb 2003;41:623.

Palmieri F et al: Pulmonary cryptosporidiosis in an AIDS patient: successful treatment with paromomycin plus azithromycin. Int J STD AIDS 2005;16:515.

Sasaki M et al: A case of malabsorption syndrome caused by isosporiasis in an immunocompetent patient. J Gastroenterol 2004;39:88.

Smith HV et al: New drugs and treatment for cryptosporidiosis. Curr Opin Infect Dis 2004;17:557.

Wichro E et al: Microsporidiosis in travel-associated chronic diarrhea in immune-competent patients. Am J Trop Med Hyg 2005;73:285.

Zardi EM et al: Treatment of cryptosporidiosis in immunocompromised hosts. Chemotherapy 2005;51:193.


Essentials of Diagnosis

  • Most infections are asymptomatic.

  • In some cases, acute or chronic diarrhea, mild to severe, with bulky, greasy, frothy, malodorous stools, free of blood and pus.

  • Upper abdominal discomfort, cramps, distention, excessive flatus, and lassitude.

  • Cysts and occasionally trophozoites in stools.

  • Trophozoites in duodenal fluid.


General Considerations

Giardiasis is a protozoal infection of the upper small intestine caused by the flagellate Giardia lamblia (also called G intestinalis and G duodenalis). The parasite occurs worldwide, most abundantly in areas with poor sanitation. In the United States and Europe, the infection is the most common intestinal protozoal pathogen; the US estimate is of 100,000 to 2.5 million new infections yearly and 5000 hospital admissions. Occurrence is particularly high among children.

The organism occurs in feces as a symmetric, heart-shaped flagellated trophozoite measuring 10–25 × 6–12 mcm and as a cyst measuring 11–14 × 7–10 mcm. Only the cyst form is infectious by the oral route; trophozoites are destroyed by gastric acidity. Humans are a reservoir for the infection; animals, including dogs, cats, beavers, and other mammals, have been implicated but not confirmed as reservoirs or zoonotic sources of infection. Under suitable moist, cool conditions, cysts can survive in the environment for weeks to months. The infectious dose is low, requiring as few as ten cysts.

Cysts are transmitted as a result of fecal contamination of water or food, by person-to-person contact, or by anal-oral sexual contact. Multiple cases are common in households, children's day care centers (often the nidus for spread of organisms to the community), and mental institutions. Outbreaks occur as a result of contamination of water supplies. Giardiasis is a well-recognized problem in special groups including travelers to Giardia-endemic areas, persons who swallow contaminated recreational water, male homosexuals, and persons with impaired immune states.

After the cysts are ingested, trophozoites emerge in the duodenum and jejunum. Infrequently, they cause epithelial damage, atrophy of villi, hypertrophic crypts, and extensive cellular infiltration of the lamina propria; mucosal invasion is rare; hematogenous dissemination does not occur. Hypogammaglobulinemia, low secretory IgA levels in the gut, achlorhydria, and malnutrition favor the development of infection. Gastric giardiasis may represent reflux from the duodenum or localized infection.

Clinical Findings

A. Symptoms and Signs

A large proportion of infected persons (especially children) remain asymptomatic cyst carriers, and their infection clears spontaneously. Giardia should be considered in most cases of diarrhea, especially where it is prolonged and associated with marked weight loss. Syndromes include (1) acute diarrhea, (2) chronic diarrhea, and (3) malabsorption. The incubation period is usually 1–3 weeks but may be longer. The illness may begin gradually or suddenly. The acute phase may last days or weeks, but it is usually self-limited, although cyst excretion may be prolonged. In a few patients, the disorder may become chronic and last for years. The disease can become life-threatening in infants, the aged, and immunosuppressed persons; in AIDS, it may be more frequent and severe than previously thought.

In both the acute and chronic forms, diarrhea ranges from mild to severe; most often it is mild. There may be no complaints other than of one bulky, loose bowel movement a day, often after breakfast. With larger numbers of movements, the stools become increasingly watery but are usually free of blood and pus; they are copious, frothy, malodorous, and greasy. The diarrhea may be daily or recurrent; if recurrent, stools may be normal to mushy during intervening days, or the patient may be constipated. Weight loss is frequent; weakness may occur. Infants and young children may show impaired growth and cognitive development. Less common are anorexia, nausea and vomiting, midepigastric discomfort and cramps (often after meals), belching, flatulence, borborygmi, and abdominal distention. In atypical presentations, gastrointestinal symptoms can appear without diarrhea.

Malabsorption occasionally develops in the acute or chronic stage. Findings may include fat- and protein-losing enteropathy and vitamin A, vitamin B12, and disaccharidase deficiencies and marked weight loss. Certain extraintestinal manifestations (arthritis, anterior uveitis, urticaria) have been attributed to giardiasis infections, but a pathophysiologic relationship has not been established.

B. Laboratory Tests

Using stool specimens, diagnosis is (1) by standard microscopy to detect cysts and trophozoites or (2) by immunoassay by two methods: one is to detect coproantigen by an enzyme immunoassay (sensitivity 94–97%, specificity 100%), and the other to detect cysts by the direct fluorescent antibody assay (sensitivity and specificity, 96–100%). Although the coproantigen immunoassay is as sensitive and specific as microscopy and easier to perform, three stool specimens should be examined for ova and parasites if other organisms are being sought in addition to Giardia. Some immunoassays require fresh or frozen stool and cannot be used with preserved specimens; additionally, some assays detect only cysts or only trophozoites. With cure, the immunoassay normally reverts to negative, but excretion of antigen continues for several days after intact organisms are no longer excreted. Sometimes warranted is a search for trophozoites in the duodenum by (1) the duodenal string test (Entero-Test), (2) duodenal aspiration, (3) endoscopic brush cytology, or (4) duodenal biopsy (a mucosal imprint for staining should be made before sectioning). Tests for serum antibody are not recommended because of lack of sensitivity and specificity.

Detection of the parasite in feces can be difficult because the number of organisms passed varies considerably from day to day. At the onset of infection, patients may have symptoms for about a week before organisms can be detected; in chronic diarrhea, stool


examinations can be persistently negative. Three stool specimens collected at intervals of 2 days or longer should be examined by concentration methods. One specimen will detect 50–75% of cases and three specimens about 90%. Unless the specimens can be submitted within an hour, they should be preserved immediately in a fixative. Purges do not increase the likelihood of finding the organism. Use of barium, antibiotics, antacids, kaolin products, or oily laxatives may temporarily (about 10 days) reduce the number of parasites or interfere with detection.

There is no eosinophilia, and the white blood cell count is normal. Radiologic examination of the small bowel is usually normal.


Although controversial, treatment of asymptomatic patients should be considered since they can transmit the infection to others and may occasionally become symptomatic themselves. In selected cases, it may be best to wait a few weeks before starting treatment, as some infections will clear spontaneously. In the presence of a presumptive diagnosis but negative stool specimens and negative coproantigen tests, an empiric course of treatment is sometimes indicated. All persons in a household with an index case should be tested for infection; this also applies to children exposed in day care.

Treatment of adults is effective (> 90%) with tinidazole and metronidazole. A single dose of tinidazole, though more expensive, is the drug of choice because it provides the shorter course and is better tolerated. Re-treatment with an alternative drug is sometimes needed, for which albendazole or paromomycin can be used. Furazolidone and nitazoxanide are available to treat children. In follow-up, two or more stools are analyzed weekly starting 2 weeks after therapy.

All of these drugs occasionally have unpleasant side effects. The potential for carcinogenicity of furazolidone, metronidazole, and tinidazole appears to be negligible based on over 2 decades of use. Because of its limited availability and rare potential for severe toxicity, quinacrine is no longer recommended.

A. Tinidazole

An oral dose of 2 g given once has had reported cure rates of 90–100%. Adverse reactions consist of a metallic taste and mild gastrointestinal side effects in about 10% of patients; headache and vertigo are less common. The drug should not be taken with alcohol because of the potential for an antabuse-like reaction.

B. Metronidazole

The dose is 250 mg orally three times daily for 5–7 days. Metronidazole may cause gastrointestinal symptoms, headache, dizziness, a metallic taste, and candidal overgrowth, in addition to an antabuse-like reaction in alcohol users. In the United States, metronidazole for giardiasis treatment is only available for off-label use.

C. Furazolidone

The dose is 100 mg (in a palatable suspension) four times daily for 7–10 days. Gastrointestinal symptoms, fever, headache, rash, and a disulfiram-like reaction with alcohol occur. Furazolidone can cause mild hemolysis in glucose-6-phosphate dehydrogenase-deficient persons.

D. Others

Albendazole (400 mg orally daily for 5 or more days) has shown cure rates that range from 10% to 95%. Reports with paromomycin (25–35 mg/kg/d orally in three divided doses for 7 days) have been mixed; because the drug is not absorbed, it has been proposed for use in pregnancy. Nitazoxanide, approved in the United States for children under 11 years of age (500 mg twice daily for 3 days), continues under study for adult treatment. Mild side effects include abdominal pain, vomiting, diarrhea, and headache.


There is no effective chemoprophylaxis for giardiasis. Since community chlorination (0.4 mg/L) of water is relatively ineffective for inactivating cysts, filtration is required. For hikers, bringing water to a boil for 1 minute is adequate; filtration with a pore size less than 1 mcm can also be used. Relying on iodine halogenation is no longer recommended by the Centers for Disease Control and Prevention. In day care centers, appropriate disposal of diapers and frequent hand washing are essential.


With treatment and successful eradication of the infection, there are no sequelae. Without treatment, severe malabsorption may rarely contribute to death from other causes.

Ali SA et al: Giardia intestinalis. Curr Opin Infect Dis 2003;16: 453.

Bailey JM et al: Nitazoxanide treatment for giardiasis and cryptosporidiosis in children. Ann Pharmacother 2004;38:634.

Karabay O et al: Albendazole versus metronidazole treatment of adult giardiasis: An open randomized clinical study. World J Gastroenterol 2004;10:1215.

Lebwohl B et al: Giardiasis. Gastrointest Endosc 2003;57:906.


Essentials of Diagnosis

  • Exposure in an endemic area.

  • Amastigotes demonstrable in macrophages in aspirate or biopsy smears.

  • Promastigotes in cultures of aspirates or biopsy.

  • Positive serologic tests, PCR, and skin test.

Visceral leishmaniasis

  • Irregular fever, progressive hepatosplenomegaly, pancytopenia.

  • Elevated total proteins with great increase in IgG.

Old World cutaneous leishmaniasis

  • Chronic, painless, moist ulcers or dry nodules.

  • Frequently self-healing.

New World cutaneous leishmaniasis

  • Circular open ulcers; sometimes vegetative, verrucous, or nodular lesions.

Mucocutaneous leishmaniasis (espundia)

  • Initial cutaneous ulcer.

  • Followed in months to years by destructive nasopharyngeal lesions.

Diffuse cutaneous leishmaniasis

  • Chronic, painless, fleshy nonulcerating nodules, spreading locally and metastatically.

  • Skin test is negative.


Leishmaniasis is infection by species of the genus Leishmania. The disease is a zoonosis transmitted by bites of female sand flies (2 mm) (phlebotomus [Old World leishmaniasis] and lutzomyia [New World leishmaniasis] species) from wild animal reservoirs (eg, rodents, Canidae, sloths, marsupials) and from domestic dogs (they can die of Leishmania infantum infections) to humans; however, kala azar is transmitted directly from humans to humans. Leishmaniae have two distinct forms in their life cycle: (1) In mammalian hosts, the parasite is found in its amastigote form (Leishman-Donovan bodies, 2–5 mcm) within mononuclear phagocytes. When sand flies feed on an infected host, the parasitized cells are ingested with the blood meal. (2) In the sand fly vector, the parasite converts to, multiplies, and is then transmitted during feeding as a flagellated extracellular promastigote (10–15 mcm).

In tropical and temperate zones, an estimated 12 million persons are infected with leishmaniasis; 1.5–2 million new cases occur yearly, of which more than 1 million are cutaneous and 500,000 are visceral disease. Approximately 50% are in children. An estimated 60,000 deaths occur each year. The incidence of disease is increasing in many endemic areas. Severity of infection ranges from subclinical or minimally pathologic (self-curing or easily treated cutaneous lesions) to persistent, disfiguring cutaneous and mucocutaneous lesions to potentially fatal visceral disease. Imported infections into the United States each year include about 40 cutaneous infections and several cases of visceral leishmaniasis. Several hundred cutaneous and a few visceral leishmaniasis infections have been found in US military personnel after exposure in Afghanistan and Iraq.

Four clinical syndromes occur, with overlap between them, and each syndrome is caused by more than one species. The speciation of leishmaniasis is complex (about 20 species are known to infect humans) and unsettled, and some species can cause more than one syndrome.

Visceral leishmaniasis (kala azar) is caused mainly by the Leishmania donovani complex: (1) L donovani (northeastern India, Bangladesh, Nepal, Southwest Asia, Sudan, Ethiopia, Kenya, Uganda scattered foci in sub-Saharan Africa, and northern and eastern China); (2) L infantum (Mediterranean littoral, Middle East, China, central and southwestern Asia, Ethiopia, Sudan, Afghanistan, Pakistan); and (3) Leishmania chagasi (South America, Central America, Mexico). More than 500,000 cases occur yearly. The number of cases is increasing, particularly in Sudan, Bangladesh, Brazil, northeastern India, and Nepal. In each locale, the disease has its own peculiar clinical and epidemiologic features and outbreaks have occurred. Three other species—Leishmania tropica in the Middle East, the Mediterranean littoral, Kenya, India, and western Asia, and Leishmania mexicana and Leishmania amazonensis in the New World—cause visceral leishmaniasis in a few patients, generally in a milder form. Although humans are the major reservoir, animal reservoirs such as the dog, other canids, and rodents are important. In the United States and Canada, foxhounds and other breeds of dogs and wild canids have been found to be serologically positive; L infantum has been isolated. There have been no findings in humans. The incubation period is usually 4–6 months (range: 10 days to 24 months). Without treatment, the fatality rate reaches 90%. Early diagnosis and treatment reduces mortality to 2–5%. Relapses (up to 10% in India and 30% in Kenya) are most likely to occur within 6 months after completion of treatment.

Old World cutaneous leishmaniasis is caused mainly by L tropica, Leishmania major, and Leishmania aethiopica. L tropica is the agent responsible for an urban infection of dogs and humans. It is found in the Middle East, northwestern India, East Africa, central Asian area of the former Soviet Union, Afghanistan, Pakistan, Turkey, Armenia, Greece, and southern France and Italy. L major infection causes lesions in dry or desert rural areas and is primarily a disease of desert rodents. Human disease occurs in the Middle East, central Asian area of the former Soviet Union, Arabian peninsula, Afghanistan, and Africa (North, East, and sub-Saharan Africa from Senegal to Sudan and Kenya). L aethiopica infection occurs in the Ethiopian and Kenyan highlands. Ulceration is rare; spontaneous healing is slow over several years. An uncommon complication is diffuse cutaneous leishmaniasis, an anergic form with nodular lesions and high parasite count. Treatment has sometimes been successful with sodium stibogluconate plus recombinant interferon gamma.


L donovani sometimes causes cutaneous disease with visceral manifestations.

In Afghanistan, Iraq, and Kuwait, the common agents are L tropica and L major, but L infantum has also been isolated in Iraq. From 2002 to 2004, more than 600 cases of cutaneous leishmaniasis were confirmed in military personnel and 176 isolations of L major were made. In the United States, for advice on treating such cases call 202–782-1663/8691.

New World cutaneous leishmaniasis is caused by L mexicana and L amazonensis. The L mexicana complex consists of L mexicana (Texas, Oklahoma, Arizona, Mexico, Central America—about 20 locally acquired human infections have been reported), L amazonensis (Amazonian basin, Venezuela, Panama, Trinidad), L chagasi (Central and South America), and other species (Venezuela and Dominican Republic). The Leishmania (viannia) group consists of L (V) braziliensis (Central and South America), L (V) panamensis (Central America and northeastern South America), and Leishmania guyanensis (South America). L mexicana and L braziliensis infections generally result from forest-related activities or from residence in dwellings situated near forests. L panamensis is also found in drier habitats. In parts of South America, several Leishmania species are now transmitted in domestic environments.

Mucocutaneous leishmaniasis (espundia) occurs in lowland forest areas and is caused by the Leishmania (viannia) group of organisms, usually by L (V) braziliensis (Central and South America; most cases are in Brazil, Bolivia, and Peru) and rarely by L (V) panamensis (Central and northeastern South America) or L (V) peruviana (Peru).

Diffuse cutaneous leishmaniasis, caused by the L mexicana complex in the New World and L aethiopica in the Old World, is a state of deficient cell-mediated immunity in which widespread leprosy-like skin lesions are generally progressive and refractory to treatment. The skin test is negative but amastigotes are abundant.

Leishmaniasis results in lifelong latent infection. If immunoparesis supervenes, leishmaniae can become opportunistic pathogens through reactivation or new infection; the latter may occur from sharing needles or syringes. Coinfections with HIV-visceral leishmaniasis (usually due to L infantum or L donovani) have been reported in many countries (eg, eastern Africa, India, Brazil), but the problem is worse in southwestern Europe (France, Italy, Spain, Portugal), where coinfections will develop in 2–9% of people with AIDS. Coinfections are being increasingly reported with other Leishmania species elsewhere in the world. In such cases, diagnostic criteria and clinical manifestations may be altered (Leishmania antibodies become undetectable and, in visceral disease, hepatosplenomegaly and fever may not occur). In leishmaniasis treatment, drug side effects may be greater, there may be a low rate of clinical and parasitologic response, and parasitic relapse may be more frequent. Antiviral treatment may prevent exacerbation of latent Leishmania infections and may also reduce findings in active leishmaniasis.

Clinical Findings

A. Symptoms and Signs

1. Visceral leishmaniasis (kala azar)

A local nonulcerating nodule at the site of the bite may precede systemic manifestations but usually is inapparent. The onset may be acute (as early as 2 weeks after infection) or insidious. Fever often peaks twice daily, with chills and sweats, weakness, weight loss, cough, and diarrhea. The spleen progressively becomes huge, hard, and nontender. The liver is somewhat enlarged, and generalized lymphadenopathy is common. Hyperpigmentation of skin, especially on the hands, feet, abdomen, and forehead, is marked in light-skinned patients. In blacks, there may be warty eruptions or skin ulcers. Petechiae, bleeding from the nose and gums, jaundice, edema, and ascites may occur. Wasting is progressive; death, often due to intercurrent infection, occurs within months to 1–2 years. In some regions, oral and nasopharyngeal or cutaneous manifestations occur with or without visceral involvement. Post-kala azar dermal leishmaniasis may appear after apparent cure in the Indian subcontinent and Sudan. It may simulate leprosy, as multiple hypopigmented macules or nodules develop on preexisting lesions. Erythematous patches may appear on the face. Leishmaniae are present in the skin. Although serologic tests are of limited value, the PCR test usually detects the parasite. Antimony treatment should be tried but is often ineffective.

In HIV-infected persons—with or without AIDS—visceral leishmaniasis can be an opportunistic infection (see above).

2. Cutaneous leishmaniasis

Cutaneous swellings appear 2 weeks to several months after sand fly bites and can be single or multiple. Depending on the leishmanial species and host immune response, lesions begin as small papules and develop into nonulcerated dry plaques or large encrusted ulcers with well-demarcated raised and indurated margins. Satellite lesions may be present. The lesions are painless unless secondarily infected. Local lymph nodes may be enlarged. Systemic symptoms are rare, but a low-grade fever of short duration may be present at the onset. For most species, healing usually occurs spontaneously in months to 1–3 years, starting with central granulation tissue that spreads peripherally. Pyogenic complications may be followed by lymphangitis or erysipelas. Contraction of scars can cause deformities and disfigurement, especially if lesions are on the face.

a. Old World cutaneous leishmaniasis

The incubation period is 2 months or longer, and healing is complete in 1–2 years. The lesions of L tropica infection tend to be single and dry, to ulcerate slowly or not at all, and to persist for a year or longer. L major lesions are characterized by multiple, wet, rapidly ulcerating sores with crusting. Spontaneous healing is generally complete


in 6–12 months. Leishmaniasis recidivans is a relapsing form of L tropica infection in which the primary lesion nearly heals, lateral spread with central healing follows, and scarring can be extensive; it is associated with hypersensitivity and a strongly positive skin test but scarce amastigotes. Visceral involvement by L tropica has been reported rarely (including after troop exposure in Operation Desert Storm) and is relatively resistant to antimony treatment.

b. New World cutaneous leishmaniasis

Most New World cutaneous lesions are ulcers, but vegetative, verrucous, or nodular lesions may occur also. L mexicana (“chiclero's ulcer”) in the Yucatan and Central America produces destructive lesions on the ear cartilage. Up to 80% of L braziliensis cutaneous lesions progress to espundia (see below); some L braziliensis complex strains also show a chain of palpable local lymph nodes, and some L mexicana and South American strains can cause diffuse cutaneous leishmaniasis.

c. Mucocutaneous leishmaniasis (espundia)

The initial lesion, single or multiple, is on exposed skin; at first, it is papular (can be pruriginous or painful), then nodular, and later may ulcerate or become wart-like or papillomatous. Local healing follows, with scarring within several months to a year. Subsequent naso-oral involvement occurs in a small proportion of patients either by direct extension or, more often, metastatically to the mucosa. It may appear concurrently with the initial lesion, shortly after healing, or after many years. The mucosa of the anterior part of the nasal septum is generally the first area to be involved. Extensive destruction of the soft tissues and cartilage of the nose, oral cavity, and lips may follow and may extend to the larynx and pharynx. Secondary bacterial infection is common. Regional lymphangitis, lymphadenitis, fever, weight loss, keratitis, and anemia may be present.

B. Laboratory Findings

Definitive diagnosis is by finding (1) the intracellular nonflagellated amastigote in Giemsa-stained biopsies from skin, mucosal lesions, liver, or lymph nodes; or from aspirates from spleen (the most sensitive site, but also a risky procedure), bone marrow, or lymph nodes; or (2) the flagellated promastigote state in culture of these tissues (requires up to 21 days). Occasionally, the organisms are seen in mononuclear cells of Giemsa-stained smears of the buffy coat. Golden hamster or Balb/c mouse inoculation of the nose, footpad, or tail base may also be used (2–12 weeks). PCR testing has up to 100% specificity and sensitivity and can be performed on any type of biologic specimen. Where available, species identification is by molecular, isoenzyme, and monoclonal antibody methods. Serologic tests (ELISA, indirect fluorescent antibody, direct agglutination, immunoblotting, dipstick, others) and the leishmanin (Montenegro) skin test (not licensed in the United States) may facilitate diagnosis, but none are sufficiently sensitive or specific to be used alone or for speciation purposes or to distinguish current from past infection. Cross-reactions occur with Chagas' disease. No satisfactory antigen detection system is available.

Specimens from skin lesions should be obtained through intact skin (cleansed with 70% alcohol) at a raised edge of an ulcer margin. Local anesthesia can be used. To obtain tissue fluid for staining, press blood out of the site with two fingers, incise a 3-mm slit, and then scrape with the blade. When doing a biopsy, an impression smear is made, a portion is macerated for culture, and the remainder is reserved for pathologic sections. For needle aspiration, sterile preservative-free saline is inserted with a 23- to 27-gauge needle; the aspirate is then cytospun at 800 g for 5 minutes.

The diagnosis of visceral leishmaniasis can sometimes be made by demonstrating the organism in buffy coat preparations of blood, preferably obtained at night. More commonly, definitive diagnosis depends on Giemsa-stained smears, touch preparations, culture, or animal inoculation of aspirates of sternal marrow or iliac crest, liver, enlarged lymph nodes, or spleen. Although splenic aspiration is the most sensitive test, because of its hazard (intra-abdominal bleeding and death), it should be reserved for last and should be performed only by experienced persons; contraindications are a soft spleen in the acute phase, a prolonged prothrombin time, severe anemia, and platelet counts under 40,000/mcL. In immunocompetent persons, serologic tests are sensitive (> 90%) but false-positives may occur, especially in malaria and typhoid fever. The direct agglutination IgM test and the ELISA become positive early; the immunofluorescent IgG test becomes positive in most persons at a titer of 1:256 or higher. After treatment, the tests remain positive for months, though in immunocompromised persons, titers may be low or undetectable. The leishmanin skin test is always negative during active disease and becomes positive months to years after recovery. The PCR test has excellent sensitivity and specificity. Other characteristic findings are progressive leukopenia (seldom over 3000/mcL after the first 1–2 months), with lymphocytosis and monocytosis, normochromic anemia, thrombocytopenia, and eosinopenia. There is a marked increase in total protein up to or greater than 10 g/dL owing to an elevated IgG fraction; serum albumin is 3 g/dL or less. Liver function tests show hepatocellular damage. Proteinuria may be present.

Definitive diagnosis of diffuse cutaneous leishmaniasis is made by identification of the organisms (see above). Microscopic examination of skin scrapings has limited sensitivity, particularly in chronic infections. Where available after culture, species identification should be done by molecular methods. The skin test becomes positive within 3 months and remains positive for life; false-positives occur. Serologic tests are unreliable. Antibody may be undetectable or may appear only at low levels after 4–6 weeks; cross-reactions occur, including with leprosy.

Although they are difficult to find in mucocutaneous leishmaniasis (espundia), diagnosis is by detecting amastigotes in scrapings, biopsy impressions or histologic sections, or aspirated tissue fluid. The organism


grows with difficulty in culture or after inoculation of hamsters; if positive, speciation should be attempted. The leishmanin skin test is useful if it produces a fully developed papule in 2–3 days that disappears after a week. Standard serologic tests are often not useful; a direct agglutination for IgM antibodies may become positive in 4–6 weeks and subsequently an IgG test, but at low titer. PCR test is promising.

Differential Diagnosis

The differential diagnosis of visceral leishmaniasis includes leukemia, lymphoma, tuberculosis, histoplasmosis, infectious mononucleosis, brucellosis, malaria, typhoid, schistosomiasis, African trypanosomiasis, tropical splenomegaly syndrome, and cirrhosis. The differential diagnosis of cutaneous leishmaniasis includes tuberculosis, leprosy, fungal infections, yaws, syphilis, neoplasms, and sarcoidosis. Main considerations in the differential of mucocutaneous leishmaniasis diagnosis are paracoccidioidomycosis and other fungal infections, rhinoscleroma, polymorphic reticulosis, Wegener's granulomatosis, lymphoma, and nasopharyngeal carcinoma, yaws, syphilis, leprosy, and sarcoidosis.


Treatment is less than adequate because of drug toxicity, long courses required, and frequent need for hospitalization. The drug of choice is a pentavalent antimonial, either sodium stibogluconate or meglumine antimoniate; resistance and treatment failures are increasing in frequency. Second-line drugs used in cases unresponsive to the antimonials—but potentially more toxic—are the deoxycholate formulation of amphotericin B and pentamidine. Three lipid-formulated amphotericins permit a shorter course of treatment with less toxicity and high effectiveness. AmBisome, recently approved for use in the United States, is considered by some workers to be the drug of choice for the treatment of visceral leishmaniasis but is very expensive. Miltefosine, an oral drug, has recently been approved in India for the treatment of visceral leishmaniasis.

A. Sodium Stibogluconate

Sodium stibogluconate is provided as a solution that contains 100 mg of antimony (Sb) per milliliter; only fresh solutions should be used. A generic formulation of sodium stibogluconate—at one-fourteenth the cost—has been shown to be equivalent in efficacy and safety to Pentostam. Treatment is started with a 200-mg Sb test dose followed by 20 mg Sb/kg/d; although dosages greater than 20 mg/kg should not be given, there is no upper limit to the total daily dose. The drug can be administered as a 5% solution intramuscularly (may be locally painful), but intravenous administration is preferred (cough may occur) when the volume is high, as is the case for most adults. Meglumine antimoniate (85 mg Sb/mL) is equal in efficacy and toxicity when used in equivalent Sb doses (20 mg Sb/kg/d). The appropriate volume of drug is mixed with 50 mL of 5% dextrose in water and infused over at least a 10-minute interval. The selected drug is given on consecutive days: 28 days for visceral and mucocutaneous leishmaniasis and 20 days for cutaneous leishmaniasis. In certain regions of the world (especially with visceral leishmaniasis), because of resistance, longer courses are indicated.

Although few side effects occur initially, they are more likely to appear with cumulative doses. Most common are gastrointestinal symptoms, fatigue, fever, myalgia, arthralgia, phlebitis, and rash; hemolytic anemia, hepatitis, renal and heart damage, and pancreatitis are rare. The side effects are reversible. Patients should be monitored weekly for the first 3 weeks and twice weekly thereafter by serum chemistries, complete blood counts, and electrocardiography.

Therapy is discontinued if the following occur: aminotransferases three to four times normal levels or significant arrhythmias, corrected QT intervals greater than 0.50 s, or concave ST segments. Relapses should be treated at the same dosage level for at least twice the previous duration. In the United States, the only drug available is stibogluconate, obtainable from the Parasitic Drug Service, Centers for Disease Control and Prevention, Atlanta, GA 30333 (404–639-3670).

B. Amphotericin B

For the treatment of visceral leishmaniasis, the parenteral dosage of AmBisome (a liposomal formulation now approved for use in the United States) is 3 mg/kg/d on days 1–5, 14, and 21 and may be repeated; the dosage for immunocompromised persons is 4 mg/kg/d on days 1–5, 10, 17, 24, 31, and 38. A report indicated that comparable effectiveness could be achieved with lower doses over a shorter period; cumulative doses of 3.75 or 7.5 mg/kg were given in five divided doses over 5 days. Single-dose treatment is under evaluation. Infusion-related side effects include gastrointestinal symptoms, fever, chills, dyspnea, hypotension, and hepatic and renal toxicity. The dosage for the liposomal formulations for cutaneous and mucosal leishmaniasis has not been established. Conventional amphotericin B deoxycholate, as given in India, is slow infusion (4–6 hours) of 1 mg/kg daily for 20 days; this dosage achieved 99% cure rates but with side effects as above; an alternative dosage is 0.5–1 mg/kg/d or every second day intravenously for up to 8 weeks.

C. Pentamidine Isethionate

Pentamidine isethionate, 2–4 mg/kg intramuscularly (preferable) or intravenously, is given daily or on alternate days (fifteen doses for visceral and four doses for cutaneous leishmaniasis). For some forms of visceral leishmaniasis, it may be necessary to repeat treatment using up to twice the dose, but resistance may persist.

D. Paromomycin (Aminosidine)

When this drug was applied topically in various formulations in cutaneous leishmaniasis, it had variable success that differed by region. One ointment preparation


is paromomycin 15% and methylbenzethonium chloride 12% in soft paraffin, applied twice daily for 15 days; skin reactions may occur. The ointment cannot be used in regions of mucocutaneous leishmaniasis as it does not prevent metastatic disease. In parenteral treatment of refractory visceral leishmaniasis, paromomycin is showing promise but has the potential for causing renal or otic toxicity.

E. Miltefosine

Miltefosine, an alkyl phospholipid, is the first oral drug for the treatment of leishmaniasis. Approved for use in India for visceral leishmaniasis at a daily dose of 2.5 mg/kg in two divided doses for 3–4 weeks, it has resulted in 95% cure rates. Side effects included vomiting (40%), diarrhea (20%), and occasional transient and reversible elevations of aminotransferases, blood urea nitrogen (BUN), and creatinine. Owing to its teratogenic potential, the drug cannot be used in pregnancy. Preliminary reports have also shown efficacy in cutaneous leishmaniasis in Columbia but not in Guatemala. The drug is not available in the United States.

1. Visceral leishmaniasis

The drugs of choice (see above for doses) are liposomal amphotericin B and sodium stibogluconate. The liposomal formulation (AmBisome, available in the United States) replaces amphotericin B because of its reduced side effects but at a much higher cost. Whereas Mediterranean kala azar may respond to 10–15 doses of stibogluconate (one per day), the disease in Kenya, Sudan, and India requires at least 30 days of treatment. With incomplete response or relapse, the treatment should be repeated for 60 days. Drug resistance is now so high in parts of Bihar state, India, that cure rates are only 10–35%. In India, reported cure rates were 95% for liposomal amphotericin B (total dosage 15 mg/kg) and 89% for paromomycin (16 mg/kg/d for 21 days). Miltefosine, an oral treatment (approved for use in India; not available in the United States) has shown cure rates to 95% (see above for dosage, side effects, and contraindications). A fifth alternative drug is pentamidine; its efficacy has so declined in India that the drug is seldom used there.

2. Old World leishmaniasis

Especially in the Middle East, this type of leishmaniasis is generally self-healing in about 6 months and does not metastasize to the mucosa. Thus, it may be justified to withhold treatment if the lesions are small, in an unobtrusive place, and appear to be healing. Intralesional antimony is sometimes used in therapy. Parenteral sodium stibogluconate (20–28 days) should be used to treat patients with large or multiple lesions or if the lesions are on cosmetically or functionally important areas (eg, the wrist). Complete healing may not be evident until weeks after the first or second course of treatment. Amphotericin B desoxycholate and pentamidine are used for failures. Pentamidine is often effective against L aethiopica lesions and ketoconazole (400–600 mg/d for 4–6 weeks) against L major and L (V) panamensis. Miltefosine (2.5 mg/kg/d for 4 weeks), fluconazole (200 mg/kg/d for 6 weeks), and ketoconazole (600 mg/kg/d for 4 weeks) continue under evaluation. Other treatments for less severe disease are physical measures (local cryotherapy or heat therapy, electrocoagulation, surgical removal). Paromomycin ointment may also be effective against L tropica.

3. New World leishmaniasis

In New World cutaneous L mexicana infections from Mexico and Central America, solitary nodules or ulcers in inconspicuous sites generally will heal spontaneously. Variable success has been had with paromomycin ointment (see above), ketoconazole, heat application, or metronidazole (750 mg three times daily for 10 days). Preliminary trials with oral miltefosine (150 mg/d for 3–4 weeks) had reported cure rates of 94%. Other drugs continue under evaluation. Lesions on the ear, face, or hands should be treated with sodium stibogluconate. Cutaneous lesions acquired in regions of mucocutaneous leishmaniasis may be due to L braziliensis, L guyanesis, or L panamensis and should be treated with a full course of sodium stibogluconate. Cure rates for L braziliensis and L guyanesis have been as low as 60% and 30%, respectively.

4. Mucocutaneous leishmaniasis (espundia)

This group of parasites should be treated because of their potential for developing into mucocutaneous disease. However, failure rates are high, even when a full course (28 days) of sodium stibogluconate treatment is used (see above). If repeated and extended antimony treatment fails, amphotericin B desoxycholate or pentamidine is used. Under evaluation are the liposomal formulations of amphotericin B and combined antimony and gamma interferon treatment. Corticosteroids may be needed to control local inflammation due to release of antigens. Antibiotics are usually needed to treat associated bacterial or fungal infections.

5. Diffuse cutaneous leishmaniasis

In spite of repeated doses of antimony, pentamidine, or amphotericin, cures are rare.

Prevention & Control

Infection occurs when humans encroach on sand fly habitats—warm, humid, dark microclimates, including rodent burrows, rock piles, or tree holes; these are often in sylvatic areas near forests or semiarid ecosystems. Peridomestic sandflies are found on debris close to buildings. Biting is generally at twilight or at night but may occur in shaded areas during the day. Personal protection may fail but is partially accomplished by clothing (pants, long sleeves) that covers exposed skin, permethrin applied to clothing, DEET repellent (see under Malaria), avoidance of endemic areas (especially at night), use of mosquito coils, and use of fine-mesh sand fly netting and screens for sleeping (may be too warm in tropical areas). Although sand flies can traverse the mesh of standard mosquito nets, permethrin-impregnated nets may prevent this. Often useful in control are destruction of animal reservoir hosts, mass treatment of humans in kala azar-prevalent areas, residual insecticide spraying in domestic and peridomestic areas, keeping dogs and other domesticated


animals out of the house, particularly at night, and use of permethrin-impregnated collars for dogs.

Davis AJ et al: Recent advances in antileishmanial drug development. Curr Opin Investig Drugs 2005;6:163.

Magill AJ: Cutaneous leishmaniasis in the returning traveler. Infect Dis Clin North Am 2005;19:241.

Markle WH et al: Cutaneous leishmaniasis: recognition and treatment. Am Fam Physician 2004;69:1455.

Murray HW: Treatment of visceral leishmaniasis in 2004. Am J Trop Med Hyg 2004;71:787.

Shazad B et al: Comparison of topical paromomycin sulfate (twice/day) with intralesional meglumine antimoniate for the treatment of cutaneous leishmaniasis caused by L. major. Eur J Dermatol 2005;15:85.

Sinha PK et al: Diagnosis & management of leishmania/HIV co-infection. Indian J Med Res 2005;121:407.

Weina PJ et al: Old world leishmaniasis: an emerging infection among deployed US military and civilian workers. Clin Infect Dis 2004;39:1674.


Essentials of Diagnosis

  • History of exposure in a malaria-endemic area.

  • Periodic attacks (every 2–3 days) of sequential chills, fever, and sweating.

  • Malaise, headache, myalgia, nausea, vomiting, splenomegaly; anemia, leukopenia.

  • Characteristic parasites in erythrocytes, identified in thick or thin blood films.

  • Complications of falciparum malaria: Cerebral findings (mental disturbances, neurologic signs, convulsions, coma), prostration, hemolytic anemia, hyperpyrexia, hypotension, bleeding, secretory diarrhea or dysentery, hypoglycemia, metabolic acidosis, noncardiogenic pulmonary edema, hepatic or renal failure.

General Considerations

Four species of the genus Plasmodium are responsible for human malaria: P vivax, P malariae, P ovale, and P falciparum. Although the disease has been eradicated from most temperate zone countries, it continues to be endemic in many parts of the tropics and subtropics, and imported cases occur in the United States and other countries free of transmission. Malaria is present in parts of Mexico, Haiti, Dominican Republic, Central and South America, Africa, the Middle East, the Indian subcontinent, Southeast Asia, China, and Oceania. P vivax and P falciparum are responsible for most infections and are found throughout the malarious regions. P falciparum is the predominant species in Africa and the only one in Haiti and the Dominican Republic. P malariae is also widely distributed but is less common. P vivax is uncommon in much of Africa (except North Africa); in West Africa, it is replaced mainly by P ovale, which otherwise is rare. P vivax infection is uncommon among blacks because their red blood cells do not have the Duffy factor surface antigen. Annually worldwide, there are an estimated 500 million clinical cases of malaria that result in 1–3 million deaths; these deaths mainly occur among young children who live in sub-Saharan Africa. An estimated 30,000 travelers from the developed world are infected yearly with malaria, and several hundred die. Each year the United States experiences more than 1000 imported infections (44% due to P falciparum) and few cases of locally acquired, mosquito-transmitted cases from an imported case. An average of six deaths occur each year, almost all due to falciparum malaria. About 60% of the imported cases were acquired in tropical Africa; most of these cases were in persons who had failed to take malaria prophylaxis or had taken an inappropriate drug for the region of exposure.

Malaria is transmitted from human to human by the bite of infected female anopheles mosquitoes. Resistance of the vector to insecticides continues to increase. Congenital transmission and acquisition by blood transfusion also occurs. There are no animal reservoirs for human malaria.

The mosquito becomes infected by ingesting human blood containing the sexual forms of the parasite (microgametocytes and macrogametocytes). In the mosquito salivary glands, the gametocytes develop into sporozoites. When the mosquito next feeds on humans, inoculated sporozoites go to the liver (exoerythrocytic stage) where they transform within hepatic cells (hepatic schizogomy) into merozoites. The erythrocytic stage follows when merozoites released into the blood stream infect red blood cells. Subsequent parasitic transformation in the red blood cells (blood schizogomy) results in the following parasitic forms: the asexual forms (immature [trophozoites] and mature [merozoites]) and the two sexual gametocytes; lysis and release of these forms initiate the primary attack. The merozoites immediately invade new red cells to repeat the cycle many times over weeks. However, for P vivax and P ovale infections only, some sporozoites become a dormant form, the hypnozoite, upon invading hepatic cells. Reactivation of the hypnozoites can occur up to 6–8 months later initiating either a delayed primary infection or a relapse; the latter is due to failure of early treatment to adequately eradicate the hypnozoites. A different form of recurrent malaria is recrudescence, which can occur for all four malarial parasites; it is due to failure of early treatment to eliminate all infected red blood cells.

In P falciparum and P malariae malaria, the liver infection ceases spontaneously in less than 4 weeks; thereafter, multiplication is confined to the red cells. Thus, 4 weeks after departure from an endemic area, treatment that eliminates these species from the red cells will cure the infection. Cure of P vivax and P ovale malaria, however, requires treatment to eradicate infection from both red cells and liver hypnozoites.


The incubation period after exposure or after stopping chemoprophylaxis is, for P falciparum, approximately 12 days (range: 9–60 days); for P vivax and P ovale, 14 days (range: 8–27 days [initial attacks for some temperate strains may not occur for up to 8 months]); and for P malariae, 30 days (range: 16–60 days). Untreated infections can continue: P falciparum persists for up to 1.5 years but usually ends in 6–8 months; P vivax and P ovale infections persist for as long as 5 years; and P malariae infections have lasted for as long as 50 years. Protective immunity results from infection but decays after several years if reinfection does not occur.

Clinical Findings

A. Symptoms and Signs

Typical malarial attacks show sequentially, over 4–6 hours, shaking chills (the cold stage); fever (the hot stage) to 41°C or higher; and marked diaphoresis (the sweating stage). Associated symptoms may include malaise, headache, dizziness, gastrointestinal symptoms (anorexia, nausea, slight diarrhea, vomiting, abdominal cramps), myalgia, arthralgia, backache, and dry cough.

Either from the onset or with progression of the disease, the attacks may show an every-other-day (tertian) periodicity in vivax, ovale, or falciparum malaria or an every-third-day (quartan) periodicity in malariae malaria. Splenomegaly usually appears when acute symptoms have continued for 4 or more days; the liver is frequently mildly enlarged. The presence of a rash or lymphadenopathy suggests an additional or other diagnosis. The patient may be tired between attacks but otherwise feels well. After this primary attack, recurrences are common, each separated by a latent period.

Because of its frequent and severe complications, P falciparum is the more serious infection and causes the most deaths, rarely within 24 hours. Severe disease results in part from intense sequestration and cytoadherence of parasitized red cells in capillaries and postcapillary venules. The severely ill patient may present with hyperpyrexia, prostration, impaired consciousness, agitation, hyperventilation, and bleeding. Other complications include (1) hypotension or shock; (2) cerebral malaria (headache, mental disturbances, neurologic signs, retinal hemorrhages, convulsions, delirium, coma); (3) hemolytic anemia; (4) noncardiogenic pulmonary edema or acute respiratory distress syndrome; (5) acute tubular necrosis and renal failure—rarely, this is associated with blackwater fever (dark urine), which most commonly is due to severe hemolysis following quinine treatment; (6) acute hepatopathy, with centrilobular necrosis and jaundice; (7) hypoglycemia; (8) cardiac dysrhythmias; (9) gastrointestinal syndromes (including secretory diarrhea and dysentery); (10) lactic acidosis; (11) water and other electrolyte imbalance; and (12) disseminated intravascular coagulation. The prognosis is poor if more than 20% of infected red cells contain mature parasites, if more than 5% of neutrophils contain pigment, or if parasitemia is > 500,000/mcL. Gram-negative bacteremia may contribute to death.

Immunologic disorders resulting from chronic infection are tropical splenomegaly and nephrotic syndrome (the latter due to P malariae only). Malaria infections do not appear to act as an opportunistic infection in AIDS patients, with the possible exception of malaria infection in pregnancy.

B. Laboratory Findings

Thick and thin peripheral blood films, Giemsa-stained, are the mainstay of diagnosis but require a high level of expertise to read; clinical diagnosis is only 20–60% reliable compared with microscopy. Blood from finger sticks or from the earlobe are preferred sources but should be free-flowing and uncontaminated by alcohol; if venipuncture blood is used, it should be examined shortly after it is drawn to avoid changes in morphology. Specimens should be obtained at about 8-hour intervals for 3 days, including during and between febrile periods. Patients need to stop their malarial prophylaxis during the diagnostic period because inadequate prophylaxis may have suppressed detectable parasitemia. The level of parasitemia should be quantified.

Because antibody becomes detectable only 8–10 days after onset of symptoms, serologic tests are not useful in diagnosis of acute attacks. The tests may be useful, however, after repeated attacks, especially if multiple blood films are negative. As antibody persists for 10 or more years, serologic tests are rarely useful in distinguishing current and past infection.

Alternative diagnostic tests—some commercially available and applicable in particular settings and others still under evaluation—have variable disadvantages of cost, of needing expert interpretation or specialized equipment, or of lacking the ability to differentiate the malarial species; the tests are not satisfactory for field use or for establishing cure. The tests include a variety of rapid antigen detection methods (including a dipstick format), fluorescent antibody methods, and PCR.

During paroxysms, there may be transient leukocytosis. Leukopenia develops subsequently, with a relative increase in large mononuclear cells. A marked anemia (normochromic, normocytic with reticulocytosis) may gradually develop.

Differential Diagnosis

It is imperative to consider malaria in every febrile patient who has a history of travel to an area where malaria is endemic. Uncomplicated malaria must be distinguished from a variety of other causes of splenomegaly, anemia, or hepatomegaly. Often considered are influenza, urinary tract infections, typhoid fever, infectious hepatitis, dengue, kala azar, amebic liver abscess, leptospirosis, and relapsing fever. Malaria complications can mimic many diseases.


Prevention is based on evaluating the risk of exposure to infection, preventing mosquito bites, and chemoprophylaxis.


Advice should also be given regarding medical care if malaria-like symptoms occur while traveling. All persons who will be exposed should receive chemoprophylaxis. Travelers should be advised that in spite of all precautions, no prophylactic regimen gives complete protection. Fever or other symptoms can develop in malaria as early as 6 days (range: 6–60 days) after exposure or stopping prophylaxis; for P vivax infections, however, the delay may be up to 8–12 months. To protect indigenous people in endemic areas, insecticide-treated bed nets are effective and are becoming more affordable.

A. Consultative Resources Regarding Risks, Chemoprophylaxis, and Treatment

Consultation with a center working on malaria may be necessary to obtain up-to-date information on risk and prophylaxis by country and on malarial treatment. A World Health internet source is http://www.who.int/ith/en/. A source of information and advice in the United States is the Malarial Branch, Centers for Disease Control and Prevention (CDC), Atlanta, Georgia. Recorded prophylaxis information for the public and health care professionals is available by telephone, 877–394-8747; fax, 888–232-3299; and Internet, http://www.cdc.gov (choose the Travelers' Health category). Additional information for professionals on prophylaxis or for management of acute attacks, phone 770–488-7788; after business hours, 770–488-7100 or 404–639-2888; additional guidelines for recommended treatment are at http://www.cdc.gov/malaria. Also, see references below.

B. Risk of Exposure

The risk of exposure to mosquitoes may be difficult to estimate since it varies by climate, rainy season, altitude, degree of mosquito control in urban versus rural areas, and according to whether exposure will occur during the time malaria mosquitoes are biting. Malaria transmission occurs in large parts of Central and South America, Hispaniola, Africa, Asia, the Middle East, Eastern Europe, and the South Pacific. Travel to urban areas of Central and South America and Southeast Asia entails minimal risk, and chemoprophylaxis is often not recommended for travelers to these areas.

C. Preventing Mosquito Bites

If being out of doors between dusk and dawn (the primary feeding time for anopheles mosquitoes) is necessary, protective measures should be used: Clothing should cover most of the body, and DEET (N,N-diethyl-3-methylbenzamide) mosquito repellent should be applied to exposed areas every 3–4 hours. To minimize the slight risk of toxic encephalopathy from DEET, use 30–50% concentrations (not higher; lower concentrations are shorter lasting) and apply sparingly and only to exposed skin and outer clothing; avoid inhalation and contamination of eyes, mouth, wounds, or irritated skin; and wash skin after coming indoors. The Ultrathon formulation provides a 33% DEET concentration with extended protection (12 hours). Picaridin has been in use in Europe as an insect repellent as a 20% formulation. It has recently been approved for use in the United States as a 7% formulation but needs further evaluation for its comparative effectiveness to DEET. Living quarters should preferably be air-conditioned or be well screened. If screening is not available, mosquito bed nets should be used at night, preferably ones impregnated every 6 months with permethrin (0.2 g/m2; Permanone) or deltamethrin. To kill mosquitoes in living quarters, use an antimosquito pyrethrum-containing spray or a powdered insecticide dispenser of pyrethroid tablets or burn pyrethroid mosquito coils. Garments can also be impregnated (sprayed or soaked) with permethrin, which repels for several weeks.

D. Advice Regarding Treatment of Malaria-Like Febrile Symptoms Occur While Traveling

The traveler should insist that blood smears be done and, if negative, repeated at intervals. If malaria is suspected but blood smears cannot be done, malaria treatment should be started empirically.

Emergency (“standby”) presumptive self-treatment is a recognized resource for individuals who may be exposed to malaria and for whom medical attention cannot be provided within 24 hours. Such persons are advised beforehand to carry medication for self-treatment if fever or flu-like symptoms develop. However, it is imperative that medical follow-up be sought promptly. Patients should be given written instructions. The choice among available drugs depends on the malarial species to which the patient may be exposed and anticipated drug resistance (see above). In chloroquine-sensitive areas, for persons who have taken no prophylaxis, use the chloroquine 3-day course of treatment (see Table 35-3). In chloroquine-resistant areas, use Malarone (atovaquone 250 mg/proguanil 100 mg) tablets taking four tablets daily for 3 days; the patient should not have been taking Malarone for prophylaxis. Mefloquine, halofantrine, and quinine are not recommended because of their potential for toxicity.

Drugs Used in Chemoprophylaxis & Treatment (Tables 35-2 and 35-3)

A. Drug Classification

By chemical groups, some of the major antimalarial drugs are as follows: 4-aminoquinolines—chloroquine, hydroxychloroquine, amodiaquine;* diaminopyrimidines—pyrimethamine, trimethoprim; biguanides—proguanil (chlorguanide,* chlorproguanil*); 8-aminoquinolines—primaquine; cinchona alkaloids—quinine, quinidine; sulfonamides—sulfadoxine, sulfadiazine, sulfamethoxazole; sulfones—dapsone; 4-quinoline-carbinolamines—mefloquine; and antibiotics—tetracycline,


doxycycline, clindamycin; and others—halofantrine,* artemisinin (qinghaosu)* and its derivatives, and atovaquone. Pyrimethamine and proguanil are known as antifolates, since they inhibit dihydrofolate reductase of plasmodia. Drug combinations used to treat chloroquine-resistant P falciparum malaria include Fansidar (pyrimethamine plus sulfadoxine), Maloprim (pyrimethamine plus dapsone), Lapdap (proguanil plus dapsone), and Malarone (atovaquone plus proguanil). Chloroquine combined


with proguanil has been used in prophylaxis in sub-Saharan Africa but is no longer recommended by the Centers for Disease Control and Prevention. Artemisinin and its derivatives are being used in treatment and continue under evaluation in fixed-dose combinations with other drugs: eg, artemether-lumefantrine (co-artemether), artesunate-Fansidar, artesunate-mefloquine, and artesunate-proguanil-dapsone.

Table 35-2. Prevention of malaria in nonimmune adult travelers.1

  Central America west of the Panama Canal, the Caribbean, Mexico, and parts of the Middle East and China.
    Dose: Chloroquine phosphate, 500 mg salt (300 mg base) orally weekly. Give a single dose of chloroquine weekly starting 1–2 weeks before entering the endemic area, while there, and for 4 weeks after leaving.
REGIONS WITH CHLOROQUINE-RESISTANT P falciparum MALARIA: All other regions of the world; the frequency and intensity of resistance vary by region.
  Malarone (atovaquone [250 mg] combined with proguanil [100 mg] [preferred method])4,6
    Dose: One tablet orally daily at the same time each day. Give one tablet the day before entering the endemic area, daily while there, and daily for 1 week after leaving.
  Mefloquine (alternative method)4,7
    Dose: One 250-mg tablet salt (228 mg base) orally weekly. Give a single dose of mefloquine weekly starting 2–3 weeks before entering the endemic area, while there, and for 4 weeks after leaving.
  Doxycycline (alternative method)4,8
    Dose: 100 mg orally daily. Give the daily dose for 2 days before entering the endemic area, while there, and for 4 weeks after leaving.
    Start primaquine only after returning home, during the last 2 weeks of chemoprophylaxis. Dose: 52.6 mg salt (30 mg base) daily for 14 days. An alternative regimen in regions where chloroquine is effective in prophylaxis is chloroquine phosphate, 500 mg (salt), plus primaquine phosphate, 78.9 mg (salt), weekly for 8 weeks.
1See text for additional information on drug cautions, contraindications, and side effects. For additional information on prophylaxis for specific countries, see the references or call the Centers for Disease Control and Prevention, Atlanta, GA at 770-488-7788 (for fax response: 888-232-3299). The information is also available on the Internet at http://www.cdc.gov (choose the Traveler's Health category).
2The blood schizonticides (chloroquine, mefloquine, Malarone, and doxycycline), when taken for 4 weeks (7 days for Malarone) after leaving the endemic area, are curative for sensitive P falciparum and P malariae infections; primaquine, however, is needed to eradicate the persistent liver stages of P vivax and P ovale.
3See text for a standby drug for emergency self-treatment of presumptive malaria; the drug should be used only when a physician is not immediately available. It is imperative, however, that medical follow-up be sought promptly.
4A test dose of the selected prophylactic drug should be given before departure to allow for changing to an alternative drug in the event of significant side effects: chloroquine (once weekly for 2 weeks), Malarone (daily for 2 days), doxycycline (daily for 2 days), mefloquine (weekly for 3 weeks); side effects from mefloquine sometimes do not appear until after the third or later doses.
5Chloroquine and proguanil can be used by pregnant women.
6Malarone is available in the United States. It eradicates falciparum infections after 1 week of postexposure treatment; its efficacy against P malariae, however, is undetermined. To eradicate P vivax and P ovale infections, a course of primaquine is needed, which should be started early in the final week of Malarone treatment. Malarone has not been shown to be safe in pregnancy. Malarone is more expensive than mefloquine.
7Because of the high frequency of resistance, mefloquine should not be used in Thailand or adjacent countries. Mefloquine is generally not recommended in the first trimester of pregnancy or under some other conditions (see text).
8Doxycycline is used in Thailand and adjacent countries and in other regions by persons who cannot tolerate mefloquine or Malarone. It is contraindicated in pregnant women. Take with evening meals. See text for side effects.
9Primaquine is indicated only for persons who have had a high probability of exposure to P vivax or P ovale (see text), and who have not taken the drug for daily prophylaxis. The drug should be taken with food and is contraindicated in pregnancy. Before use, patients must be screened for glucose-6-phosphate dehydrogenase deficiency. Note that the dosage recommended by CDC has increased.

The effectiveness of antimalarial drugs differs with different species of the parasite and with different stages of the life cycle. Drugs that act in the liver to eliminate developing exoerythrocytic schizonts or latent hypnozoites are called tissue schizonticides (primaquine). Those that act on blood schizonts are blood schizonticides or suppressive agents (eg, chloroquine, amodiaquine, proguanil, pyrimethamine, mefloquine, quinine, quinidine, halofantrine,


artemisinin and its derivatives, and atovaquone). Gametocides are drugs that prevent infection of mosquitoes by destroying gametocytes in the blood (eg, primaquine for P falciparum and chloroquine for P vivax, P malariae, and P ovale). Sporonticidal agents are drugs that render gametocytes noninfective in the mosquito (eg, pyrimethamine, proguanil).

Table 35-3. Treatment of malaria in nonimmune adult populations.

Treatment1 of Infection with All Species (Except Chloroquine-Resistant P falciparum or P vivax) Treatment1 of Infection with Chloroquine-Resistant P falciparum or P vivax Strains
Oral treatment of uncomplicated P falciparum2 or P malariae infection
Chloroquine phosphate, 1 g (salt)3,4 as initial dose, then 0.5 g at 6, 24, and 48 hours.
Oral treatment of P vivax,5 P ovale infection, or species not identified
Chloroquine3,4 as above followed by 0.5 g on days 10 and 17 plus primaquine phosphate, 52.6 mg (salt)3,4,5 daily for 14 days starting about day 4.
Treatment of severe attacks
Parenteral quinine dihydrochloride6 or quinidine gluconate.7 Start oral chloroquine therapy as soon as possible; follow with primaquine if needed.4
Parenteral artesunate,8 artemether,8 or chloroquine9 until the patient can take oral chloroquine. Follow with primaquine if needed.4
Oral treatment of uncomplicated P falciparum resistant to chloroquine
Malarone10 two tablets twice daily with food for 3 days (each tablet contains atovaquone [250 mg] and proguanil [100 mg]).
Quinine sulfate, 10 mg/kg 3 times daily for 3–7 days,11 plus one of the following: (1) doxycycline,10 100 mg twice daily for 7 days; (2) clindamycin,10 7 mg/kg mg 3 times daily for 7 days; (3) tetracycline,10 250–500 mg 4 times daily for 7 days.
Artesunate,8 4 mg/kg/d orally for 3 days plus mefloquine12 (750 mg followed by 500 mg 12 hours later)
Mefloquine,12 750 mg (salt) followed after 6-12 hours by 500 mg.
Atovaquone/doxycycline, 500 mg/100 mg, twice daily for 3 days.
Oral treatment of P vivax resistant to chloroquine
Malarone or mefloquine (dosages above).
Quinine plus doxycycline, or tetracycline plus primaquine (dosages above).
Parenteral treatment of severe attacks13
Artemether,8 or artesunate8; followed by oral mefloquine12 (750 mg followed by 500 mg 12 hours later)
Quinine dihydrochloride6 or quinidine gluconate7 plus intravenous doxycycline, tetracycline, or clindamycin. Start oral therapy with quinine sulfate plus the second drug as soon as possible to complete the course11 of treatment.
1See text for cautions, contraindications, and side effects of each drug. For advice on management, call the Centers for Disease Control and Prevention (CDC), Atlanta, GA 770-488-7788; after business hours, 770-488-7100, or go to its website http://www.cdc.gov/malaria .
2In falciparum malaria, if the patient has not shown a clinical response to chloroquine (48-72 hours for mild infections, 24 hours for severe ones), parasitic resistance to chloroquine should be considered. Chloroquine should be stopped and treatment started with an oral drug used for chloroquine-resistant strains.
3500 mg chloroquine phosphate = 300 mg base; 52.6 mg of primaquine salt = 30 mg base.
4Chloroquine alone is curative for infection with sensitive strains of P falciparum and P malariae, but primaquine is needed to eradicate the persistent liver stages of P vivax and P ovale. Start primaquine after the patient has recovered from the acute illness; continue chloroquine weekly during primaquine therapy. Patients should be screened for glucose-6-phosphate dehydrogenase deficiency before use of primaquine. An alternative mode for primaquine therapy is combined primaquine, 78.9 mg (salt), and chloroquine, 0.5 g (salt), weekly for 8 weeks.
5Strains of P vivax partially resistant to primaquine have appeared in some regions (see text). This is being dealt with by an increase in the primaquine dosage to 52.6 mg (salt) daily for 14 days.
6Parenteral quinine dihydrochloride. As a loading dose, give 20 mg/kg (salt) in 500 mL of 5% glucose solution intravenously slowly over 4 hours; repeat using 10 mg/kg every 8 hours until oral therapy is possible (maximum, 1800 mg/d). If more than 48 hours of parenteral treatment is required, some authorities reduce the quinine dose by one-third to one-half. Total plasma concentrations of 8-15 mg/mL is effective and does not cause serious toxicity. Blood pressure and ECG should be monitored constantly to detect arrhythmias or hypotension. As severe hypoglycemia may occur, blood glucose levels should be monitored. Extreme caution is required in treating patients with quinine who previously have been taking mefloquine in prophylaxis. In the United States, quinine dihydrochloride is no longer available.
7When parenteral quinine is unavailable (as in the United States), quinidine gluconate can be used, administered as a continuous infusion. A loading dose of 10 mg/kg (salt) (maximum, 600 mg) is diluted in 300 mL of normal saline and administered over 1-2 hours, followed by 0.02 mg/kg/min (maximum, 10 mg/kg every 8 hours) by infusion pump until oral quinine therapy is possible. If more than 48 hours of parenteral treatment is required, some authorities reduce the quinidine dose by one-third to one-half. Total plasma concentrations of 3.5-7 mg/mL is effective and does not cause serious toxicity. Fluid status, glucose, blood pressure, and ECG should be monitored closely; widening of the QRS interval or lengthening of the QT interval requires discontinuation.
8Not available in the United States. Give artesunate intravenously (2.4 mg/kg on the first day, followed by 1.2 mg/kg daily) or artemether intramuscularly (3.2 mg/kg on the first day, followed by 1.6 mg/kg daily); continue the drug for a minimum of 3 days until the patient can start oral artesunate. If parenteral treatment is not available, artemisinin rectal suppositories are being evaluated (40 mg/kg loading dose, then 20 mg/kg at 24, 48, and 72 hours) followed by oral medication. With all preparations of the artemisinin drugs, as soon as oral medication can be tolerated, treat concurrently with another effective blood schizonticide (Malarone preferred).
9Give parenteral chloroquine (1) preferably intravenously, 10 mg base/kg in isotonic fluid by constant rate of infusion over 8 hours, followed by 15 mg/kg over the next 24 hours; or (2) intramuscularly or subcutaneously, 3.5 mg base/kg every 6 hours.
10Contraindicated in pregnant women.
11Although oral quinine sulfate is usually given for 3 days, it should be continued for 7 days in patients who acquired infections in Southeast Asia and South America, where diminished responsiveness to quinine has been noted.
12Serious side effects are rare. See text for cautions and contraindications. In the United States, a 250-mg tablet of mefloquine contains 228 mg of base; outside the United States, each 275-mg tablet contains 250 mg of base. Mefloquine is hazardous with quinine, quinidine, or halofantrine.
13All of the drugs given intravenously should be administered slowly.

None of the drugs prevent infection (ie, are true causal prophylactic drugs). However, proguanil, chlorproguanil, atovaquone, and primaquine—and to some extent the antibiotics—prevent maturation of the early P falciparum. Blood schizonticides destroy circulating plasmodia and thus prevent malarial attacks (suppressive prophylaxis) and, when given weekly for 4 weeks after departure from the endemic area, result in cure of P falciparum and P malariae infections. Only primaquine destroys the hypnozoites of P vivax and P ovale and, when given with a blood schizonticide, prevents relapse from infection with these parasites and thus effects radical cure (terminal prophylaxis).

B. Parasite Resistance to Drugs

Resistance has developed to all classes of antimalarial drugs except the artemisinins. To slow the development of resistance, the antimalarial drugs are increasingly being evaluated in combinations with an artemisinin derivative.

1. P falciparum resistance

a. Chloroquine

P falciparum resistance to chloroquine has been confirmed or is probably present in all malarious areas except Haiti, the Dominican Republic, Mexico, Central America north and west of the Panama Canal, Argentina, North Africa, most of the Middle East, including Iraq, (resistance is present, however, in Oman, Yemen, Saudi Arabia, United Arab Emirates, Afghanistan, and Iran) and the Koreas. In some regions, some strains of P falciparum are only partially resistant to the drug, as manifested by temporary subsidence of symptoms and transient decrease or disappearance in asexual parasitemia, followed by return of both after several days to weeks.

b. Pyrimethamine-sulfadoxine (Fansidar)

Fansidar resistance is present at high levels in Southeast Asia, southern China, and the Amazon basin. Lower degrees are reported in sub-Saharan Africa (more in the east [20–40%] than the west), western Oceania, and parts of the Indian subcontinent and the Pacific coast of South America.

c. Pyrimethamine or proguanil

Resistance to either of these drugs when used alone is common in most endemic areas, but the degree and distribution are not accurately known.

d. Mefloquine

Along the border of Thailand with Myanmar and Cambodia and within parts of these countries and Laos and Vietnam, the frequency of P falciparum resistance to mefloquine reaches 30–60%. Sporadic or low levels of resistance have also been reported from southern Asia and parts of Africa, South America, the Middle East, and Oceania.

e. Quinine and quinidine

Variable degrees of decreased responsiveness have been reported sporadically


in Southeast Asia (particularly in the border regions of Thailand) and western Oceania and rarely in sub-Saharan Africa and South America.

f. Halofantrine

A high degree of resistance has been reported in eastern Thailand. Strains resistant to halofantrine are sometimes resistant to mefloquine as well.

g. Malarone

Rare instances of P falciparum resistance to Malarone have been reported documented in Africa and reported elsewhere.

h. Artemisinin derivatives

There are no known artemisinin-resistant P falciparum strains.

2. P vivax resistance

a. Antifolates

Resistance of P vivax blood schizonts to pyrimethamine and proguanil, including the pyrimethamine-containing drugs Fansidar and Maloprim, has been reported in many areas of the world, particularly Southeast Asia.

b. Chloroquine

There are frequent reports from Indonesia, Irian Jaya, and Papua New Guinea of P vivax blood schizonts resistant to chloroquine. Decreased susceptibility is also appearing in the Solomon Islands, Myanmar, India, Thailand, and from Central and South America.

c. Primaquine

Partial resistance of some strains of P vivax hepatic schizonts and hypnozoites to primaquine has been reported in areas of Southeast Asia, (17% failure rate in Thailand), Papua New Guinea (30%), the Amazon Basin, Central America, Somalia (43% in American military personnel), and Guyana. Treatment is usually successful with a higher dose (30 mg of base daily for 14 days) or a longer course (15 mg of base daily for 28 days).

3. P ovale and P malariae

P ovale has not shown resistance but strains of P malariae resistant to chloroquine have been reported from Indonesia.

C. Selected Drugs: Indications, Limitations, and Adverse Side Effects

1. Chloroquine phosphate

Chloroquine is the drug of choice in chemoprophylaxis and in treatment for all forms of malaria except for infections due to resistant strains of P falciparum and P vivax (see above). However, in P vivax and P ovale infections, primaquine is needed to eradicate the persistent liver phases and thus prevent relapse.

Oral chloroquine is usually well tolerated when used for malaria prophylaxis or treatment and is safe to use in pregnancy. Transient gastrointestinal symptoms, mild headache, pruritus (especially in blacks), dizziness, blurred vision, anorexia, malaise, and urticaria may occur; taking the drug after meals or in divided twice-weekly doses may reduce these side effects.

In parenteral treatment of severely ill patients, quinine, quinidine, or the parenteral artemisinin derivatives are the preferred drugs. If none are available, chloroquine can be given intramuscularly or intravenously. However, parenteral chloroquine can be severely toxic unless it is given in small amounts (3.5 mg [base]/kg) intramuscularly every 6 hours or by slow intravenous infusion.

Rare reactions from oral chloroquine include impaired hearing, psychosis, convulsions, blood dyscrasias, skin reactions, hypotension, and hemolysis in G6PD-deficient persons. When given in large doses for prolonged periods as an anti-inflammatory agent in autoimmune diseases, chloroquine has caused ocular damage. Theoretically, a total cumulative dosage of 100 g (base) may be critical in the development of ocular, ototoxic, and myopathic effects. However, with weekly long-term administration of chloroquine, serious eye damage has not been confirmed; therefore, periodic eye examinations may no longer be indicated. Chloroquine should be used with caution in patients who have histories of liver damage, alcoholism, or neurologic or hematologic disorders. It is contraindicated in patients with psoriasis. Chloroquine suppresses the immune response to the rabies vaccine.

Certain antacids and antidiarrheal agents (kaolin, calcium carbonate, and magnesium trisilicate) should not be taken within about 4 hours before or after chloroquine administration, since they interfere with its absorption.

2. Mefloquine hydrochloride

Mefloquine is used for oral prophylaxis and treatment of chloroquine-resistant and multidrug-resistant P falciparum malaria. In treatment, it is used only for mildly to moderately ill patients; severely ill patients require parenteral treatment with an alternative drug. Mefloquine has strong blood schizonticidal activity against the four malarial parasites (except for some P falciparum strains resistant to it)—but it is not active against P falciparum gametocytes or the hepatic stages of P vivax or P ovale, which require a course of primaquine. With weekly doses of mefloquine, the steady state drug level is reached in about 7 weeks, and adverse reactions thus may not appear for 3–7 weeks. The steady state interval can be reduced to 4 days, revealing adverse reactions within a week, by giving an initial course of 250 mg daily for 3 days followed by the standard weekly dose; this, however, is not standard practice.

With the lower doses used in prophylaxis, frequent (25–50%) minor and transient side effects are nausea, vomiting, epigastric pain, diarrhea, headache, dizziness, syncope, and extrasystoles. A small proportion of patients (up to 4%) experience anxiety, mood changes, insomnia, and nightmares. Severe neuropsychiatric symptoms are rare (estimated 1:1500 to 1:10,000). If prophylaxis is continued for more than a year, periodic liver function and ophthalmologic tests should be done. With treatment doses—particularly over 1000 mg—gastrointestinal symptoms and fatigue are more likely to occur, and the frequency of severe neuropsychiatric symptoms (visual disturbances, vertigo, tinnitus, insomnia, restlessness, anxiety, depression, confusion, disorientation, acute psychosis, or seizures) may be of the order of 1:1200. In experimental animals,


the drug affects fertility and is teratogenic; it also causes degenerative changes in the epididymis in rats and in the lens and retina of some species. In human males, however, no deleterious effects on spermatozoa were found, and no effects have been noted in the human retina or lens. Because the drug may affect fine motor coordination and spatial orientation, caution in its use is recommended for pilots, drivers, and machinery operators.

Mefloquine is contraindicated in the presence of a cardiac conduction abnormality, liver impairment, or a history of a psychiatric or neurologic disorder, including epilepsy. Also contraindicated is concurrent administration of mefloquine with quinine, quinidine, chloroquine, or halofantrine. If these drugs precede use of mefloquine, 12 hours should elapse before mefloquine is started; however, because of the long elimination half-life of mefloquine (13–26 days), extreme caution is required because of arrhythmias if one of these drugs is used to treat malaria after mefloquine has been taken. Concurrent administration with tetracyclines or ampicillin results in increased mefloquine blood levels.

The development of neuropsychiatric symptoms during prophylaxis is an indication for stopping the drug. Patients taking anticonvulsant drugs may have breakthrough seizures. Mefloquine is no longer contraindicated when β-blockers and calcium channel blockers are taken. CDC has advised that mefloquine can be used throughout pregnancy; nevertheless, its use during the first trimester should be based on risk-benefit assessment. Women of childbearing potential who take mefloquine for antimalarial prophylaxis should preferably avoid conception for the duration of mefloquine usage and for 2 months after the last dose.

Note: The tablet formulation in the United States contains 250 mg of the salt (= 228 mg of base). However, in Canada and many other countries, the tablets contain 274 mg of the salt (= 250 mg of base). Mefloquine should not be taken on an empty stomach and should be taken with 8 oz of water.

3. Malarone

Malarone—atovaquone 250 mg and proguanil 100 mg—is a fixed-combination oral medication recently approved in the United States for prophylaxis and treatment of multidrug-resistant falciparum malaria, P vivax, and P ovale; effectiveness against P malariae has not been determined. In a limited number of studies in nonimmune adults, Malarone's prophylactic efficacy was 98% against P falciparum and 84% against P vivax. In treatment, its use is currently limited to uncomplicated malaria (cure rates 87–100%); data on effectiveness in treatment of severe malaria and in P malariae and P ovale infections are limited.

Malarone's components, proguanil and atovaquone, used together, are synergistic, but failures are frequent to either component used alone. Because the agents are effective against the liver and blood stages of P falciparum, only 7 days of treatment is needed after leaving an endemic area, and primaquine is not required to eradicate a falciparum infection. Cross-resistance between Malarone and other antimalarials has not been noted. In P vivax and P ovale infections, however, in which the Malarone components are effective only against the erythrocytic stages, primaquine must be used to eradicate the liver form (hypnozoites). Malarone supersedes Fansidar as the preferred drug for standby treatment (see above).

Malarone appears to be better tolerated than chloroquine and causes significantly fewer neuropsychiatric side effects than mefloquine. The drug is taken orally with food to increase absorption of atovaquone and to reduce gastrointestinal side effects (10%: nausea, vomiting, diarrhea, abdominal pain, epigastric discomfort). These symptoms may also be reduced by giving the drug in divided doses twice daily. Other side effects include headache, rash, dizziness, and mild reversible elevations of liver aminotransferases. One case of anaphylaxis has been reported, and the drug has been associated with the Stevens-Johnson syndrome. There are insufficient data on fetal risks to allow Malarone to be used in pregnancy. Concomitant administration of Malarone with rifampin, tetracycline, or metoclopramide is associated with 40–50% reductions in atovaquone plasma levels. The drug is contraindicated in patients with severe renal impairment.

4. Primaquine phosphate

Primaquine is used to prevent relapse by eliminating persistent liver forms of P vivax or P ovale in patients who have had an acute attack and for individuals returning from an endemic area who have probably been exposed to malaria. However, in persons with a low probability of exposure, it may be preferable to avoid primaquine's potential toxicity by not giving the drug. Instead, such patients are advised to seek medical evaluation in the event of malaria-like symptoms, which usually occur within 2 years after infection but can occur up to 4 years after. Because primaquine is effective against the liver stages of all malarial parasites, including chloroquine-resistant P falciparum, it has been reevaluated recently for chemoprophylaxis when taken daily (30 mg base). A prophylactic efficacy of 85–95% has been shown against P falciparum and P vivax with apparent safety in long-term use, though the drug is not licensed for this indication. Primaquine is sometimes given as a single 45 mg (base) dose to eliminate P falciparum gametocytes.

Primaquine is generally well tolerated. Occasional side effects of the drug are gastrointestinal disturbances (minimized if taken with food), headache, dizziness, or neutropenia. Primaquine should not be used in pregnancy (risk of hemolytic disease in the fetus), in autoimmune disorders, or concurrently with quinine.

All patients should be tested for glucose-6-phosphate dehydrogenase (G6PD) deficiency before therapy is begun. They should be monitored carefully during treatment because primaquine may cause mild, self-limited hemolysis or marked hemolysis (pallor,


weakness, abdominal pain, dark urine) or methemoglobinemia. G6PD deficiency is most common among persons of Mediterranean, African, or certain East Asian extractions. Patients with severe G6PD deficiency (< 10% residual enzyme activity) should not receive primaquine. For individuals with 10–60% residual activity, it is generally safe to give combined primaquine phosphate, 78.9 mg (45 mg base), and chloroquine phosphate, 0.5 g (0.3 g base), weekly for 8 weeks. However, for persons suspected of having the Mediterranean or Canton forms of G6PD deficiency, it may be preferable not to give primaquine but to treat attacks of malaria with chloroquine as they occur. Under development is tafenoquine, a congener of primaquine; it is more slowly eliminated than primaquine and is probably less toxic.

5. Quinine

Oral quinine sulfate in conjunction with another drug (see Table 35-3) is used to treat malaria due to multidrug-resistant strains of P falciparum; however, compliance with the 7-day course is poor because of quinine side effects.

Quinine should be taken with food. Mild to moderate quinine toxicity (cinchonism) is manifested by headache, nausea, slight visual disturbances, dizziness, and mild tinnitus. These symptoms may abate as treatment continues and usually do not require discontinuation of treatment. Where available, quinine blood levels can be monitored; desired plasma levels are 5–10 mcg/mL. Severe side effects (cinchonism) requiring temporary or permanent discontinuation of therapy are rare and begin to appear at plasma levels greater than 7 mcg/mL; findings include fever, skin eruptions, deafness, marked visual abnormalities (scotomas, diplopia, contracted visual fields, retinal vessel spasticity, optic atrophy, blindness), other central nervous system abnormalities (vertigo, somnolence, confusion, seizures), disturbances in cardiac rhythm or conduction, massive intravascular hemolysis with renal failure (blackwater fever), agranulocytosis, and thrombocytopenia.

Parenteral quinine dihydrochloride is used in the treatment of severe attacks of malaria due to P falciparum strains sensitive or resistant to chloroquine. The drug is given intravenously at a slow rate (Table 35-3); rapid infusions may be severely toxic. The drug should be used with extreme caution and only for patients who cannot take the medication orally; appropriate oral therapy should be started as soon as possible. Infusions may cause thrombophlebitis and hypoglycemia (blood glucose levels should be monitored). In the United States, parenteral quinine is no longer available and parenteral quinidine gluconate is used instead.

Manufacturers' recommendations for drug interactions (including aluminum-containing antacids, digoxin, anticoagulants, cimetidine, and rifampin) should be consulted. Quinine is safe to use in pregnancy. Systemic clearance of quinine slows in proportion to the severity of the disease.

6. Quinidine gluconate

Quinidine is the dextrorotatory diastereoisomer of quinine. The two drugs are equally efficacious in parenteral treatment of severe malaria (Table 35-3). They are also similar with regard to toxicity and drug interactions, but quinidine has a greater cardiosuppressant effect. The principal adverse effect associated with quinine and quinidine use in severe malaria is hypoglycemia, which usually develops after 24 hours of treatment; it is a particular problem in pregnancy.

7. Pyrimethamine-sulfadoxine (Fansidar)

Fansidar is supplied as tablets that contain pyrimethamine (25 mg) and sulfadoxine (500 mg). Fansidar's limitations are that it is effective only against susceptible strains of P falciparum (see above); its low efficacy against P vivax, P ovale, or P malariae; and the fact that it is slow-acting. Fansidar is no longer used for weekly prophylaxis because of rare reports of severe cutaneous toxicity and death. However, in single-dose treatment, Fansidar is generally well tolerated. Fansidar is currently used by some clinicians for intermittent prophylaxis for pregnant women in Africa south of the Sahara. Cutaneous reactions to the drug are more common in persons who are HIV-positive.

Fansidar is contraindicated for persons with known sulfonamide sensitivity and those in the last month of pregnancy (the sulfadoxine component, which has a long half-life, can cause kernicterus in the newborn). The drug should be used with caution in the presence of impaired renal or hepatic function, in patients with G6PD deficiency (hemolysis occurs in some), and in those with severe allergic disorders or bronchial asthma. If folic acid is needed, ingestion should be delayed 1 week to avoid an inhibitory effect on the antimalarial action of Fansidar.

8. Antibiotics

a. Doxycycline

Doxycycline is effective against chloroquine-sensitive and chloroquine-resistant P falciparum, P vivax, and (apparently) against P ovale and P malariae. It is used prophylactically against chloroquine-resistant and mefloquine-resistant falciparum malaria in Thailand and adjacent countries and elsewhere for patients who cannot tolerate mefloquine or Malarone (Table 35-2). Doxycycline is also used as an adjunct drug with quinine for the treatment of resistant falciparum malaria (Table 35-3). Side effects include infrequent gastrointestinal symptoms (take with meals—but not at bedtime—plus copious amounts of water to avoid esophageal irritation); candidal vaginitis (advise carrying a self-treatment antifungal regimen, either vaginal suppositories or cream); and rare photosensitivity (prevention may be achieved by use of sunscreens that absorb ultraviolet radiation (UVA) and by avoidance of exposure to direct sunlight as much as possible). Milk, which reduces absorption, should be avoided. The drug is contraindicated in pregnancy, in nursing mothers, in children under 8 years of age, and in persons with hepatic dysfunction. No data are available on the long-term use of the drug.


b. Clindamycin

Clindamycin is highly effective in treatment when combined with quinine (Table 35-3). It should not be used as monotherapy, however, because of its slow onset of action. Side effects (gastrointestinal symptoms, perioral rash) are self-limited and mild; Clostridium difficile diarrhea is rare. Safety in pregnancy needs further evaluation.

9. Artemisinin (qinghaosu) and its derivatives

Artemisinin and its derivatives are available in some countries but not in the United States. The drugs are rapid-acting and effective against all malarial parasites and are partially gametocidal, but they are not active against the persistent liver stages of P vivax and P ovale. Artesunate, considered the most rapid-acting form, is water-soluble and is given orally or by intravenous infusion. Other parenteral preparations are oil-soluble artemether (erratically absorbed orally) and the newly marketed artemotil. Rectal suppository formulations are sometimes available. Having shown no parasite resistance, the artemisinin drugs are the only agents that remain reliably active against multidrug-resistant P falciparum, including agents resistant to quinine. The drugs are used only to treat acute malaria, including severe malaria. Because of their short half-lives, they cannot be used in prophylaxis. Mild adverse events—symptoms that also occur in malaria—are headache, gastrointestinal symptoms, pruritus, and fever. Instances of allergic reactions have been described. Animal studies suggest a potential for embryotoxicity (opinions differ on the safety of the drug in pregnancy) and central nervous system toxicity (but this has not been demonstrated in human prospective studies, except in one study that reported ototoxicity with co-artemeter). As recrudescences are common after treatment (10%), the drugs should not be used alone but in combination with a long-acting drug (eg, mefloquine or Malarone). The combinations also reduce the transmissibility of malaria by preventing gametocyte development. A combination approved by WHO is Riamet (Coartem), which is lumefantrine (120 mg) combined with artemether (20 mg); its dosage in treatment is four tablets initially, again at 8 hours, and then twice daily for the next 2 days. Cure rates up to 98% have been reported.

10. Proguanil

Proguanil (chlorguanide, Paludrine; not available in the United States), 200 mg/d, is a blood schizonticide against three of the malaria parasites (unknown degree against P malariae) and has some causal prophylactic action. The drug is no longer used alone but only in combination therapy. Proguanil (100 mg) with atovaquone (250 mg) (Malarone) has recently been approved in the United States for prophylaxis and treatment of multidrug-resistant falciparum malaria. Proguanil (100 mg daily) in combination with chloroquine (0.5 g weekly) for prophylaxis for travelers going to areas with low-intensity chloroquine-resistant P falciparum is no longer recommended for travelers going to areas with chloroquine-resistant malaria. Rarely reported side effects are nausea, vomiting, hair loss, and mouth ulcers. The drug is safe to use in pregnancy; it should not be used in persons with hepatic or renal dysfunction.

Chemoprophylaxis for Nonimmune Populations

See Table 35-2 for methods and dosages and under the individual drugs (above) for details on cautions, contraindications, and toxicities.

Antimalarials should be taken with water at mealtime. The selected drug should be tested for side effects in advance of departure (to allow time for selection of an alternative drug if necessary) and started sufficiently in advance of exposure that a satisfactory prophylactic blood level is achieved. On returning home, primaquine is given to eradicate persistent liver stages of P vivax or P ovale if there has been significant exposure to these parasites (see above under Primaquine).

A. Chemoprophylaxis in Regions Where P falciparum Is Sensitive to Chloroquine

1. Drug of choice

Chloroquine prevents attacks for all forms of malaria and is curative for P falciparum and P malariae when taken for 4 weeks after leaving the endemic area. For persons who cannot tolerate chloroquine, reducing the dose to 250 mg twice weekly or switching to hydroxychloroquine sulfate (400 mg [salt]) can be tried.

2. Alternative drugs

Malarone, mefloquine, and doxycycline are alternatives to chloroquine. Schizonticides not used for chemoprophylaxis are halofantrine (erratic absorption and variable bioavailability), Fansidar (hypersensitivity reactions with rare deaths; frequent parasite resistance to the drug), amodiaquine (agranulocytosis and toxic hepatitis), pyrimethamine (widespread resistance of both P falciparum and P vivax), artemisinin and related drugs (short duration of action), proguanil by itself (high failure rate), and generally quinine (toxicity).

B. Chemoprophylaxis in Regions Where P falciparum Is Resistant to Chloroquine

1. Drugs of choice

Malarone is preferred but is more expensive. Alternative drugs are mefloquine (more side effects, sometimes severe) and doxycycline.

2. Second alternative drugs

There is continuing evaluation of primaquine (30 mg base) starting 1 day before entering the endemic area, daily while there, and for 7 days afterward. Although it is not licensed for this use in the United States, the drug is recommended for this use by the Centers for Diseases Control and Prevention under special circumstances. The drug is contraindicated in pregnancy and in persons with G6PD deficiency. Under evaluation is tafenoquine, an analog of primaquine that is more potent than the parent drug and will require only weekly doses. Under exceptional circumstances, the daily use of quinine can be considered.


C. Chemoprophylaxis in Southeast Asia

Multidrug P falciparum resistance is extensive in Southeast Asia. The drugs of choice are doxycycline, Malarone, and artesunate-mefloquine. Chloroquine and Fansidar cannot be used throughout the region because of resistance, and resistance to mefloquine and halofantrine is widespread.

D. Prophylaxis for Pregnant Women

Pregnant women should be protected; malaria infection during pregnancy may be particularly severe with high maternal mortality and fetal and perinatal loss. The safest drug, where it remains effective, is weekly chloroquine (or hydroxychloroquine). Drugs contraindicated in pregnancy are primaquine, doxycycline, mefloquine in the first trimester (increase in stillbirths), Fansidar (toxicity), and Malarone (safety data are limited). The artemisinin drugs are not effective for prophylaxis because of their short half-life, and their safety has not been established. Generally, therefore, travel by pregnant women to areas with P falciparum resistance to chloroquine and mefloquine is not recommended.

E. Emergency Self-Treatment

In selected instances, medication should be provided for emergency self-treatment of breakthrough attacks (see above).

Treatment of Acute Attacks in Nonimmune Adult Populations

See under individual drugs and Table 35-3 for dosages.

A. General Considerations

At times when parasitologic confirmation is not readily available, it may be necessary to start treatment immediately based only on clinical findings. Patients with falciparum infections should be hospitalized. It is important to determine whether a patient has been treated with antimalarials in the previous 1–2 days (3 weeks for mefloquine because of its slow excretion) to avoid the risk of overdose or adverse drug interactions. In the event of mefloquine treatment failure after its use in prophylaxis, it is hazardous—although it may be essential—to use quinine or quinidine (Table 35-3); under these circumstances, the safest drug to use is artemisinin or one of its derivatives (not available in the United States).

It is essential to determine the density of parasites on the blood smear (as a measure of severity of infection) and to recheck at least twice daily. Within 48–72 hours after start of treatment, patients usually become afebrile and improve clinically; within 48 hours, parasitemia is generally reduced by about 75% (though there may be an initial increase during the first 6–12 hours). In the presence of adequate drug ingestion and retention, if there is no improvement within 48–72 hours for mild infections or 24 hours for severe ones or if there is increasing asexual parasitemia after 1–2 days, parasite resistance to the drug must be assumed and treatment changed.

B. Drug Treatment of All Forms of Malaria Except P falciparum and P vivax Strains Resistant to Chloroquine (Table 35-3)

1. Elimination of asexual erythrocytic parasites

Infection by all four species of malaria is treated with oral chloroquine. Alternative oral drugs if chloroquine cannot be tolerated are Malarone, mefloquine, quinine sulfate, plus doxycycline or clindamycin or atovaquone plus doxycycline.

If the patient is severely ill, treat with intravenous quinine dihydrochloride* or quinidine gluconate, parenteral preparations of artemisinin derivatives,* or parenteral chloroquine. Start oral therapy with chloroquine as soon as possible.

2. Eradication of P vivax or P ovale infections

This is accomplished with a course of primaquine.

3. Elimination of persistent gametocytemia

Gametocytes of P vivax, P ovale, and P malariae can be eliminated by chloroquine. Gametocytes of P falciparum are eliminated by a single dose of 26.3 mg of primaquine salt.

4. Treatment of semi-immunes

Treatment of attacks in semi-immune patients generally requires shorter courses of drug treatment.

C. Drug Treatment of Falciparum Malaria Acquired in Areas Where P falciparum Is Resistant to Chloroquine

Start treatment with oral quinine sulfate and a second drug. Alternative drugs are Malarone, mefloquine, artesunate* followed by mefloquine, atovaquone plus doxycycline. In Southeast Asia, mefloquine (when used alone) may not be effective because of multidrug resistance.

If the patient is severely ill, treat with intravenous quinine or quinidine. A second drug (doxycycline, tetracycline, or clindamycin) should also be given parenterally. Oral treatment with quinine plus the antibiotic should be started as soon as possible. For intravenous use, quinine is safer than quinidine; in comparison, the alternative drugs, the parenteral artemisinin derivatives—artesunate* and artemether*—are the safest but are equally effective. Artesunate and artemether should be followed by oral mefloquine.

D. Special Measures for Management of Severe P falciparum Malaria

(See references for further details.) Patients with falciparum malaria, even with low peripheral parasitic counts, should be hospitalized. Deterioration can occur even after start of adequate treatment. Any patient


with a falciparum parasitemia greater than 2% should be treated with parenteral antimalarials. Severe (complicated) falciparum malaria is a medical emergency that requires intensive care with monitoring of electrolytes and acid-base balance, and immediate antimalarial treatment without waiting for all laboratory results to become available. Indications for parenteral treatment are (1) failure to ingest or retain drugs, (2) cerebral malaria, (3) multiple complications, and (4) peripheral asexual parasitemia of 5% (250,000/mcL) or higher. When possible, parenteral treatment should be intravenous, but quinine, artesunate, and chloroquine can be given intramuscularly; chloroquine can also be given subcutaneously. Patients receiving intravenous quinine and quinidine require a continuous infusion of 5–10% glucose as well as continuous ECG monitoring (especially to detect widening of the QRS complex or lengthening of the QT interval). Black urine suggests hemoglobinuria. Renal failure, metabolic acidosis, pulmonary edema, gram-negative sepsis, jaundice, severe anemia, and shock may ensue. Rehydration of the patient should be done with great caution, particularly in the first 24 hours, since overhydration may precipitate noncardiogenic pulmonary edema. In general, 2–3 L of fluid is required the first day, followed by 10–20 mL/kg/d; intake and output should be carefully recorded. After rehydration, the central venous pressure should be maintained at approximately 5 cm of water (pulmonary artery occlusion pressure < 15 mm Hg). For renal failure, early hemofiltration (more rapid than peritoneal dialysis) may be necessary and need to be sustained for 4–7 days or longer. Mechanical ventilation may also be indicated. Blood glucose levels should be monitored every 6 hours during the acute and early convalescent period, since hypoglycemia may be severe, either as a result of the malaria infection or the use of quinine or quinidine. In cerebral malaria, maintain the airway and exclude other treatable causes of coma (hypoglycemia, bacterial meningoencephalitis). The presence of papilledema is a contraindication to lumbar puncture. With convulsions, maintain the airway and treat with diazepam (0.15 mg/kg intravenously or 0.5 mg/kg rectally) or with paraldehyde (0.1 ml/kg intramuscularly, preferably dispensed from a glass syringe). Keep the temperature below 38.5°C using acetaminophen (paracetamol) plus tepid sponging and fanning. Patients with clinically significant disseminated intravascular coagulation should be treated with fresh whole blood, clotting factors, or platelets as needed. For hematocrits below 20% or hemoglobins below 7 g/dL, transfusion of fresh whole blood or packed cells is required. Bacterial infections are common (eg, pneumonia, cystitis, salmonellosis). Exchange transfusion (5–10 L) should be considered when more than 10% of red blood cells are parasitized (5% if severe dysfunction of other organs is present). Corticosteroids, aspirin, other anti-inflammatory agents, dextran, norepinephrine, deferoxamine, and anticoagulants should not be used.

Follow-Up for P falciparum Malaria

Blood films should be checked daily until parasitemia clears; check weekly thereafter for 4 weeks to observe for recrudescence of infection.


The uncomplicated and untreated primary attack of P vivax, P ovale, or P falciparum malaria usually lasts 2–4 weeks; that of P malariae lasts about twice as long. Attacks of each type of infection may subsequently recur (once or many times) before the infection terminates spontaneously. With prompt antimalarial therapy, the prognosis is generally good, but in P falciparum infections, when severe complications such as cerebral malaria develop, the prognosis is poor (14–17% mortality) even with treatment. After cerebral malaria, residual neurologic deficits may remain.

Baird JK: Effectiveness of antimalarial drugs. N Engl J Med 2005;352:1565.

Chen LH et al: New strategies for the prevention of malaria in travelers. Infect Dis Clin North Am 2005;19:185.

Greenwood PM et al: Malaria. Lancet 2005;365:1487.

Health Information for International Travel 2005–2006. U.S. Department of Health and Human Services, Centers for Disease Control and Prevention, Atlanta, Georgia. Available from 877–252-1200 International Travel and Health: Vaccination Certificate Requirements and Health Advice. WHO, 2006.

Pasvol G: Management of severe malaria: interventions and controversies. Infect Dis Clinic North Am 2005;19:211.

Prevention of malaria. Med Lett Drug Ther 2005;47:100.

Woodrow CJ et al: Artemisinins. Postgrad Med J 2005;81:71.


Essentials of Diagnosis

Acute primary infection:

  • Fever, malaise, headache, lymphadenopathy (especially cervical), myalgia, arthralgia, stiff neck, sore throat; occasionally, rash, hepatosplenomegaly, retinochoroiditis, confusion; in various combinations.

  • Positive serologic tests with high and rising IgG and IgM.

  • Isolation of Toxoplasma gondii from blood or body fluids; tachyzoites in histologic sections of tissue or cytologic preparations of body fluids.

Acute primary or recrudescent infection in immunocompromised patients:

  • Central nervous system mass lesions; retinochoroiditis, pneumonitis, myocarditis less common; sometimes other findings as above.

  • Positive IgG titers moderately high; IgM antibody usually absent. Tissue diagnosis as above.


General Considerations

Toxoplasma gondii, an obligate intracellular protozoan, is found worldwide in humans and in many species of animals and birds. The parasite is a coccidian of cats, the definitive host, and exists in three forms: The trophozoite (tachyzoite) (3 × 7 mcm) is the rapidly proliferating form in tissues and body fluids that causes acute disease. The trophozoites can enter and multiply in most mammalian nucleated cells. The cyst, containing viable bradyzoites, is the latent form that can persist indefinitely as a chronic infection and is found particularly in muscle and nerve tissue. The oocyst is the form passed only in the feces of the cat family. In the intestinal epithelium of cats, a sexual cycle occurs, with subsequent release of oocysts for 3–14 days; cats may, however, become reinfected and excrete oocysts multiple times. The oocysts, which contain infective sporozoites, are infectious within 12 hours to several days after passage and can remain infective in moist soil for weeks to years.

Human infection results (1) from ingestion of cysts in raw or undercooked meat; (2) from ingestion of oocysts in contaminated food or water, by careless handling of contaminated cat litter, or from soil by soil-eating children; (3) from transplacental transmission of trophozoites; or (4) rarely, from direct inoculation of trophozoites, as in blood transfusion and organ transplants. Reservoirs of human infection are rodents and birds eaten by cats, and infected domestic animals used for human food. Antibody prevalence rates range from less than 5% in some parts of the world (absence of cats and minimal ingestion of meat) to 23% overall in the United States (16% in women aged 12–49) and over 80% in France. This range is due, in part, to culture differences that determine whether meat is eaten raw or undercooked.

On ingestion, bradyzoites (from cysts) or sporozoites (from oocysts) invade multiple cells types and propagate as trophozoites; cell death and inflammation follow, but true granulomas do not form.

Clinical Findings

A. Symptoms and Signs

Over 80% of primary infections, including during pregnancy, are asymptomatic. The incubation period for symptomatic persons is 1–2 weeks. Generally, on recovery, both asymptomatic and symptomatic infections persist as chronic latent (cyst) infections. Reactivation occurs almost exclusively in severely immunocompromised patients.

The clinical manifestations of toxoplasmosis may be grouped into four syndromes.

1. Primary infection in the immunocompetent host

Most symptomatic infections are acute, mild, febrile multisystem illnesses that resemble infectious mononucleosis. Lymphadenopathy, usually nontender, particularly of the head and neck, is the most common finding. Other features in various combinations are malaise, myalgia, arthralgia, headache, sore throat, and maculopapular or urticarial rash. Hepatosplenomegaly may occur. Rarely, severe cases are complicated by pneumonitis, meningoencephalitis, hepatitis, myocarditis, polymyositis, and retinochoroiditis. Symptoms may fluctuate, but most patients recover spontaneously within a few months.

2. Congenital infection

Congenital transmission occurs only as a result of infection (generally asymptomatic) in a nonimmune woman during pregnancy. In the United States, an estimated 400 to 4000 congenital infections occur yearly. Following maternal infection, the frequency of transmission to the fetus varies by trimester: 15%, 30%, and 60%, respectively, in the first, second, and third trimesters. Fetal infection is more severe when maternal infection occurs in the first trimester. However, if maternal infection occurs in the third trimester, most of the infected fetuses will have a subclinical infection at birth but, if left untreated, 85% will later develop overt disease, particularly chorioretinitis or delays in development. Treatment of the mother reduces the congenital infection rate by about 60%. See specialized sources for clinical manifestations, approach to diagnosis, and treatment.

3. Retinochoroiditis

In most cases, this develops gradually weeks to years after congenital infection (the preponderant form, which is generally bilateral) or infrequently after an acquired infection in a young child (generally unilateral). Acquired or reactivated infections in older children and adults rarely progress to retinochoroiditis. The inflammatory process persists for weeks to months as focally necrotic retinal lesions (yellow or white patches with blurred margins). Visual defects, which include blurring, central defects, and scotomas, are accompanied by pain and photophobia. Rarely, progression may result in glaucoma and blindness. With healing, white or dark-pigmented scars may result. Panuveitis may accompany retinochoroiditis.

4. Reactivated disease in the immunologically compromised host

Reactivated toxoplasmosis occurs in patients with AIDS, cancer, or those given immunosuppressive drugs. The infection may present in specific organs (brain, lungs, and eye most commonly, but also heart, skin, gastrointestinal tract, and liver) or as disseminated disease. Encephalitis will develop in 30–50% of AIDS patients seropositive for past Toxoplasma infection and 10–30% will die of the infection. Brain lesions include meningitis (uncommon), mass lesions (single or multiple), or diffuse intracerebral Toxoplasma lesions, associated with clinical findings of fever, headache, altered mental status, seizures, and focal (or, infrequently, nonfocal) motor or sensory neurologic deficits (see also Chapter 31).

B. Laboratory Findings

Diagnosis depends principally on serologic tests, which are sensitive and reliable. However, diagnosis is


occasionally made from tissue (blood, bone marrow aspirates, cerebrospinal fluid sediment, sputum, and other tissues or body fluids or placental tissue) either by (1) demonstration of trophozoites or characteristic histology, (2) isolation of the organism in mice (more sensitive) or in tissue culture (more rapid, 3–6 days), or (3) amplification of T gondii DNA by PCR. The latter has become particularly useful through testing of amniotic fluid for congenital infection and testing immunocompromised patients for recrudescence. Detection of circulating antigen or antigen in body fluids is infrequently used and controversial. Interpretation of the results and deciding which patients should be treated or when to advise termination of a pregnancy may require assistance from a reference or research laboratory with large experience in toxoplasmosis.

1. Histology

Cysts or trophozoites may be directly identified in blood (buffy coat from centrifuged heparinized blood), other tissues, or body fluids by staining with standard stains or with specific antibody marked with fluorescein. Demonstration of cysts in biopsied tissue does not establish a causal relationship to clinical illness, since cysts may be found in both acute and chronic infections. However, finding tachyzoites confirms active infection. In the placenta, fetus, or newborn, the presence of cysts does indicate congenital infection.

2. Serologic tests

Parallel testing of serial blood specimens collected 3–4 weeks apart is necessary because a single high titer does not confirm the diagnosis. The Sabin-Feldman dye test, indirect hemagglutination and immunofluorescent (IFA), ELISA, Western blot, PCR, IgG avidity, and other tests can be done on blood, cerebrospinal fluid, aqueous humor, and other body fluids. The dye test is the standard but is rarely used because of laboratory safety factors; though extremely sensitive and specific, it does not separate IgM from IgG antibody. The ELISA, immunosorbent, IFA, and Western blot tests do separate IgM and IgG. IgM antibody appears 1–2 weeks after start of infection, reaches a peak at 6–8 weeks, and then gradually declines over 18 months. However, since IgM antibody can persist at low titers for 5 years or longer, a positive finding does not necessarily represent recent infection; a negative finding does rule out acute infection acquired in recent months. False-positive tests for IgM antibodies are common and therefore the test should be confirmed. IgG antibody appears within 1–2 weeks after onset of infection, peaks in 1–2 months, and may persist at high titers for many years and then at low levels for life. When positive, it reliably indicates present or past infection; a negative result reliably rules out either time frame. IgA antibody appears during the first month, reaches a peak in the second and third months, and then declines. IgM and IgA antibodies, particularly IgA, can be important in diagnosing acute infection because they rarely are found in chronic infection. Normally, maternal IgM and IgA are unable to cross the intact placenta; antibody that does pass through during the birth process has a half-life of 2–4 days for IgM and 10 days for IgA.

The following are selected serologic and other findings in specific toxoplasmosis syndromes.

a. Acute infection in immunocompetent persons

In screening, test initially for IgG antibody, which reliably establishes the presence or absence of infection. In a few patients, antibody may not be detectable within 3 weeks of initial infection; if acute disease is suspected, test again in 3 weeks. The diagnosis is established by seroconversion from negative to positive or by a 16-fold rise in serologic titers by any test. Acute infection can also be diagnosed by detection of tachyzoites in tissue, isolation of organism, or amplification of its DNA in blood or body fluids. The presence of circulating ELISA-IgA also favors the diagnosis of acute infection. A presumptive diagnosis is based on a single IgM titer of over 1:64 and a very high IgG titer (> 1:1000). However, because of the relatively high frequency of false-positive IgM tests, confirmatory testing should always be done, preferably in a reference laboratory.

b. Recrudescent infection in immunosuppressed patients

In AIDS patients, Toxoplasma can sometimes be isolated from the blood. Alternatively, definitive diagnosis is by finding Toxoplasma organisms in cerebrospinal fluid (Wright-Giemsa stain or by PCR amplification) or by brain biopsy. To avoid the latter, empiric antibiotic treatment is generally started after presumptive evidence is obtained by MRI (the more sensitive test) or CT scan (typically: multiple, isodense or hypodense, ring-enhancing mass lesions). Single-photon emission CT is under evaluation as a highly specific diagnostic method. Antibody titers cannot be depended on, since most patients have IgG titers that reflect past infection, significant rises are infrequent, and IgM antibody is rare. Absence of IgG does not rule out the diagnosis of toxoplasmic retinochoroiditis or encephalitis. The cerebrospinal fluid may show mild pleocytosis (predominantly lymphocytes and monocytes), elevated protein, and normal glucose. (See also Chapter 31.)

c. Toxoplasmic retinochoroiditis

This is usually associated with stable, usually low IgG titers and no IgM antibody. If IgG antibody in aqueous humor is higher than in the serum, the diagnosis is supported.

3. Other laboratory findings

Leukocyte counts are normal or reduced, often with lymphocytosis or monocytosis with rare atypical cells, but there is no heterophil antibody. Chest radiographs may show interstitial pneumonia. In cerebral imaging studies in HIV-infected persons, toxoplasmosis typically appears as multiple lesions with a predilection for the basal ganglion.

Differential Diagnosis

In acute febrile disease, consider cytomegalovirus infection, infectious mononucleosis, and other causes


of pneumonitis, myocarditis, myositis, hepatitis, and splenomegaly. With lymphadenopathy, possibilities include sarcoidosis, tuberculosis, tularemia, lymphoma, cat-scratch disease, and metastatic carcinoma. With brain lesions in the immunosuppressed host, consider lymphoma, tuberculoma, brain abscess, metastatic carcinoma, and fungal lesions.


A. Approach to Treatment

In immunocompetent hosts, the lymphadenopathic form of the disease is usually not treated unless findings are severe or persistent or there is overt visceral disease. If treatment is started, it should continue for 3–4 weeks and the patient reevaluated. Serologic tests are not useful for evaluating response to treatment.

Since most episodes of retinochoroiditis are self-limited, opinions vary on indications for, type of, and the practical benefits of treatment. (See specialized texts.)

Immunocompromised patients with active infection (primary or recrudescent) must be treated. See Chapter 31 for details. Therapy should continue for 4–6 weeks after cessation of symptoms, which may require up to a 6-month course, to be followed by drug prophylaxis as long as immunosuppression persists. In HIV-infected persons, acute toxoplasmosis must be treated followed by continued prophylaxis; in patients who have a positive IgG Toxoplasma serology but are asymptomatic, prophylaxis is desirable.

For details on management of maternal infection and congenitally infected newborns, see specialized sources.

B. Choice of Drugs

The treatment of choice in nonimmunocompromised patients is pyrimethamine, 25–100 mg orally once daily, plus sulfadiazine, 1–1.5 g orally four times daily; continue this treatment for 3–4 weeks. Add folic acid at a dosage of 10–15 mg/d to prevent bone marrow suppression. Patients should be screened for a history of sulfonamide sensitivity (skin rashes, gastrointestinal symptoms, hepatotoxicity). To prevent crystal-induced nephrotoxicity, good urinary output should be maintained; alkalinization with sodium bicarbonate may also be useful. Pyrimethamine side effects include headache and gastrointestinal symptoms. Platelet and white blood cell counts should be performed at least twice weekly. Clindamycin (600 mg orally four times daily) may be a useful alternative drug because it concentrates in the choroid. Atovaquone (750 mg orally three or four times daily), azithromycin (1200–1500 mg orally), dapsone, other macrolides, and immunotherapy are under evaluation.

For the treatment of central nervous system toxoplasmosis in HIV-infected and immunocompromised persons, see Chapter 31.


Irradiated meat or meat cooked to 66°C kills cysts in tissues; freezing meat decreases infectivity but does not eliminate it. Hands, kitchen surfaces, and cooking utensils must be thoroughly cleaned with soap and water after contact with raw meat. Under appropriate environmental conditions, oocysts passed in cat feces can remain infective for a year or more. Thus, children's play areas, including sandboxes, should be protected from cat (and dog) feces; hand washing is indicated after contact with soil potentially contaminated by animal feces. Indoor cats should be fed only dry, canned, or cooked meat. Litter boxes should be changed daily and scalded, as freshly deposited oocysts are not infective for 48 hours.

Although universal screening is conducted in some countries, authorities in the United States generally do not consider it warranted because of low prevalence. Pregnant women should have their serum examined for Toxoplasma IgG and IgM antibody. If the IgM test is negative but an IgG titer is present and less than 1:1000, no further evaluation is necessary. Those with negative titers should take measures to prevent infection—preferably by having no further contact with cats and cat litter, by thoroughly cooking meat (66°C/150°F), and by hand washing after handling raw meat and before eating. Gloves should be worn when gardening; fruits and vegetables should be thoroughly washed; ingestion of dried meat should be avoided. For seronegative women who continue to have significant environmental exposure, serologic screening should be conducted several times during pregnancy.


The outlook for acute toxoplasmosis in adults is excellent as long as the patient is immunocompetent. In immunosuppressed patients, the disease is usually fatal if untreated; improvement results if treatment is started early, but recrudescence is common. Chronic asymptomatic infection is usually benign.


*Not available in the United States.

Available in the United States but approved for antimalarial use only as the combination drug atovaquone/proguanil (Malarone).

Cold CJ et al: Diagnosis—disseminated toxoplasmosis. Clin Med Res 2005;3:186.

Collazos J: Opportunistic infections of the CNS in patients with AIDS: diagnosis and management. CNS Drugs 2003;17: 869.

Lopez A et al: Preventing congenital toxoplasmosis. MMWR Recomm Rep 2000;49:59.

Montoya JG et al: Diagnosis and management of toxoplasmosis. Clin Perinatol 2005;32:705.

Montoya JG et al: Toxoplasmosis. Lancet 2004;363:1965.

Remington JS et al: Recent developments for diagnosis of toxoplasmosis. J Clin Microbiol 2004;42:941.

Stanford MR et al: Antibiotics for toxoplasmic retinochoroiditis: an evidence-based systematic review. Ophthalmology 2003;110:926.


Helminthic Infections

Trematode (Fluke) Infections

Schistosomiasis (Bilharziasis)

Essentials of Diagnosis

  • History of fresh water exposure in an endemic area.

  • Acute phase: Abrupt onset (2–8 weeks postexposure) of abdominal pain, weight loss, headache, malaise, chills, fever, urticaria, myalgia, diarrhea (sometimes bloody), dry cough, hepatomegaly, and eosinophilia.

  • Chronic phase: Either (1) diarrhea, abdominal pain, blood in stool, hepatomegaly or hepatosplenomegaly, and bleeding from esophageal varices (Schistosoma mansoni or Schistosoma japonicum infection); or (2) terminal hematuria, urinary frequency, urethral and bladder pain, and pyelitis (Schistosoma haematobium infection).

  • Depending on species, characteristic eggs in feces, urine, or scrapings or biopsy of rectal or bladder mucosa; positive serology.

General Considerations

Schistosomiasis, which infects more than 200 million persons worldwide, induces severe consequences in 20 million persons annually, resulting in over 200,000 deaths. The disease is caused mainly by three blood flukes (trematodes). Schistosoma mansoni, which causes intestinal schistosomiasis, is widespread in Africa and occurs in the Arabian peninsula, South America (Brazil, Venezuela, Suriname), and the Caribbean (including Puerto Rico but not Cuba). Vesical (urinary) schistosomiasis, caused by Schistosoma haematobium, is found throughout the Middle East and Africa. Asiatic intestinal schistosomiasis, due to Schistosoma japonicum, is important in China and the Philippines, and a small focus is present in Sulawesi, Indonesia, but transmission in Japan has been interrupted. A number of schistosome species of animals sometimes infect humans, including Schistosoma intercalatum in central Africa and Schistosoma mekongi in the Mekong delta in Thailand, Cambodia, and Laos. In the United States, an estimated 400,000 immigrants are infected, but transmission does not occur because appropriate snail intermediate hosts are absent.

Mammals are important reservoirs for S japonicum. Humans are the main reservoir for S mansoni and S haematobium; the few animal species infected with S mansoni are not epidemiologically important.

In the life cycle involving humans, the adult worms live in terminal venules of the bowel (S mansoni, S japonicum, S intercalatum, S mekongi) or bladder (S haematobium). When eggs passed in feces or urine reach fresh water, a larval form is released that subsequently infects snails, the intermediate host. After development, infective larvae (cercariae) leave the snails, enter water, and infect exposed persons through the skin or mucous membranes. After penetration, the cercariae become schistosomula larvae that reach the portal circulation in the liver, where they rapidly mature. After a few weeks, adult worms pair, mate, and migrate mainly to terminal venules of specific veins, where females deposit their eggs. By means of lytic secretions, some eggs reach the lumen of the bowel or bladder and are passed with feces or urine. Others are retained in the bowel or bladder wall, while still others are carried in the circulation to the liver, lung, and (less often) to other tissues.

Except for the allergic response in the acute syndrome (see below), disease is primarily due to delayed hypersensitivity. Antigens released by the eggs stimulate a local T cell-dependent granulomatous response, followed by a strong fibrotic reaction. Live worms, however, produce no lesions and rarely cause symptoms. The type or degree of tissue damage and symptoms varies with the intensity of infection (worm burden), host genetic factors, site of egg deposition, concurrent infection (eg, hepatitis B), and duration of infection.

S mansoni adults migrate to the inferior mesenteric veins of the large bowel and S japonicum to the superior and inferior mesenteric veins in the large and small bowel. Ulcers and polyps (common only in Egypt) result from granuloma formation and fibrosis in the bowel wall. Egg accumulation in the liver may result in periportal fibrosis and portal hypertension of the presinusoidal type, but liver function typically remains intact even in advanced disease. Portal-systemic collateralization due to portal hypertension can result in embolization of eggs to the lungs, with subsequent endarteritis, pulmonary hypertension, and cor pulmonale. Because greater numbers of eggs are produced by S japonicum, the resulting disease is often more severe.

Adult S haematobium mature in the venous plexus of the bladder, ureters, rectum, prostate, and uterus. Ulcers and polyps result from granuloma formation and fibrosis in the bladder wall, and eggshell remnants may calcify. Stricture or distortion of the ureteral orifices or terminal ureters may result in hydroureter, hydronephrosis, and ascending infection. Lesions in the pelvic organs rarely progress to extensive fibrosis and infection. Eggs are carried to the liver or lungs, but severe pathologic changes in these organs are less frequent than in S mansoni and S japonicum infections.

In size, adult S mansoni are 6–13 × 1 mm. The prepatent period—from cercarial penetration until appearance of eggs in feces—is about 50 days. The life span of the worms ranges from 5 to 30 years or more.


Clinical Findings

A. Symptoms and Signs

Although a large proportion of infected persons have light infections (< 100 eggs per gram of feces) and are asymptomatic, an estimated 50–60% have symptoms and 5–10% have advanced organ damage. In children, schistosomal infections may contribute to decreased nutritional status and growth retardation. Persons with concomitant AIDS and schistosomiasis should be treated for the latter infection. Some evidence shows that in coinfections, responsiveness to schistosomiasis treatment is reduced and susceptibility to schistosomiasis reinfection is increased.

1. Cercarial dermatitis

Following cercarial penetration, clinical findings progress from a localized itchy erythematous or petechial rash to macules and papules that last 2–6 days. Most cases occur in fresh or marine water (worldwide) and are due to skin invasion by bird schistosome cercariae, parasites that do not mature in humans and do not cause systemic symptoms. The syndrome is uncommon with human schistosome infections.

2. Acute schistosomiasis (Katayama syndrome)

This syndrome, primarily an allergic response to the developing schistosomes, may occur with the three schistosomes (rare with S haematobium). The syndrome is usually not seen in natives but does occur in travelers, especially to Africa. The incubation period is 2–8 weeks, with serology becoming positive some weeks later followed by ova appearing in the stools. The severity of illness ranges from mild to (rarely) life-threatening, when use of corticosteroid treatment can be considered. In addition to fever, malaise, urticaria, diarrhea (sometimes bloody), myalgia, dry cough, leukocytosis, and marked eosinophilia, the liver and spleen may be temporarily enlarged. Pulmonary infiltrates and prostration may be present. The patient again becomes asymptomatic in 2–8 weeks.

3. Chronic schistosomiasis

This stage begins 6 months to several years after infection. In S mansoni and S japonicum infections, findings include diarrhea, abdominal pain, irregular bowel movements, blood in the stool, a hard enlarged liver, and splenomegaly. With subsequent slow progression over 5–15 years or longer, the following may appear: anorexia, weight loss, weakness, polypoid intestinal tumors, and features of portal and pulmonary hypertension. Immune complex glomerulonephritis may also occur.

In S haematobium infection, early symptoms of urinary tract disease are frequency and dysuria, followed by terminal hematuria and proteinuria. Frank hematuria may be recurrent. Sequelae may include bladder polyp formation, cystitis, chronic salmonella infection, pyelitis, pyelonephritis, urolithiasis, hydronephrosis due to ureteral obstruction, renal failure, and death. Severe liver, lung, genital, or neurologic disease is rare. Squamous cell bladder cancer has been associated with vesicular schistosomiasis.

4. Other complications

Portal hypertension may result in a contracted liver, splenomegaly, pancytopenia, esophageal varices, and variceal bleeding. Abnormal liver function, jaundice, ascites, and hepatic coma are end-stage findings. Pulmonary hypertension with cor pulmonale and edema due to right heart failure may supervene. Large bowel complications include stricture, granulomatous masses, and persistent salmonella infection; colonic polyposis is manifested by bloody diarrhea, anemia, hypoalbuminemia, and clubbing. Central nervous system lesions, transverse myelitis, or optic neuritis may result from egg metastasis or ectopic worms.

B. Laboratory Findings

Screening and diagnosis require testing for eggs in feces and urine (which may be irregular in excretion and require repeated testing), for occult blood in feces and urine, for protein and leukocytes in urine, and serology. Ova collected in fresh, nonpreserved specimens should be examined for internal detail (flame cell activity or miracidial movement) or by the hatching test to determine that some are alive and that the infection therefore warrants treatment.

1. Eggs

Definitive diagnosis is by finding characteristic live eggs in excreta or mucosal biopsy.

In S haematobium infection, eggs may be found in the urine or, less frequently, in the stools. Eggs are sought in urine specimens collected between 9 am and 2 pm or in 24-hour collections. They are processed either by examination of the sediment or preferably by membrane filtration. Occasionally, eggs are sought by vesical mucosa biopsy.

In S mansoni and S japonicum infections, eggs may be found in stool specimens by direct examination, but some form of concentration is usually necessary; the Kato-Katz quantitative method is preferred over formal ether concentration. One stool examination can reach 70% sensitivity and four, 92%. If results are negative, rectal mucosal biopsy of inflamed or granulomatous lesions or random biopsy specimens at two or three sites of normal mucosa may yield the diagnosis. Biopsy specimens should be examined both as crush preparations between two glass slides and histologically. If eggs are found, a quantitative test should be done after collecting a 24-hour urine or stool; heavy infections are those with counts over 400 eggs per gram.

2. Serologic tests

ELISA, immunoblot, and other tests are used in screening and may detect some egg-negative or ectopic infections. Deficiencies of the tests are that they are commonly negative early in infection and, as they remain positive for long periods of time, do not distinguish active from past infection. The Centers for Disease Control and Prevention uses a “fast ELISA” for screening (specificity 99%; sensitivity varies by parasite: S mansoni [99%], S haematobium [95%], S japonicum [> 50%]) and a Western blot (specificity [96%]) for confirmation and speciation.


Positive tests do not correlate with worm burden. Accumulating research evidence supports the view that detection of antigen in blood and urine is sensitive, correlates with intensity of infection, and can distinguish old from new infection—and that loss of circulating antigen 5–10 days after treatment is indicative of cure. Skin testing is no longer recommended.

3. Other tests

Anemia is common. Eosinophilia, common during the acute stage, usually is absent in the chronic stage. In S mansoni and S japonicum infections, barium swallow, esophagoscopy, barium enema or colonoscopy, chest x-ray, or an ECG may be indicated. Ultrasound examination of the liver may show the pathognomonic pattern of periportal fibrosis and replaces the need for liver biopsy. The clinical settings in which ultrasonography is most useful are (1) evaluation of portal hypertension, (2) distinguishing schistosomiasis from cirrhosis, and (3) documenting regression of lesions following treatment; in early infections, however, findings are inconsistently present.

In S haematobium infection, occult hematuria can often be detected either microscopically or by reagent strip test, particularly if the first portion of the urine specimen is evaluated. In advanced disease, cystoscopy may show “sandy patches,” ulcers, and areas of squamous metaplasia; lower abdominal plain films may show calcification of the bladder wall or ureters. Sonography is considered the imaging technique of choice but may fail to show the calcification. CT—which may demonstrate pathognomonic “turtleback” calcifications—intravenous pyelography, and retrograde cystography and pyelography may be useful. Up to 20% of the time, S mansoni eggs are found in the urine.

Differential Diagnosis

Early intestinal schistosomiasis may be mistaken for amebiasis, bacillary dysentery, or other causes of diarrhea and dysentery. Later, malignancy or the various causes of portal hypertension or of bowel polyps must be considered. In endemic areas, vesical schistosomiasis must be differentiated from other causes of urinary symptoms such as genitourinary tract cancer, bacterial infections of the urinary tract, nephrolithiasis, and the like.


A. Medical Treatment

Treatment should be given only if live ova are identified. The safety and effectiveness of current drugs make it possible to treat all active infections orally, including advanced disease, and without concern for serious side effects. Praziquantel can be used to treat all species; alternative drugs of choice are oxamniquine for S mansoni and metrifonate (withdrawn from the US market) for S haematobium. Praziquantel is active against immature schistosomes during the first 2 days after cercarial penetration and then is inactive for approximately the next 4 weeks. Artemisinin and its derivatives, recently found to be active against the immature and adult forms, are being evaluated for prophylaxis, treatment of early infection, and cotreatment with praziquantel. Instances of decreased sensitivity and treatment failure of both oxamniquine and praziquantel have been recognized in some localities. Schistosomal spinal cord infection has been successfully treated with combined praziquantel and corticosteroids.

After treatment, periodic laboratory follow-up for continued passage of eggs is essential, starting at 3 months and continuing at intervals for 1 year; if found, viability should be determined, since dead eggs are passed for some months. No specific treatment is indicated for bird cercarial dermatitis, except for topical applications to relieve itching.

1. Praziquantel

Cure rates of 63–85% and higher are achieved at 6 months for S haematobium, S mansoni, and S japonicum infections, with marked reduction in egg counts (> 90%) in those not cured.

The praziquantel dosage is 20 mg/kg orally—give twice in 1 day for S haematobium and S mansoni and three times in 1 day for S japonicum and S mekongi. The dosages should be given at 4- to 6-hour intervals with a meal; the tablets should not be chewed.

Mild and transient side effects persisting for hours to 1 day are common and include malaise, headache, dizziness, and anorexia. Less frequent are fatigue, drowsiness, nausea, vomiting, generalized abdominal pain, loose stools, pruritus, urticaria, arthralgia and myalgia, and low-grade fever. Minimal elevations of liver enzymes have occasionally been reported. Because of drug-induced dizziness, patients should not drive and should be cautioned if their work requires physical coordination or alertness. WHO has recommended using praziquantel in pregnancy. In areas where cysticercosis may coexist with a schistosomal infection being treated with praziquantel, treatment is best conducted in a hospital to monitor for death of cysticerci, which may be followed by neurologic complications. Recently reported for praziquantel are comutagenic effects with several mutagens and carcinogens; the authors conclude that the import of these findings needs further study.

2. Oxamniquine

Oxamniquine, not available in the United States, is highly effective only in S mansoni infections. For strains in the western hemisphere and western Africa, a dose of 15 mg/kg orally is given once. Some experts recommend 40–60 mg/kg/d in two or three divided doses for 2–3 days in all of Africa and in the Arabian peninsula. The drug is administered with food; when divided doses are needed, they are separated by 6–8 hours. Cure rates are 70–95%, with marked reduction in egg counts in those not cured. Side effects occur within hours: dizziness is most common; less frequent are drowsiness, nausea and vomiting, diarrhea, abdominal pain, and headache. An orange or red discoloration of the urine may occur. Rarely reported is central nervous system stimulation with behavioral changes, hallucinations, or seizures;


patients should be observed for 2 hours after ingestion of the drug for appearance of these findings. Since the drug makes some patients dizzy or drowsy, it should be used with caution in patients whose work or activity requires mental alertness. Instances of parasite resistance to the drug have been reported. Because the drug has shown mutagenic and embryotoxic effects, it is contraindicated in pregnancy.

B. Surgical Measures

In selected instances, surgery may be indicated for removal of polyps and for obstructive uropathy. For bleeding esophageal varices, sclerotherapy is the treatment of choice; whether some patients may benefit from propranolol treatment is under evaluation. As a last resort in patients who have repeated bleeding, shunting procedures (esophagogastric devascularization with splenectomy or distal—but not proximal—splenorenal shunt) are used, though their effectiveness and relative usefulness are not well established. Severe pancytopenia is an indication for splenectomy.


Travelers to endemic areas should avoid swimming and other fresh water exposure. Use of topical agents to prevent cercarial penetration or oral prophylaxis has not been established.


With treatment, the prognosis is excellent in early and light infections. There may be shrinkage or elimination of bladder and bowel ulcerations, granulomas, and polyps and reduction in fibrosis by sonography. In advanced disease with extensive involvement of the intestines, liver, bladder, or other organs, the outlook is poor even with treatment. In endemic areas, mass treatment of children diminishes the risk of developing severely diseased organs, even though reinfection may occur.

Da Silva LC et al: Schistosomiasis mansoni—clinical features. Gastroenterol Hepatol 2005;28:30.

Inyang-Etoh PC et al: Efficacy of artesunate in the treatment of urinary schistosomiasis, in an endemic community in Nigeria. Ann Trop Med Parasitol 2004;98:491.

Laosebikan AO et al: Schistosomal portal hypertension. J Am Coll Surg 2005;200:795.

Utzinger J et al: Schistosomiasis and soil-transmitted helminthiasis: common drugs for treatment and control. Expert Opin Pharmacother 2004;5:263.

Vennervald BJ et al: Morbidity in schistosomiasis: an update. Curr Opin Infect Dis 2004;17:439.


The large intestinal fluke, Fasciolopsis buski, is a common parasite of humans and pigs in central and southern China, Taiwan, Southeast Asia, Indonesia, eastern India, and Bangladesh. When eggs shed in stools reach water, they hatch to produce free-swimming larvae that penetrate and develop in the flesh of snails. Cercariae subsequently escape from the snails and encyst on various water plants. Humans are infected by eating these plants uncooked (usually water chestnuts, bamboo shoots, or caltrops). Adult flukes (length 2–7.5 cm) mature in about 3 months and live in the small intestine attached to the mucosa or buried in mucous secretions. The number of parasites ranges from a few to several thousand.

After an incubation period of 2–3 months, manifestations of gastrointestinal irritation appear in all but light infections. Symptoms in severe infections include nausea, anorexia, upper abdominal pain, and diarrhea, sometimes alternating with constipation. Ascites and edema of the face and lower extremities may occur later; the physiologic mechanism is not understood. Intestinal obstruction, ileus, cachexia, and extreme prostration have been described.

Diagnosis depends on finding characteristic eggs or, occasionally, flukes in the stools. Leukocytosis with moderate eosinophilia is common. No serologic test is available. Because the adult worms live for only 6 months, absence from the endemic area for a longer period makes the diagnosis unlikely.

The drug of first choice is praziquantel, 25 mg/kg three times in 1 day only. The alternative drug is niclosamide (not available in the United States), administered as for taeniasis but given every other day for three doses.

In light infections—even without treatment—the prognosis is good; generally, spontaneous cure occurs within 1 year. In rare cases—particularly in children—heavy infections with severe toxemia have resulted in death from cachexia or intercurrent infection.

Many other human intestinal fluke infections include Metagonimus yokogawai (Far East and Indonesia), Heterophyes heterophyes (Middle East and Sudan), and Nanophyetus salmincola (California); these infections are treated with praziquantel 25 mg/kg three times in 1 day.

Le TH et al: Case report: unusual presentation of Fasciolopsis buski in a Vietnamese child. Trans R Soc Trop Med Hyg 2004;98:193.


Infection by Fasciola hepatica, the sheep liver fluke, results from ingestion of encysted metacercariae on watercress or other aquatic vegetables or in water. A wide range of herbivorous mammals are reservoir hosts. The disease in humans probably occurs worldwide but is most prevalent in sheep-raising countries, particularly where raw salads are eaten. The infection has been reported from Europe; mainland United States; Hawaii; the West Indies; the Middle East; China; Siberia; and North, East, and South Africa. Eggs of the worm, passed in host feces into fresh water, release a miracidium that infects snails; the snails subsequently release


cercariae that in turn encyst as metacercariae on vegetation (some cercariae become metacercariae directly in the water) to complete their life cycle. The adult flukes are leaf-shaped and measure 3 × 1.5 cm.

In humans, metacercariae excyst, penetrate and migrate through the liver, and mature in the bile ducts, where they cause local parenchymal necrosis and abscess formation. Although the infection is usually mild, three clinical syndromes can develop: acute, chronic latent, and chronic obstructive. The acute illness, associated with migration of immature larvae through the liver, shows an enlarged and tender liver, high fever, leukocytosis, and marked eosinophilia (to 90%). Pain may be present in the epigastrium or right upper quadrant or referred to a shoulder, and the patient may experience headache, anorexia, vomiting, myalgia, urticaria, and other allergic reactions. Jaundice, cachexia, and prostration may appear in severe illness. Anemia and hypergammaglobulinemia are common; other liver function tests may be abnormal. Early diagnosis is difficult in the acute phase because eggs are not found in the feces for 3–4 months. The chronic latent phase may be asymptomatic or characterized by hepatomegaly and other acute findings. The chronic obstructive phase takes place if the extrahepatic bile ducts are occluded, producing a clinical picture similar to that of sclerosing cholangitis, biliary cirrhosis, or choledocholithiasis. Occasionally, adult flukes migrate and produce lesions and symptoms in ectopic sites.

Diagnosis is established by detecting characteristic eggs in the feces; repeated examinations may be necessary. Sometimes the diagnosis can only be made by finding eggs in biliary drainage and, in rare instances, only after liver biopsy or at surgical exploration. Exogenous transient fecal carriage can occur as a result of ingestion of egg-containing cow or sheep liver. Hepatobiliary imaging methods, which include ultrasonography and endoscopic retrograde cholangiopancreatography, may show adult parasites in the gallbladder or ducts. Eosinophilia is characteristic, and hypergammaglobulinemia and abnormal liver function tests may be present. Serologic tests are often useful in presumptive diagnosis, particularly in the acute phase (before eggs have appeared) or in ectopic infection. The “fast” ELISA and immunoblot tests are 95–100% sensitive and highly specific, though cross-reactions occur with schistosomiasis. Serum and coproantigen tests are promising. Successful treatment correlates with a decline in antibody titer.

Triclabendazole (Egatin—available in the United States from Novartis Agribusiness), a veterinary fasciolicide, is the drug of choice; 10 mg/kg orally given once with food achieves a cure rate of 80% with an absence of side effects. In severe infection, some workers recommend 20 mg/kg in divided doses for 1 day. The treatment may need to be repeated. Instances of F hepatica resistance to triclabendazole in domestic animals have been reported. Bithionol (given as for paragonimiasis) is the alternative drug of choice; its deficiencies are its long course, failure rates of up to 50%, and frequent adverse reactions. Recent reports indicate some effectiveness for metronidazole (750 mg/d orally in divided doses for 3 weeks), but albendazole usage has shown high failure rates. Results with praziquantel have been variable; generally, it is ineffective even when used for up to 7 days at a dose of 25 mg/kg three times daily. For any of these drugs, the destruction of parasites followed by release of antigen in sensitized patients may evoke symptoms. Bithionol is available in the United States only from the Parasitic Disease Drug Service, Centers for Disease Control and Prevention, Atlanta, GA 30333. In biliary obstruction due to Fasciola, endoscopic biliary sphincterotomy with extraction of the flukes has been effective and safe.

In endemic areas, aquatic plants should not be eaten raw; washing does not destroy the metacercariae, but cooking will. Drinking water must be boiled or purified. Fasciola gigantica may be encountered in Asia and Africa and Metorchis conjuctus in Canada.

Cheung J et al: Biliary fascioliasis. Gastrointest Endosc 2005;61:596.

Saba R et al: Human fascioliasis. Clin Microbiol Infect 2004;10:385.

Sezgin O et al: Hepatobiliary fascioliasis: clinical and radiologic features and endoscopic management. J Clin Gastroenterol 2004;38:285.

Talaie H et al: Randomized trial of a single, double and triple dose of 10 mg/kg of a human formulation of tricladendazole in patients with fascioliasis. Clin Exp Pharmacol Physiol 2004;31:777.

Clonorchiasis & Opisthorchiasis

Infection by Clonorchis sinensis, the Chinese liver fluke, is endemic in areas of Japan, Korea, China, Taiwan, Southeast Asia, and the far eastern part of Russia. Over 20 million people are affected and, in some communities, prevalence can reach over 80%. Opisthorchiasis is caused by worms of the genus Opisthorchis, generally either O felineus (central, eastern, and southern Europe, eastern Asia, Southeast Asia, India) or O viverrini (Thailand, Laos, Vietnam). Clinically and epidemiologically, opisthorchiasis and clonorchiasis are identical.

Certain snails are infected when they ingest eggs shed into water in human or animal feces. Larval forms escape from the snails, penetrate the flesh of various freshwater fish, and encyst as metacercariae. Fish-eating wild and domestic mammals—including dogs, cats, and pigs—and humans maintain the life cycle. Human infection results from eating such fish, either raw or undercooked. Pickling, smoking, or drying may not suffice to kill the metacercariae. In humans, the ingested parasites excyst in the duodenum and ascend the bile ducts into the medium and small biliary radicals, but also into the larger ducts and the gallbladder, where they mature and remain throughout their lives (15–25 years), shedding eggs in the bile. In size, the worms are 7–20 × 1.5–3 mm. In the chronic stage of infection, there is progressive


bile duct thickening, periductal fibrosis, dilation, biliary stasis, and secondary infection. Little fibrosis occurs in the portal tracts.

Most patients harbor few parasites and are asymptomatic. Among symptomatic patients, an acute and chronic syndrome occurs. Acute symptoms follow entry of immature worms into the biliary ducts and may persist for several weeks. Findings include malaise, low-grade fever, an enlarged, tender liver, pain in the hepatic area or epigastrium, urticaria, arthralgia, leukocytosis, eosinophilia, an elevated serum alanine aminotransferase, and jaundice. The acute syndrome is difficult to diagnose, since ova may not appear in the feces until 3–4 weeks after onset of symptoms.

In chronic infections, findings include weakness, anorexia, epigastric pain, diarrhea, prolonged low-grade fever, intermittent episodes of right upper quadrant pain, localized hepatic area tenderness, and progressive hepatomegaly; liver function tests are normal except in severe cases.

Complications include intrahepatic bile duct calculi that may lead to recurrent pyogenic cholangitis, biliary abscess, or endophlebitis of the portal-venous branches. Although focal initially, this may gradually result in destruction of the liver parenchyma, fibrosis and, in a few patients, cirrhosis with jaundice and ascites. Chronic cholecystitis, cholelithiasis, and a nonfunctional, enlarged gallbladder may occur. Flukes may also enter the pancreatic duct, causing acute pancreatitis or cholelithiasis. Cholangiocarcinoma has been causally linked with prolonged clonorchis and opisthorchis infection.

Diagnosis is made by finding characteristic eggs in stools (repeated concentration tests may be necessary) or duodenal aspirate (sensitivity approaches 100%); endoscopic retrograde cholangiopancreatography may be indicated. In severe infection, the number of eggs per gram of feces may not reflect the heavy worm burden. In complete biliary obstruction, eggs can be detected in bile only by needle aspiration or at surgery. In advanced chronic disease, (1) liver function tests will indicate parenchymal damage; (2) CT and sonography may show diffuse dilation of small intrahepatic bile ducts with no or minimal dilation of the large intra- and extrahepatic ducts; and (3) transhepatic cholangiograms may show alternating stricture and dilation of the biliary tree, with worms visualized as filling defects. Where available, of the several evaluated serologic tests, the ELISA is preferred (sensitivity, 77%); however, unless a specific monoclonal antibody is used, cross-reactions are common with other trematode and cestode infections, tuberculosis, and liver cancer. During the chronic stage, leukocytosis varies according to the intensity of infection; eosinophilia may be present.

The drug of choice is praziquantel. With a dosage of 25 mg/kg orally three times daily for 2 days (with a 4- to 6-hour interval between doses), cure rates over 95% can be anticipated for clonorchis infections. One day of treatment may be sufficient for opisthorchis infections. (For side effects, see Schistosomiasis, above.) Albendazole, at a dosage of 400 mg orally twice daily for 7 days, appears to be less effective (cures, 40–65%). In severe disease, treatment may be facilitated by endoscopic nasobiliary drainage plus antiparasitic medication. In relapsing cholangitis, antibiotics are indicated to cover pathogens.

The disease is rarely fatal, but patients with advanced infections and impaired liver function may succumb more readily to other diseases. The prognosis is good for light to moderate infections.

Choi BI et al: Clonorchiasis and cholangiocarcinoma: etiologic relationship and imaging diagnosis. Clin Microbiol Rev 2004;17:540.

Fry LC et al: Sclerosing cholangitis caused by Clonorchis sinensis. Gastrointest Endosc 2002;56:114.

Thomas NE et al: Small-cell carcinoma of the extrahepatic bile duct and concurrent clonorchiasis. Diagn Cytopathol 2005;32:92.

Wang KX et al: Clinical and epidemiological features of patients with clonorchiasis. World J Gastroenterol 2004;10:446.

Zhi FC et al: Treatment of severe Clonorchiasis sinensis by endoscopic nasobiliary drainage and oral praziquantel. World J Gastroenterol 2004;10:21.


Paragonimus westermani, the lung fluke, commonly infects humans (estimated 20 million) throughout the Far East (prevalence in Korea has reached 4%); foci are also present in West Africa, South and Southeast Asia, the Pacific Islands, Indonesia, and New Guinea. Many carnivores and omnivores in addition to humans serve as reservoir hosts for the adult fluke (8–16 × 4–8 × 3–5 mm). About a dozen other paragonimus species also infect humans in China, Japan, Mexico, Central and South America, and Africa. Paragonimus killicotti is found in North America. Most of these parasites, which are not well adapted to humans, produce ectopic lesions in the brain, skin (larva migrans), and other organs but do not mature into adult flukes.

Eggs reaching water, either in sputum or feces, hatch in 3–6 weeks. Released miracidia penetrate and develop in snails. Emergent cercariae encyst as metacercariae in the tissues of crabs and crayfish. Human infection results if metacercariae are ingested when the crustaceans are eaten raw or pickled or food, vessels, drinking water, or fingers become contaminated. The metacercariae excyst in the small intestine and penetrate the peritoneal cavity. Most migrate through the diaphragm and enter the peripheral lung parenchyma; some may lodge in the brain (about 1% of all cases) or at other ectopic sites. In the lungs, the parasite becomes encapsulated by granulomatous fibrous tissue, reaching up to 2 cm in diameter. The lesion, which usually opens into a bronchiole, may subsequently rupture, resulting in expectoration of eggs, blood, and inflammatory cells. Rarely, the eggs may also enter the general circulation and produce ectopic lesions in any


tissue. The prepatent period until appearance of expectorated eggs is about 6 weeks.

In pulmonary infections, most persons have light to moderate worm burdens and are asymptomatic. In symptomatic cases, low-grade fever and dry cough are present initially; subsequently, pleuritic pain is common, and a rusty, blood-flecked, viscous sputum or frank hemoptysis may occur. Following slow progression, complications of bronchitis, bronchiectasis, bronchopneumonia, lung abscess, fibrosis, and pleural thickening or effusion may appear.

Only a minority of patients with cerebral infections present with acute disease, usually manifested by meningitis. In chronic central nervous system disease, seizures, cranial neuropathies, findings of space-occupying lesions, or meningoencephalitis may occur; death can follow. Parasites in the peritoneal cavity or the intestinal wall may cause abdominal pain, diarrhea or dysentery, and a palpable tumor mass. Painless, migratory subcutaneous nodules (a few millimeters to 1 cm in diameter) occur with about 10% of P westermani infections.

Pulmonary disease is diagnosed by finding (1) characteristic eggs in sputum (rusty sputum is nearly pathognomonic), feces, gastric aspirates, bronchoscopic washings, biopsy specimens, or pleural fluid; or (2) adult flukes in subcutaneous nodules or other surgical specimens. If eggs are not found after multiple direct sputum examinations, they may be detectable in a 24-hour sputum collection processed by alkaline sodium hypochlorite concentration. Stool examination for eggs has low sensitivity. Serologic tests are conducted using serum, cerebrospinal fluid, and pleural effusion fluid; the sensitivity and specificity of the ELISA are 99% and 97% and of the immunoblot 96% and 99%. The tests do not differentiate active from prior infection; a newly reported IgM test may do so. Most treated and cured patients become seronegative. Antigen detection assays are promising. Eosinophilia (sometimes to a high level) and low-grade leukocytosis are common. Chest films may show infiltrates, segmental or lobar consolidation, small cysts (5–30 mm), cavitary lesions (1–4 cm), fibrosis, nodules, pleural thickening or effusion, or calcifications. By CT, round, low-attenuation cystic lesions (5–15 mm) filled with fluid or gas are seen within the consolidation.

In acute cerebral disease, CT shows multilocular, ring-like enhancement with surrounding low-density areas. In chronic cerebral disease, plain skull films often show round or oval-shaped calcifications, sometimes surrounded by low-density areas that are highly specific for the disease. Cerebrospinal fluid may be turgid or bloody, with numerous eosinophils, and eggs may be found. The EEG is almost always abnormal. It is rare for cerebral disease to occur in the absence of pulmonary disease.

Paragonimiasis and tuberculosis must be differentiated, though chest x-ray appearance alone does not make the distinction. Since paragonimus ova are destroyed by Ziehl-Neelsen stain for acid-fast bacilli, the sputum should first be examined for the eggs. The presence of a large number of eosinophils or Charcot-Leyden crystals in sputum suggests paragonimiasis.

In pulmonary paragonimiasis, praziquantel is the drug of choice (25 mg/kg orally after meals three times daily for 2 days, with a 4- to 6-hour interval between doses). (For side effects, see above under Schistosomiasis.) In regions where there may be concurrent cysticercosis, praziquantal should not be used. Bithionol is the alternative drug (30–50 mg/kg orally, given on alternate days for 10–15 doses; the daily dose should be divided into a morning and evening dose). Bithionol side effects are frequent but generally mild and transient. Gastrointestinal side effects, particularly diarrhea, occur in most patients. Liver function should be tested serially. Bithionol is available in the United States only from the Parasitic Disease Drug Service, Centers for Disease Control and Prevention, Atlanta, GA 30333. Antibiotics may be necessary for secondary pulmonary infection. Cure rates of over 90% can be anticipated for both praziquantel and bithionol. A second alternative drug for pulmonary disease is triclabendazole, a veterinary fasciolicide, which continues under clinical trials and is available from the manufacturer Novartis. Cure rates reach 91% with a dosage of 10 mg/kg daily for 2 days; if treatment is repeated in 3 months, 100% cure rates have been reported. Drug side effects of dizziness and diarrhea are mild and transient.

In the acute stage of cerebral paragonimiasis, particularly meningitis, praziquantel or bithionol may be effective. With death of parasites, severe local reactions may occur; corticosteroids should therefore be given as in cerebral cysticercosis. In the chronic stage, both surgical removal of the parasites and drug usage are likely to be ineffective in diminishing neurologic symptoms.

Calvopina M et al: Comparison of two single-day regimens of triclabendazole for the treatment of human pulmonary paragonimiasis. Trans R Soc Trop Med Hyg 2003;97:451.

Castilla EA et al: Cavitary mass lesion and recurrent pneumothoraces due to Paragonimus kellicotti infection: North American paragonimiasis. Am J Surg Pathol 2003;27:1157.

Jeon K et al: Clinical features of recently diagnosed pulmonary paragonimiasis in Korea. Chest 2005;128:1423.

Kim TS et al: Pleuropulmonary paragonimiasis: CT findings in 31 patients. AJR Am J Roentgenol 2005;185:616.

Cestode Infections

Tapeworm Infections (See Also Cysticercosis and Echinococcosis, Below)


Six tapeworms infect humans frequently. The large tapeworms are Taenia saginata (the beef tapeworm, up to 25 m in length), Taenia solium (the pork tapeworm, 7 m), and Diphyllobothrium latum (the fish tapeworm, 10 m). A fourth large tapeworm, Taenia asiatica recently


differentiated by DNA methods, has been found in China, the Koreas, Indonesia, and Southeast Asia; although acquired by humans by ingestion of pig viscera, it apparently does not cause cysticercosis. The small tapeworms are Hymenolepis nana (the dwarf tapeworm, 25–40 mm), Hymenolepis diminuta (the rodent tapeworm, 20–60 cm), and Dipylidium caninum (the dog tapeworm, 10–70 cm). Four of the six tapeworms occur worldwide; the pork and fish tapeworms have more limited distribution.

An adult tapeworm consists of a head (scolex), a neck, and a chain of individual segments (proglottids) in which eggs form in mature segments. The scolex is the attachment organ and generally lodges in the upper part of the small intestine.

Multiple infections are the rule for small tapeworms and may occur for D latum; however, it is rare for a person to harbor more than one or two of the taeniae.

A. Beef Tapeworm

The infection occurs in most countries with beef husbandry but is highly endemic in parts of the Far East, central and eastern Africa, and the central Asian area of the former Soviet Union. Gravid segments of T saginata in the human intestine detach themselves from the chain and are passed in feces to soil. When proglottids or eggs are ingested by grazing cattle or other domesticated bovines, the eggs hatch to release embryos that encyst in muscle as cysticerci. Humans are infected by eating raw or undercooked beef containing viable cysticerci, Cysticercus bovis. Humans are the definitive host; in the human intestine, the cysticercus develops into the adult worm.

B. Pork Tapeworm

This tapeworm is particularly prevalent in Mexico, Latin America, the Iberian Peninsula, the Slavic countries, Africa, Southeast Asia, India, and China. In the United States and Canada, cysticercosis in hogs is uncommon and human infection is rare, usually encountered in persons infected abroad. The infection is no longer found in northwestern Europe. The life cycle of T solium is similar to that of T saginata except that pigs ingest human feces containing proglottids and eggs to become the host of the larval stage. Humans, the definitive host, become infected when they eat undercooked pork containing viable Cysticercus cellulosae. Humans are also the intermediate host when they become infected with the larval stage (see Cysticercosis, below) by accidentally ingesting eggs in human feces; the eggs are immediately infectious. Transmission of eggs may occur as a result of autoinfection (hand to mouth), direct person-to-person transfer, ingestion of food or drink contaminated by eggs, or (rarely) regurgitation of proglottids into the stomach.

C. Fish Tapeworm

D latum is found in temperate and subarctic lake regions in many areas of the world, including northern Europe, Canada, Alaska, the Pacific Coast of the United States, Japan, Taiwan, Siberia, Manchuria, Australia, southern South America, and southern Africa. Eggs passed in human feces that reach fresh water are taken up first by crustaceans that in turn are eaten by fish, both of which are intermediate hosts. Human infection results from eating raw or inadequately cooked brackish or freshwater fish, including salmon. Nonhuman reservoir hosts include dogs, bears, and other fish-eating mammals.

D. Dwarf Tapeworm

H nana is the most common cestode. It can reach high prevalence, particularly in children, in regions of the world with poor fecal hygiene and in closed institutions. Humans are the definitive host of the human strain of the parasite; rodent-adapted strains occur in rodents. The life cycle is unusual in that both larval and adult stages are found in the human intestine, internal autoinfection can occur, and generally there is no intermediate host. Transmission usually results from eggs transferred directly from human to human (the eggs are immediately infective) but sometimes involves fomites, water, or food or the swallowing of fleas or beetles infected with the larval stage. H nana infections in children are usually lost spontaneously in adolescence.

E. Rodent Tapeworm

H diminuta is a common parasite of rodents. Many arthropods (eg, rat fleas, beetles, and cockroaches) serve as intermediate hosts. Humans—most commonly young children—are infected by accidentally swallowing the infected arthropods, usually in cereals or stored products.

F. Dog Tapeworm

D caninum infection generally occurs in young children in close association with infected dogs or cats. Transmission results from swallowing the infected intermediate hosts, ie, fleas or lice.

Clinical Findings

A. Symptoms and Signs

1. Large tapeworms

Large tapeworm infections are generally asymptomatic. Occasionally, vague gastrointestinal symptoms (eg, nausea, diarrhea, abdominal pain) and systemic symptoms (eg, fatigue, hunger, dizziness) have been attributed to the infections. Vomiting of proglottid segments or obstruction of the bile duct, pancreatic duct, or appendix is rare.

Some persons (mostly Scandinavian residents) who harbor the fish tapeworm develop a macrocytic megaloblastic anemia accompanied by thrombocytopenia and mild leukopenia. Gastric acidity is normal. The anemia is a result of the worm's competing with the host for vitamin B12. Clinical findings are indistinguishable from those of pernicious anemia and include glossitis, dyspnea,


tachycardia, and neurologic findings (numbness, paresthesias, disturbances of coordination, impairment of vibration and position sense, and dementia).

2. Small tapeworms

Light infections are generally asymptomatic. Heavy infections, particularly with H nana, may cause diarrhea, abdominal pain, anorexia, vomiting, weight loss, and irritability.

B. Laboratory Findings

Infection by a beef or pork tapeworm is often discovered by the patient finding segments in stool, clothing, or bedding. To determine the species, proglottid segments are either flattened between glass slides and examined microscopically for anatomic detail or differentiated by enzyme electrophoresis of glucose phosphate isomerase. Eggs are only infrequently present in stools, but the perianal cellophane tape test, as used to diagnose pinworm, is sometimes useful in detecting T saginata eggs. However, T solium and T saginata eggs look alike and do not permit species differentiation except by specialized methods. Where available, the best method for diagnosing taeniasis and differentiating the species is the ELISA coproantigen test (sensitivity 95% and specificity 99%); it is 2–3 times as sensitive as detection of ova. The test is being evaluated for its ability to confirm cure.

Fish tapeworm is diagnosed by finding characteristic operculated eggs in stool; repeat examinations and concentration may be necessary. Proglottids are occasionally vomited or passed in feces; their internal morphology is diagnostic. The presence of hydrochloric acid in the stomach differentiates tapeworm anemia from pernicious anemia; in both conditions, the Schilling test is abnormal.

H nana and H diminuta infections are diagnosed by finding characteristic eggs in feces; proglottids are usually not seen. D caninum infection is diagnosed by detection of proglottids (the size of melon seeds) in feces or after their active migration through the anus.

Serologic tests are not available for tapeworm infections.


A. Specific Measures

Although niclosamide (not available in the United States) and praziquantel are both drugs of choice for most tapeworm infections, praziquantel is more effective in hymenolepiasis, and some workers consider it to be somewhat more effective in taeniasis. In areas endemic for neurocysticercosis, a dose of praziquantel of 5 mg/kg or higher carries a small risk of activating these lesions. Niclosamide preferably should not be used in pregnancy.

1. T saginata and D latum

Praziquantel in a single oral dose of 10 mg/kg achieves cure rates of about 99%. At this dose, side effects (see under Schistosomiasis, above) are minimal. With a single dose of four tablets (2 g) of niclosamide, cure rates over 90% can be anticipated. The drug is given in the morning before the patient has eaten. The tablets must be chewed thoroughly and swallowed with water. Eating may be resumed in 2 hours. Niclosamide usually produces no side effects.

Pretreatment and posttreatment purges are not used for either drug. The anemia and neurologic manifestations of D latum respond to vitamin B12 as used in treatment of pernicious anemia.

2. T solium

The choice of drugs and methods of treatment are as above. Neither drug kills eggs released from disintegrating segments; therefore, to avoid the theoretical possibility of cysticercosis from hatching eggs, give a moderate purgative 2–3 hours after treatment to rapidly eliminate segments and eggs from the bowel. The patient must be instructed about the need after defecation for careful washing of the hands and perianal area and for safe disposal of feces for 4 days following therapy.

3. H nana

Praziquantel, the drug of choice, produces 95% cure rates with a single 25-mg/kg dose. Niclosamide, the alternative drug, produces cure rates of 75% when given at the above dosage for 5–7 days; some workers repeat the course 5 days later. Another alternative drug is nitazoxanide (500 mg orally for 3 days).

4. H diminuta and D caninum

Treatment is with niclosamide or praziquantel in dosages as for H nana. Cure rates are not established.

B. Follow-Up Care

In treatment of large tapeworm infections, a disintegrating worm is usually passed within 24–48 hours of treatment. Since efforts are not generally made to recover and identify the scolex, cure can be presumed only if regenerated segments have not reappeared 3–5 months later. If it is preferred that parasitic cure be established immediately, the head (scolex) must be found in posttreatment stools; a laxative is given 2 hours after treatment, and stools must be collected in a preservative for 24 hours. To facilitate examination, toilet paper must be disposed of separately.

Prevention & Prognosis

C cellulosae in pork is killed by cooking at 65°C or freezing at -20°C for 12 hours; C bovis in beef at 56°C or -10°C for 5 days. Pickling is not adequate. Because the prognosis is often poor in cerebral cysticercosis (see below), T solium infections must be immediately eradicated.

Dick TA et al: Diphyllobothriasis: update on human cases, foci, patterns and sources of human infections and future considerations. Southeast Asian J Trop Med Public Health 2001;32(Suppl 2):59.

Flisser A et al: Portrait of human tapeworms. J Parasitol 2004;90:914.

Ito A et al: Cysticercosis/taeniasis in Asia and the Pacific. Vector Borne Zoonotic Dis 2004;4:95.


Juan JO et al: Comparative clinical studies of nitazoxanide, albendazole and praziquantel in the treatment of ascariasis, trichuriasis and hymenolepiasis in children from Peru. Trans R Soc Trop Med Hyg 2002;96:193.


Essentials of Diagnosis

  • History of exposure to a person infected with Taenia solium or ingestion of pork contaminated with cysticeri; concomitant or past intestinal tapeworm infection.

  • Seizures, headache, and other findings of a focal space-occupying central nervous system lesion.

  • Subcutaneous or muscular nodules (5–10 mm); calcified lesions on x-rays of soft tissues.

  • Brain imaging shows calcified or uncalcified cysts by CT or MRI; positive serologic tests.

General Considerations

Human cysticercosis is infection by the larval (cysticercus) stage of the pork tapeworm T solium (see above). Worldwide, an estimated 20 million persons are infected with the larval stage; yearly, about 400,000 persons have neurologic symptoms and 50,000 die of the disease. Antibody prevalence rates to 10% are recognized in some endemic areas. The infection is one of the most important causes of seizures in the developing world. In the United States in recent years, hundreds of cases annually have been recognized in immigrants and travelers.

The natural history of the infection is incompletely known. Cysticerci complete their development within 2–4 months after egg ingestion and larval entry and live for months to 20 years. Several factors give rise to symptoms: Initially, a live larva grows within a thin-walled 10–20 mm cyst (the vesicular cyst) but remains minimally antigenic, causes little or no perilesional inflammation, and does not enhance with contrast media on neuroimaging. Attached to the inner wall of the cyst is an invaginated protoscolex with four suckers and a crown of hooks. When host immune response or chemotherapy causes gradual death of the cyst, marked inflammation and pericyst edema can occur, producing a ring-like or nodular area of enhancement with contrast media (the granulomatous or enhancing cyst); concurrent events include cyst enlargement, mechanical compression, increased intracranial pressure, cerebrospinal fluid changes, and sometimes a vasculitis that results in small cerebral infarcts. The immune response is intense in many patients, but some show a remarkable tolerance. Later, as the cyst degenerates over 2–7 years, it may become undetectable with imaging or be replaced by fibrosis with calcification that is detectable; perilesional edema may be present around these foci. Seizures are thought to occur both from parenchymal irritation at sites of active inflammation and from gliosis associated with end-stage calcified lesions.

Locations of cysts in order of frequency are the central nervous system (where cysts at different life cycle stages—live, transitional, dead—may be present at the same time), subcutaneous tissues, striated muscle, vitreous humor of the eye and, rarely, other tissues.

Clinical Findings

A. Symptoms and Signs

1. Neurocysticercosis

In many patients, cysts remain asymptomatic. When symptomatic, the incubation period is highly variable (usually from 1 to 5 years). Almost any neurologic symptoms can occur based on the number and location of cysts; manifestations are due to mass effect, inflammatory response, or obstruction of the brain foramina and ventricular systems.

a. Acute invasive stage (cysticercotic encephalitis)

This rare event, occurring shortly after invasion, results from extensive acute spread of cysticerci to the brain parenchyma. Fever, headache, myalgia, marked eosinophilia, and coma may occur.

b. Parenchymal cysts

Cysticerci can present singly or multiply and may be scattered or in clumps. Findings include epilepsy (focal or generalized), intracranial hypertension (intense headache, vomiting, papilledema, visual loss), sensory defects, movement disorders, and altered mental status. Vasculitis can lead to small- or large-vessel infarcts. Sometimes the neurologic deficits are transient.

c. Subarachnoid space cysts and meningeal cysts

Small to large cysts are generally located in the cortical sulci or basal cisterns. The arachnoid is the principal basal membrane affected. Adhesive arachnoiditis may result in obstructive hydrocephalus, intracranial hypertension, arterial thrombosis leading to transient ischemia or stroke, and cranial nerve dysfunction (most often of the optic nerve).

d. Ventricular cysts

Ventricular cysts (more common in the fourth ventricle) may float freely (usually singly) within the ventricles or cerebral aqueduct or may be attached to the ventricular wall. They are usually asymptomatic but can cause increased intracranial pressure as a result of intermittent or total blockage.

e. Racemose cysts

These are rare aberrant forms that are multiple-branched, nonencysted, and lack a scolex; they present as grape-like irregular clusters and may reach over 10 cm in diameter. They generally are found in the ventricular and basal subarachnoid spaces, where they cause marked adhesive arachnoiditis and often obstructive hydrocephalus.

f. Spinal cord cysts

Cysts can be extraspinal or intraspinal and can cause arachnoiditis (meningitis, radiculopathy) or pressure symptoms.


2. Ophthalmocysticercosis

Usually there is a single cyst, free-floating in the vitreous or under the retina. Presenting symptoms include periorbital pain, scotomas, and progressive deterioration of visual acuity. Findings may include disk hemorrhage and edema, retinal detachment, iridocyclitis, and chorioretinitis. MRI but not CT may assist in diagnosis; immunologic tests are negative.

3. Subcutaneous and striated muscle cysticercosis

Subcutaneous cysts are usually asymptomatic; they present as nodules that tend to appear and disappear, or they may die and calcify and be detected on plain radiographs.

B. Diagnostic Criteria and Laboratory Tests

Definitive diagnosis of neurocysticercosis is (1) by CT or MRI detection of brain or spinal cord cystic lesions that show the scolex (“hole-with-dot”) image; (2) by visualization of the parasite by ophthalmoscopic examination (subretinal or in the anterior chamber); or (3) by finding the parasite in histologic sections of brain or spinal cord tissue (not usually recommended). Ranging from highly suggestive to compatible with the diagnosis are various combinations of other major and minor findings (criteria): (1) lesions on neuroimaging studies, (2) positive immunologic tests with serum or cerebrospinal fluid, (3) resolution of intracranial cystic lesions either spontaneously or after treatment, (4) cysticercosis outside the central nervous system, (5) clinical history, and (6) epidemiologic findings (personal history of a tapeworm, tapeworm in a household contact, travel in an endemic area).

1. Imaging

Plain radiographs of muscle (especially of thigh and calf) may detect oval or linear calcified lesions (4–10 × 2–5 mm). The lesions are usually multiple, sometimes in the hundreds, and the long axes of the cysts are nearly always in the plane of the surrounding muscle fibers. Plain skull films may demonstrate one or more cerebral calcifications (generally 5–10 mm; sometimes 1–2 mm when only the scolex is calcified).

The most useful procedures for examining the skull are imaging initially by nonenhanced CT and then by MRI and enhanced CT. CT patterns include (1) vesicular cysts (viable cysts with no host immune reaction), which are rounded areas of low density with little or no enhancement after contrast medium; (2) colloidal cysts (dead or dying cysts with host immune reaction), which are hypodense or isodense lesions surrounded by edema associated with ring-like or nodular enhancement; and (3) granuloma or calcifications (dead cysts), which are often several millimeters in diameter but variable in size. Signs of increased intracranial pressure and diffuse brain edema may also be seen. A combination of images is often found, owing to different developmental stages. As compared with CT, MRI has superior sensitivity and resolution for vesicular cysts (isodense, similar to cerebrospinal fluid) and for colloidal cysts (hyperdense). However, CT is superior for granulomas and calcifications, the most frequent presentations of cysticercosis, which MRI may miss. The MRI sometimes detects pathognomonic 2- to 4-mm nodules (protoscoleces) within cyst fluid. Intraventricular cysts (isodense) are not seen on noncontrast CT but require intraventricular contrast medium. Recently described are findings of old calcified lesions that show perilesional edema and contrast enhancement at the time of symptom relapse. Spinal cysticercosis is evaluated by CT myelography or MRI.

2. Immunologic tests

With serum, the enzyme-linked immunoelectrotransfer blot (EITB) assay has nearly 100% specificity and 94–98% sensitivity. Both parameters are paradoxically lower, however, when the test is performed on cerebrospinal fluid. However, the test's sensitivity drops to about 30% if only one live cyst is present and is also low in patients with only calcified cysts. Where the EITB assay is not available, the older ELISA has a 63% specificity and 65% sensitivity with serum; the ELISA with cerebrospinal fluid, however, has a high specificity (95%) and sensitivity (87%) for both IgM and IgG antibody. As antibodies persist after cyst death, neither the EITB nor ELISA distinguishes current from past infection, and these tests cannot be used to monitor therapy; however, another ELISA (under study) to detect circulating antigen may do so. It is unknown whether the EITB or ELISA can distinguish between intestinal infection and neurocysticercosis.

3. Other laboratory tests

Cerebrospinal fluid typically shows increased protein, decreased glucose, and a cellular reaction of mainly lymphocytes and eosinophils; eosinophilia that may be over 20% is diagnostically important. Lumbar puncture is contraindicated, however, in case of increased intracerebral pressure. The electroencephalogram may be abnormal. Though the patient usually no longer harbors a tapeworm, all family members should examine their stools over several days for passage of proglottids, and stool specimens should be examined for proglottids and eggs.

Differential Diagnosis

The differential diagnosis includes tuberculoma, primary or metastatic tumor, hydatid disease, vasculitis, chronic fungal disorders, pyogenic brain abscess, toxoplasmosis and other parasitic diseases, and neurosyphilis. CT and MRI findings of cystic lesions without a scolex, single or multiple ring or nodular enhancing lesions, or parenchymal round calcifications may also be found in some of these other diseases.


Treatment should be individualized based on the number and location of cysts and their viability. Medical treatment, which is usually preferable to surgery, is most effective for parenchymal cysts; less effective for intraventricular, subarachnoid, or racemose cysts. When only one or a few live parenchymal cysts are present, the evidence is still insufficient to establish that medical


treatment is preferable to symptomatic management followed by normal death of the parasites. Some clinicians wait 3 months with selected patients to see whether cysts will spontaneously disappear without treatment. Although single enhancing lesions are likely to do well when treated only with anticonvulsants, some experts add albendazole or praziquantel treatment; however, patients with only calcified cysts without enhancement do not need these drugs.

Albendazole and praziquantel are both effective in treatment. Albendazole is preferred because its course of treatment is shorter (1 week) than that of praziquantel (2 weeks); because albendazole is less expensive; and because coadministration of albendazole and a corticosteroid (to treat inflammation) results in increased albendazole absorption, whereas combined use of praziquantel and a corticosteroid greatly decreases plasma levels of praziquantel. Both drugs are given with fatty meals, which increases absorption fourfold to fivefold. Treatment should be conducted in hospital. Between the second and fifth days after starting treatment, increased inflammatory reactions around dying parasites may be manifested by meningismus, headache (analgesics may be sufficient for mild symptoms), vomiting, hyperthermia, mental changes, and convulsions; decompensation with death is very rare. It remains controversial whether to give corticosteroids concomitantly to avoid or diminish this reaction or to use them only if marked symptoms appear or increase. Even when corticosteroids are given prospectively, the inflammatory reaction may occur. Prednisone, 1 mg/kg/d in two or three divided doses, starting 1–2 days before use of the drug and continuing at diminishing doses for about 14 days afterward, is one regimen. The reaction usually subsides in 48–72 hours, but continuing severity may require corticosteroids in higher dosage and mannitol. For patients with seizures, anticonvulsants should be given during drug treatment and probably for an indefinite time afterward. Antiparasitic drug use is controversial for ventricular cysts; for ocular cysts, only surgical resection is used.

Cure rates following treatment (disappearance of cysts and clearing of symptoms) ranged up to 85% for albendazole and 50–60% for praziquantel. Of the remaining patients, many have amelioration of symptoms, including intracranial hypertension and seizures.

A. Medical Measures

1. Albendazole

The dosage is 15 mg/kg in divided doses daily with a fatty meal. The duration of treatment is unsettled. Seven to 14 days may be sufficient for some patients, but a longer course (up to 28 days) is used for some types of infection; it can be repeated as necessary. Up to 3 months of treatment may be needed for ventricular and subarachnoid cysts. For albendazole side effects, see below under Hydatid Disease.

2. Praziquantel

Give 50–100 mg/kg/d orally in three divided doses for 15–30 days. Shorter courses are being tried. Phenytoin, phenobarbital, carbamazepine, cimetidine, and corticosteroids, when administered with praziquantel, reduce serum levels of the latter; high doses of praziquantel have been tried in these circumstances. Ingestion with a high-carbohydrate meal enhances absorption.

B. Other Measures

Seizures are treated with anticonvulsant drugs. Surgery has successfully removed accessible orbital, cisternal, ventricular, cerebral, meningeal, and spinal cord cysts. During the acute phase of cysticercotic encephalitis, if intracranial hypertension is present, mannitol (2 g/kg/d intravenously) and corticosteroids are used but albendazole and praziquantel are withheld. Obstructive hydrocephalus requires ventricular shunting plus a corticosteroid. Subarachnoiditis and vasculitis are treated with albendazole or praziquantel plus a corticosteroid. Albendazole or praziquantel, when used with ocular or spinal medullary lesions, may cause irreversible damage even when corticosteroids are given; therefore, an ophthalmologic examination should always be done in advance of antiparasitic drug treatment.


The fatality rate for untreated neurocysticercosis is about 50%; survival time from onset of symptoms ranges from days to many years. Drug treatment has reduced the mortality rate to about 5–15%. Surgical procedures to relieve intracranial hypertension along with use of corticosteroids to reduce edema improve the prognosis for those not effectively treated with the drugs.


Indiscriminate defecation, free roaming pigs, and ingestion of undercooked pork allow the maintenance of the life cycle and human disease.

Garcia HH et al; Cysticercosis Working Group in Peru: Neurocysticercosis: updated concepts about an old disease. Lancet Neurol 2005;4:653.

Garcia HH et al: New concepts in the diagnosis and management of neurocysticercosis (Taenia solium). Am J Trop Med Hyg 2005;72:3.

Hawk MW et al: Neurocysticercosis: a review. Surg Neurol 2005;63:123.

Nash TE: Human case management and treatment of cysticercosis. Acta Trop 2003;87:61.

Yancey LS et al: Cysticercosis: recent advances in diagnosis and management of neurocysticercosis. Curr Infect Dis Rep 2005;7:39.

Echinococcosis (Hydatid Disease, Hydatidosis)

Human echinococcosis results from parasitism by the larval stage of four Echinococcus species of which E granulosus (cystic hydatid disease) and E multilocularis (alveolar hydatid disease) are the most important. Minor species are the polycystic species E vogeli (polycystic


hydatid disease) and E oligarthrus, both from Central and South America. Echinococcosis is a zoonosis in which humans are an intermediate host of the larval stage of the parasite. The definitive host is a carnivore (all Canidae, except for the lion,) that harbors the adult tapeworm in the small intestine; the carnivore becomes infected by ingesting the larval form in tissue of the intermediate host. The intermediate hosts, chiefly herbivorous mammals but also humans, become infected by ingesting tapeworm eggs passed in carnivore feces. The larval stage is referred to as a hydatid cyst.

1. Cystic Hydatid Disease (Unilocular Hydatid Disease)

Essentials of Diagnosis

  • History of exposure to dogs associated with livestock in a hydatid-endemic region.

  • Avascular cystic tumor of liver, lung, or, infrequently, bone, brain, or other organs as detected by imaging procedures.

  • Symptoms and signs of a space-occupying mass.

  • Positive serologic tests.

General Considerations

Human infection with E granulosus is common throughout southern South America, the Mediterranean littoral and the Middle East, central Asia, China, and East Africa. Endemic foci are in eastern Europe, Russia, Australia, New Zealand, India, and the United Kingdom. In North America, foci with low endemicity have been reported from the western United States and the lower Mississippi valley; higher endemicity occurs in Alaska and northwestern Canada.

The pastoral strain—which is more pathogenic to humans—has a transmission cycle in which dogs are the definitive host, and sheep (usually) but also cattle and other domestic livestock are intermediate hosts. However, the strain in horses, pigs, and camels may be of low or no infectivity for humans. A northern, sylvatic strain is maintained in wolves and wild ungulates (moose and reindeer) and has involved sled-dogs in northern Alaska, Canada, Scandinavia, and Eurasia. In Australia, a sylvatic strain (which overlaps with a sheep-dog cycle) is maintained between dingoes (and feral dogs) and macropod marsupials.

Human infection occurs when eggs passed in dog feces are accidentally swallowed. Liberated embryos penetrate the intestinal mucosa, enter the portal bloodstream, and are carried to the liver where they become one or more hydatid cysts (65% of all cysts). Some larvae reach the lung (25%) and develop into pulmonary hydatids. Infrequently, cysts form in the brain, bones, skeletal muscles, kidneys, spleen, or other tissues. Cysts may occur in multiple organs. Cysts of the sylvatic strain tend to localize in the lungs.

The cyst wall has three layers: an inner germinal layer that gives rise within the cyst to germinal elements, a supporting intermediate layer, and an outer layer produced by the host. In the liver, cysts may increase in size 1–30 mm in diameter per year and become enormous, but symptoms generally do not develop until they reach about 10 cm. Some cysts die spontaneously; others may persist unchanged for years. Part or all of the inner layer of hepatic and splenic cysts may calcify, which does not necessarily mean cyst death. All age groups may be infected and the case-fatality rate is estimated at 2.2%.

Clinical Findings

A. Symptoms and Signs

A liver cyst may remain silent for 10–20 or more years until it becomes large enough to be palpable, to be visible as an abdominal swelling, to produce pressure effects, or (rarely) to produce symptoms due to leakage or rupture. There may be right upper quadrant pain, nausea, and vomiting. The effects of pressure may result in biliary obstruction, with secondary bacterial cholangitis, cirrhosis, and portal hypertension. If a cyst ruptures suddenly, anaphylaxis and death may occur. If fluid and hydatid particles escape slowly, allergic manifestations may result, including a rise in the eosinophil count. Rupture can occur into the pleural, pericardial, or peritoneal space or into the duodenum, colon, or renal pelvis. Dissemination of germinal elements may be followed by the development of multiple secondary cysts. A characteristic clinical syndrome may follow intrabiliary extrusion of cyst contents—jaundice, biliary colic, and urticaria.

Pulmonary cysts cause no symptoms until they leak; become large enough to obstruct a bronchus, causing segmental collapse; or erode into a bronchus with rupture and expectoration of cyst contents. Brain cysts produce symptoms earlier and may cause seizures or symptoms of increased intracranial pressure. Cysts in the bone marrow or spongiosa do not have a host layer, are irregular in shape, erode osseous tissue, and present as pain or as spontaneous fracture. The bones most often affected are the vertebrae; many of these patients develop epidural extension with compression of the spinal cord and paraplegia. Because 20% of patients have multiple cysts, upon diagnosis each patient should be screened for cysts in the liver, spleen, kidneys, lungs, brain, bones, skin, tongue, vitreous, and other tissues.

B. Imaging

Methods of choice for liver and splenic cysts are sonography (best for demonstrating hydatid sand, daughter cysts, and floating membranes) and CT (best for information about location, depth, and calcification).


The MRI is best for detection of central nervous system cysts. Scintillation scan and angiography are rarely used. Cysts may present as solitary lesions with interior echoes or as multilocular cysts with daughter cysts. Nearly pathognomonic is the presence within a hydatid cyst of daughter cysts; they must be distinguished, however, from blood clots within the cavity of a simple cyst. Spotty calcified densities or a calcified cyst wall may be seen in the liver or spleen. Chest films may show an elevated diaphragm. Pulmonary cysts are best detected by chest films (calcification of the wall is rare); CT and MRI can also be done. An intravenous urogram or bone scan may detect cysts at other sites.

C. Laboratory Findings

The immunoblot test, where available, is the test of choice (95% specific and 91% sensitive for liver cysts); the arc 5 test is also highly diagnostic. In both tests, cross-reactions can occur in 5–25% of patients with T solium cysticercosis infections. Several other serologic tests (ELISA and indirect hemagglutination and immunofluorescence) are useful for screening, but both false-negative and false-positive results are common. Persons from whom cysts have been completely removed and carriers of calcified or dead cysts may become seronegative. False-negative tests occur with about 50% of solitary lung cysts, more often with bone cysts, and most often with brain or splenic cysts. Testing for antigen in serum or hydatid cyst fluid is now available but is less sensitive than serum antibody detection. Although hydatid cyst aspiration was contraindicated in the past, ultrasonic percutaneous aspiration followed by injection of a scolicidal agent with the use of oral albendazole is now being increasingly used in diagnosis. Eosinophilia is uncommon except after cyst rupture. The intracutaneous skin test has been abandoned because of poor specificity.

Differential Diagnosis

Noninfected hydatid cysts of the liver need to be differentiated from simple epithelial cysts and bacterial and amebic abscesses. Hydatid cysts in any site may be mistaken for a variety of malignant and nonmalignant tumors and cysts. In the lung, a cyst may be confused with cavitary tuberculosis. Allergic symptoms arising from cyst leakage may resemble those associated with many other diseases.

Treatment & Prevention

Surgery was formerly the definitive approach to therapy but has now been partially supplanted by anthelmintic treatment. Decision-making between the two modes of treatment must take into account current surgical mortality rates (up to 4%), postoperative complications (10–25%), recurrence rates after surgery (2–25%), and cure rates after albendazole treatment of about 30–40%. Other issues are whether the cyst(s) is single or multiple, surgically accessible, likely to rupture, infected, or exerting substantial mass effect. One therapeutic approach is to give a course of albendazole to selected asymptomatic patients whose cysts are small and not in danger of rupture. If, after 6–12 months, the cyst has not disappeared or clearly died, it can then be removed surgically.

A. Surgical Treatment

Operative treatment of liver cysts involves several problems: total removal of all infective components of the cyst, avoiding cyst content spillage, selection of a scolicidal agent to be placed within the cyst, management of communications between the cyst and biliary tract (if present), management of the residual cavity, and minimizing the risk of operation. The main surgical options available for liver cysts are partial hepatic resection, pericystectomy, and cystectomy. Surgery for pulmonary cysts includes extrusion of cysts (Barrett's technique), pericystectomy, and lobectomy. Interoperative use of scolicidal solutions, which include cetrimide (5%), hypertonic saline (20%), silver nitrate (0.5%), ethanol (70–95%), and sodium hypochlorite (3.75%), has come under criticism because of their potential for direct and indirect toxicity (an estimated 20% of cysts are thought to communicate with the biliary tract). Preoperatively, to reduce the risk of recurrence due to spillage, two drugs (taken with meals) are used for 1 month: albendazole, 10 mg/kg/d in two divided doses, and praziquantel, 25 mg/kg/d. Postoperatively, albendazole should be continued for 1 month; the additional use of praziquantel is under evaluation. Pulmonary cysts are treated by surgery plus chemotherapy. The treatment of bone cysts is by combined curettage, lavage, instillation of sterilization substances, and chemotherapy.

B. Drug Treatment

Albendazole is the drug of choice; mebendazole is less effective and is no longer recommended.

1. Albendazole

Albendazole is more readily absorbed than mebendazole; this permits a lower dosage of albendazole to be used, yet its active metabolite, the sulfoxide, reaches effective concentrations in cyst wall and fluid. A current regimen is four tablets (800 mg) daily in divided doses with meals for 3 months; continue for up to 6 months (some clinicians continue for up to 1 year) if there is evidence of a response. In multiple studies, apparent cure (shrinkage or disappearance of cysts) was approximately 30–40%, with substantial reduction in size in another 24%. To be emphasized, however, is that some of these changes result from the natural history of the disease. Relapses occur and should be re-treated, but long-term follow-up results have not been determined. Bone cysts are more refractory and may require a year of treatment. In the 3-month courses, drug side effects include reversible low-grade aminotransferase elevations (15%), leukopenia to 2900/mcL (2%), rare gastrointestinal


symptoms (including pain at cyst sites), dizziness or headache, alopecia, rash, and pruritus. Anaphylaxis has been reported once and eosinophilia rarely, probably related to cyst fluid leakage. Two deaths attributed to long-term albendazole use have been reported. Liver function tests and complete blood counts should be monitored weekly. The drug is contraindicated in pregnancy.

2. Praziquantel

Praziquantel kills protoscoleces within hydatid cysts but does not affect the germinal membrane. The drug is being evaluated as adjunctive therapy with albendazole both preoperatively and postoperatively to protect against cyst spillage.

C. Percutaneous Aspiration, Injection (of a Scolicidal Agent), and Reaspiration (PAIR)

Under ultrasonic guidance, PAIR is indicated in the treatment of accessible cysts in patients who are inoperable or refuse surgery and are not candidates for a chemotherapeutic trial. The procedure is contraindicated for cysts that communicate with the biliary tree, those that are superficially loculated, or those that have thick internal septal divisions. Complications are infection or leakage at the aspiration site followed by an allergic reaction or dissemination of the infection. Several thousand patients have now had the procedure while covered by oral albendazole. One case of anaphylaxis has been reported. Follow-up has not been sufficiently long to permit assessment of therapeutic efficacy or risk of spillage.

D. Prevention

In endemic areas, prevention is by prophylactic treatment of pet dogs with 5 mg/kg of praziquantel at monthly intervals to remove adult tapeworms and by health education to prevent feeding of offal to dogs.


About 15% of untreated patients eventually die because of the disease or its complications.

2. Alveolar Hydatid Disease (Multilocular Hydatid Disease)

Alveolar hydatid disease results from infection by the larval form of E multilocularis and occurs only in the northern hemisphere. The life cycle involves foxes (sometimes wolves) as definitive host and microtine rodents as intermediate host. Domestic dogs and cats can also become infected with the adult tapeworm when they eat infected wild rodents. Human infection is by accidental ingestion of tapeworm eggs passed in fox or dog feces. The disease in humans has been reported in parts of central Europe, much of Siberia, northern Japan, northwestern Canada, and western Alaska. An increase in the fox population in Europe, particularly in urban areas, has been associated with an apparent increase in human cases. Recent information has extended the Old World range southward to Iran and northern India and China. The highest prevalence (15%) has been reported from villages in China. Increasing numbers of cases have been reported from central North America (eleven US states and four Canadian provinces). The primary localization of alveolar cysts is in the liver, where they may extend locally or metastasize to other tissues. The larval mass has poorly defined borders and behaves like a neoplasm; it infiltrates and proliferates indefinitely by exogenous budding of the germinative membrane, producing an alveolus-like pattern of microvesicles. Pulmonary involvement is rare, usually occurring by direct extension from the liver. X-rays show hepatomegaly and characteristic scattered areas of radiolucency often outlined by 2- to 4-mm calcific rings. The serologic tests using affinity-purified antigen (ELISA and Western blot) are usually positive at high titer and differentiate E granulosa from E multilocularis. Treatment is by surgical removal of the entire larval mass when possible, accompanied by drug treatment. Ninety percent of patients with nonresectable masses die within 10 years. Long-term drug therapy (5 years to life) is with albendazole (800 mg/d in divided doses). Preoperative and long-term adjuvant chemotherapy has been associated with a 10-year survival of approximately 80%.

Brunetti E et al: Twenty years of percutaneous treatments for cystic echinococcosis: a preliminary assessment of their use and safety. Parassitologia 2004;46:367.

Kuzucu A et al: Complicated hydatid cysts of the lung: clinical and therapeutic issues. Ann Thorac Surg 2004;77:1200.

Sayek I et al: Cystic hydatid disease: current trends in diagnosis and management. Surg Today 2004;34:987.

Schipper HG et al: Diagnosis and treatment of hepatic echinococcosis: an overview. Scand J Gastroenterol Suppl 2004:50.

Smego RA Jr et al: Treatment options for hepatic cystic echinococcosis. Int J Infect Dis 2005;9:69.

Yaghan R et al: Is fear of anaphylactic shock discouraging surgeons from more widely adopting percutaneous and laparoscopic techniques in the treatment of liver hydatid cyst? Am J Surg 2004;187:533.

Nematode (Roundworm) Infections


Anisakiasis is larval invasion of the stomach or intestinal wall by anisakid nematodes. In the acute form, the infection may mimic surgical abdomen; in the chronic form, mild symptoms may persist for weeks to years.

Definitive hosts are marine mammals, including sea lions, seals, and dolphins. Eggs discharged with feces are ingested by crustaceans, in which larvae develop that are infective for squids, mackerel, herring, cod, halibut, rockfish, salmon, tuna, and other marine fish. In fish, in which infection rates can reach 80%, the larvae pass to the musculature and are able to transfer from fish to fish along the food chain, eventually


reaching a marine mammal, where they mature into the adult stage.

Humans are infected when they ingest larvae in marine fish or squid eaten raw, undercooked, salted, or lightly pickled. Larvae liberated in the stomach attach to or partially penetrate the gastric or intestinal mucosa (small bowel is more common; colon is rare), resulting in localized ulceration, edema, and eosinophilic granuloma formation; eventually, the parasite dies. Rarely, worms are coughed up and expectorated or penetrate the gut wall, enter the peritoneal cavity, and migrate. Most larvae, however, probably fail to cause infection and are passed in feces. Although the larvae sometimes develop to the adult stages, gravid females are not found in humans.

The infection occurs worldwide, but most cases have been reported in Japan and the Netherlands, with a few in the United States, Scandinavia, the Pacific coast of South America, and other fish-eating countries. Regional foods eaten raw such as sashimi in Japan, pickled herring in the Netherlands, and ceviche (seviche) in Latin America are common vehicles of infection.

Clinical Findings

A. Symptoms and Signs

The majority of acute cases present as gastric anisakiasis. Occasionally, acute infection is followed by a chronic course.

1. Acute gastric anisakiasis

Within hours after larval ingestion, the patient experiences nausea, vomiting, and epigastric pain that progressively becomes more severe. Allergic symptoms (urticaria, bronchospasm, angioedema, or anaphylaxis [rare]) can occur; chest pain and hematemesis are rare.

2. Acute intestinal anisakiasis

Within 1–7 days, colicky pain appears in the lower abdomen, often localized at the ileocecal region, accompanied by diarrhea, nausea, vomiting, diffuse abdominal tenderness, and mild fever.

3. Chronic disease

For weeks to several years, symptoms may continue that mimic gastric ulcer, gastritis, gastric tumor, bowel obstruction, or inflammatory bowel disease.

B. Laboratory Findings

Stools may show occult blood, but eggs are not produced. Mild leukocytosis and eosinophilia may be present. ELISA and radioallergosorbent test (RAST) serologic tests may be helpful but are not reliable in chronic disease.

C. Imaging and Endoscopy

In acute infection, gastroscopy is preferred because the larvae sometimes can be seen and removed from the stomach. X-rays of the stomach may show a localized edematous, ulcerated area with an irregularly thickened wall, decreased peristalsis, and rigidity. Double contrast technique may show the threadlike larvae. Small bowel x-rays may show thickened mucosa and segments of stenosis with proximal dilation. Ultrasound examination of gastric and intestinal lesions may also be useful.

In the chronic stage, x-rays and endoscopy of the stomach—but not of the bowel—may be helpful. The diagnosis is often made only at laparotomy with surgical removal of the parasite. A rise in IgE levels is consistent with the diagnosis.

Prevention & Treatment

Prevention is by avoidance of ingestion of raw or incompletely cooked squid or marine fish, especially salmon, rockfish, herring, mackerel and, in Spain, marinated anchovies. Early evisceration of fish is recommended. Larvae within fish may with difficulty be seen as colorless, tightly coiled or spiraled worms in 3-mm whorls or as reddish or pigmented larvae lying open in muscles or viscera. The larvae are killed by temperatures above 60°C or by freezing at -23°C for 7 days or at -35°C for 15 hours. Smoking procedures that do not bring the temperature to 60°C, marinating in vinegar, and salt-curing are not reliable.

There is no drug treatment, although a single report suggests efficacy for albendazole. Except where larvae can be removed by fiberoptic gastroscopy or colonoscopy, treatment of acute and chronic lesions is limited to symptomatic measures; symptoms generally improve in 1–2 weeks. Surgical excision of the worm may be necessary in severe cases.

Daschner A et al: Anisakis simplex: sensitization and clinical allergy. Curr Opin Allergy Clin Immunol 2005;5:281.

Montalto M et al: Anisakis infestation: a case of acute abdomen mimicking Crohn's disease and eosinophilic gastroenteritis. Dig Liver Dis 2005;37:62.

Moore DA et al: Treatment of anisakiasis with albendazole. Lancet 2002;360:54.

Pellegrini M et al: Acute abdomen due to small bowel anisakiasis. Dig Liver Dis 2005;37:65.

Weir E: Sushi, nemotodes and allergies. CMAJ 2005;172:329.


1. Angiostrongyliasis Cantonensis (Eosinophilic Meningoencephalitis)

A nematode of rats, Angiostrongylus cantonensis, is the causative agent of a form of eosinophilic meningoencephalitis. It has been reported from Hawaii and other Pacific islands, Southeast Asia, Japan, China, Taiwan, Hong Kong, Australia, Egypt, Madagascar, Nigeria, Bombay, Cuba, Puerto Rico, Bahamas, Brazil, and New Orleans.

Human infection results from the ingestion of infective larvae contained in uncooked food—either the intermediate mollusk hosts (snails, slugs, planarians),


transport hosts that have ingested mollusks (crabs, shrimp, fish), leafy vegetables contaminated by small mollusks or by mollusk slime, or from raw vegetable juice. Infection can also result from exposure to fingers contaminated during collection or preparation of snails for cooking. Human infection with this larval stage is as an intermediate host. The definitive host is rodents; mollusks become infected by ingesting larvae excreted in rodent feces.

In humans, ingested larvae (0.5 × 0.025 mm) invade the central nervous system, where, during migration, they may cause extensive tissue damage; at their death, a local inflammatory reaction ensues. The usual clinical findings (incubation period, 1–3 weeks) are those of meningoencephalitis, including severe headache, fever, neck stiffness, nausea and vomiting, and multiple neurologic findings, particularly asymmetric transient cranial neuropathies. Worms in the spinal cord may result in sensory abnormalities in the trunk or extremities; worms have also been seen in the eye.

The spinal fluid characteristically shows elevated protein, normal glucose, and eosinophilic pleocytosis (its absence does not exclude the diagnosis). Occasionally, the parasite can be recovered from spinal fluid. Peripheral eosinophilia with a low-grade leukocytosis is common. IgG antibodies can be detected by ELISA and immunoblot testing. CT and MRI may show central nervous system lesions.

The differential diagnosis includes tuberculosis, coccidioidal or aseptic meningitis, syphilis, lymphoma, gnathostomiasis, cysticercosis, paragonimiasis, echinococcosis, and schistosomiasis japonicum.

No specific treatment is available; however, some anthelmintics can be tried: albendazole (400 mg orally twice daily for 7 days), thiabendazole (25 mg/kg orally three times daily for 3 days; this dose may be toxic and need to be reduced), mebendazole (100 mg orally twice daily for 5 days), pyrantel, or ivermectin. Theoretically, parasite deaths may exacerbate central nervous system inflammatory lesions. Symptomatic treatment with analgesics or corticosteroids may be necessary. The illness usually persists for weeks to months, the parasite dies, and the patient then recovers spontaneously, usually without sequelae. However, fatalities have been recorded.

Prevention is by rat control; by cooking of snails, prawns, fish, and crabs for 3–5 minutes or by freezing them (-15°C for 24 hours); and by examining vegetables for mollusks before eating. Washing contaminated vegetables to eliminate larvae contained in mollusk mucus is not always successful.

Jin E et al: MRI findings of eosinophilic myelomeningoencephalitis due to Angiostrongylus cantonensis. Clin Radiol 2005;60:242.

Mentz MB et al: Drug trials for treatment of human angiostrongyliasis. Rev Inst Med Trop Sao Paulo 2003;45:179.

Tsai HC et al: Outbreak of eosinophilic meningitis associated with drinking raw vegetable juice in southern Taiwan. Am J Trop Med Hyg 2004;71:222.

2. Angiostrongyliasis Costaricensis

Angiostrongylus costaricensis, which causes an eosinophilic ileocolitis, has been identified in humans (predominantly children) in Mexico, Central America, Venezuela, Brazil, and the United States (Texas, California). The known geographic range of the parasite in rodents (the definitive host) extends from northern South America to Texas. Infection occurs from ingestion of the larvae in the intermediate host (slugs, snails) or from food contaminated by larvae in slug or snail mucus. In humans, the larvae mature in the mesenteric vessels. The inflammatory response to the combination of adult worms, larvae, and eggs can be severe, resulting in a marked eosinophilic granulomatous reaction and intestinal vasculitis and ischemic necrosis. Most cases involve the ileocecal region, appendix, ascending colon, and regional nodes, but other organs can be affected, including the liver and testes. Findings include fever, right lower quadrant abdominal pain and a mass, leukocytosis, and eosinophilia. Some patients have relapsing symptoms that can continue for months. Bowel complications include perforation, bleeding, incomplete or complete obstruction, and infarction. Neither eggs nor larvae are passed in stool; a latex agglutination serologic test has been devised. The intra-abdominal mass can mimic tumor. There is no specific treatment; albendazole, thiabendazole, or mebendazole can be tried (as above). Operative treatment is frequently necessary.


Essentials of Diagnosis

  • Transient pulmonary phase: Cough, dyspnea, wheezing, urticaria, with eosinophilia and pulmonary infiltrates.

  • Intestinal phase: Vague upper abdominal discomfort; occasional vomiting, abdominal distention.

  • Eggs in stools; worms passed per rectum, nose, or mouth.

General Considerations

Ascaris lumbricoides is the most common of the intestinal helminths. The infection is limited to humans and appears in all age groups, but morbidity is mainly in children. An estimated 1.3 billion people are infected worldwide, and yearly, 12 million acute cases occur with 10,000 deaths. High prevalence wherever there are low standards of hygiene and sanitation (including focally in southeastern United States) or where human feces are used as fertilizer.

Adult worms (20–40 cm × 3–6 mm) live for 1 year or more in the upper small intestine. After fertilization, the female produces enormous numbers of eggs that


pass in feces. Direct transmission between humans does not occur, as the eggs must remain on the soil for 2–3 weeks before they become infective. Thereafter, they can survive for years. Infection occurs through ingestion of mature eggs in fecally contaminated food and drink. The eggs hatch in the small intestine, releasing motile larvae that penetrate the intestinal wall to reach the right heart via the mesenteric venules and lymphatics. From the heart they move to the lung, burrow through the alveolar walls, and migrate up the bronchial tree into the pharynx, down the esophagus, and back to the small intestine. Egg production begins 60–75 days after ingestion of infective eggs.

Clinical Findings

A. Symptoms and Signs

As a result of their migration and induction of hypersensitivity, larvae in the lung cause capillary and alveolar damage, which may result in low-grade fever, nonproductive cough, blood-tinged sputum, wheezing, dyspnea, and substernal pain. There may be urticaria and localized rales. Rarely, larvae lodge ectopically in the brain, kidney, eye, spinal cord, and other sites and may cause symptoms referable to those organs.

Small numbers of adult worms in the intestine usually produce no symptoms. With heavy infection, peptic ulcer-like symptoms or vague preprandial or postprandial abdominal discomfort may be seen. Adult worms may also migrate with heavy infections; they may be coughed up, vomited, or emerge through the nose or anus. They may also force themselves into the common bile duct, pancreatic duct, appendix, diverticula, and other sites, which may lead to cholangitis, cholecystitis, cholelithiasis, pyogenic liver abscess, pancreatitis, or obstructive jaundice. With very heavy infestations, masses of worms may cause intestinal obstruction, volvulus, intussusception, or death. During typhoid fever, worms may penetrate the weakened bowel wall. Rare cases of lung abscess or laryngeal obstruction with suffocation have been described. Moderate to high worm loads, in children, have been associated with reduced nitrogen, fat, and D-xylose absorption and stunting of growth. Periodic treatment of children with albendazole for multiple intestinal parasitism has resulted in improved nutrition.

B. Imaging

During the larval migratory phase, chest radiographs may show transitory, patchy, ill-defined asymmetric infiltrations. Intestinal infection is sometimes established by chance, when radiologic examination of the abdomen (with or without barium) shows the presence of worms. The diagnosis of biliary ascariasis can be made by endoscopic retrograde cholangiopancreatography, which has the therapeutic potential of removing the worms, and by ultrasonography. In intestinal obstruction, plain abdominal films show air-fluid levels and multiple linear images of ascarides in dilated bowel loops; ultrasonography can also demonstrate the dilated bowel and worm mass.

C. Laboratory Findings

During the pulmonary phase, eosinophils may reach 30–50% and remain high for about a month; larvae are occasionally found in sputum. During the intestinal phase, diagnosis usually depends on finding the characteristic eggs in feces. Occasionally, an adult worm spontaneously passed per rectum or orally reveals an unsuspected infection. Serologic tests are not useful; there is no eosinophilia in the intestinal phase.

Differential Diagnosis

Pulmonary ascariasis with eosinophilia must be differentiated from nonparasitic causes (asthma, eosinophilic pneumonia, allergic bronchopulmonary aspergillosis) and parasitic causes (tropical pulmonary eosinophilia, toxocariasis, strongyloidiasis, hookworm, paragonimiasis). Ascaris-induced pancreatitis, appendicitis, and diverticulitis must be differentiated from other causes of inflammation of these tissues. Postprandial dyspepsia may simulate duodenal ulcer, hiatal hernia, gallbladder disease, or pancreatic disease.


Albendazole, pyrantel pamoate, and mebendazole are the treatments of choice. The drugs listed below do not require pretreatment or posttreatment purges. Stools should be rechecked at 2 weeks and patients re-treated until all ascarids are removed. Ascariasis, hookworm, and trichuriasis infections, which often occur together, may be treated simultaneously by albendazole, mebendazole, or oxantel-pyrantel pamoate.

Treatment with these anthelmintics can cause worms to migrate before they die. Because anesthesia stimulates worms to hypermotility, they should be removed in advance in patients undergoing elective surgery. In pregnancy, ascariasis should be treated after the first trimester. Albendazole and mebendazole are contraindicated in pregnancy, but pyrantel and piperazine can be used.

Drug treatment should not be used in the migratory phase. In intestinal obstruction or biliary ascariasis, surgery may be avoided by nasogastric suction followed by a standard dose of an anthelmintic given via the tube. In biliary ascariasis, endoscopic removal of the worm under ultrasonographic guidance is often successful; treatment by injection of a solution of albendazole or piperazine into the common duct followed by systemic treatment has also been effective.

A. Albendazole

In light infections, a single oral dose of albendazole (400 mg) results in cure rates over 95%; in heavy infections, however, a 2- to 3-day course is indicated. Side effects, including migration of ascaris through the nose or mouth, are rare. Albendazole is available in the United States though not approved for this indication.


B. Pyrantel Pamoate

Pyrantel pamoate as a single oral dose of 10 mg base/kg (maximum, 1 g) results in 85–100% cure rates. It may be given before or after meals. Infrequent and mild side effects include vomiting, diarrhea, headache, dizziness, and drowsiness.

C. Mebendazole

Although mebendazole is highly effective when given in a dosage of 100 mg orally twice daily before or after meals for 3 days, a single 500 mg dose or less is often sufficient. Mild gastrointestinal side effects are infrequent.

D. Piperazine

The dosage for piperazine (as the hexahydrate) is 75 mg/kg body weight (maximum, 3.5 g) orally for 2 days in succession, giving the drug orally before or after breakfast. For heavy infestations, treatment should be continued for 4 days in succession or the 2-day course should be repeated after 1 week.

Gastrointestinal symptoms and headache occur occasionally; central nervous system symptoms (temporary ataxia and exacerbation of seizures) are rare. Allergic symptoms have been attributed to piperazine. The drug should not be used for patients with hepatic or renal insufficiency or in those with a history of seizures or chronic neurologic disease.

E. Other Drugs

Using ivermectin, one oral dose (200 mcg/kg) had a cure rate of 78%; with two doses given at a 10-day interval, the cure rate increased to 99%.


The complications caused by wandering adult worms require that all ascaris infections be treated and eradicated.

Heukelbach J et al: Efficacy of ivermectin in a patient population concomitantly infected with intestinal helminths and ectoparasites. Arzneimittelforschung 2004;54:416.

Koumanidou C et al: Sonographic features of intestinal and biliary ascariasis in childhood: case report and review of the literature. Ann Trop Paediatr 2004;24:329.

Parente F et al: An unusual cause of recurrent biliary colics. Dig Liver Dis 2004;36:763.

Schulze SM et al: Acute abdomen secondary to ascaris lumbricoides infestation of the small bowel. Am Surg 2005;71:505.

Sherman SC et al: The CT diagnosis of Ascariasis. J Emerg Med 2005;28:471.

Cutaneous Larva Migrans (Creeping Eruption)

Cutaneous larva migrans, prevalent throughout the tropics and subtropics (including the southeastern and Gulf of Mexico coasts of the United States) is caused by larvae of the dog and cat hookworms, Ancylostoma braziliense and Ancylostoma caninum. Gnathostomiasis, strongyloidiasis, and a number of other animal hookworms can also be causes of parasitic migration in human skin. Moist sandy soil (eg, beaches, children's sand piles) contaminated by dog or cat feces is a common site of infection. The infection is also reported in travelers to tropical beaches, among whom delayed onset beyond several weeks has been described.

At the site of larval entry, particularly on the hands or feet, up to several hundred minute, intensely pruritic erythematous papules appear. Two to 3 days later, serpiginous eruptions appear as the larvae migrate at a rate of several millimeters a day; the parasite lies slightly ahead of the advancing border. The process may continue for weeks; the lesions may become severely pruritic, vesiculate, encrusted, or secondarily infected. Without treatment, the larvae eventually die and are absorbed.

The diagnosis is based on the characteristic appearance of the lesions and the frequent presence of eosinophilia. Biopsy is usually not indicated.

Mild transient cases may not require treatment. For mild cases, thiabendazole, if available, can be applied topically three times daily for 5 or more days as a 15% cream, which can be formulated in a hygroscopic base using crushed 500 mg tablets. For more severe cases, oral treatment is indicated. Highly effective and nearly free of side effects are ivermectin (200 mcg/kg given for 1 or 2 days) or albendazole (400 mg twice daily for 3–5 days or 400 mg daily for 7 days). Thiabendazole, given orally as for strongyloidiasis, is a less satisfactory alternative drug because it has toxic side effects in about one-third of patients. With treatment, progression of the lesions and itching are usually stopped within 48 hours. Antihistamines are helpful in controlling pruritus; an antibiotic topically or orally may be necessary to treat secondary infections.

Brenner MA et al: Cutaneous larva migrans: the creeping eruption. Cutis 2003;72:111.

Caumes E et al: From creeping eruption to hookworm-related cutaneous larva migrans. Lancet Infect Dis 2004;4:659.

Chen TM et al: An unpleasant memento. Am J Med 2005;118:604.

Dracunculiasis (Guinea Worm Disease, Dracunculosis, Dracontiasis)

Dracunculiasis is an infection of connective and subcutaneous tissues by the nematode Dracunculus medinensis. It occurs only in humans and is a major cause of disability. Since the start of the WHO eradication program, the number of infected persons has declined about 99% from an estimated 3.5 million cases. Endemic areas have been the Indian subcontinent; West and Central Africa north of the equator; and Saudi Arabia, Iran, and Yemen. The two remaining endemic foci are southern Sudan and northern Ghana. The disease occurs almost exclusively in isolated rural areas; all ages are affected, and prevalence may reach 60%.


Infection occurs by swallowing water containing the infected intermediate host, the crustacean cyclops (copepods, water fleas). In the stomach, larvae escape from the crustacean and mature in subcutaneous connective tissue. After mating, the male worm dies and the gravid female (60–80 cm × 1.7–2.0 mm) moves to the surface of the body, where its head reaches the dermis and provokes a blister that ruptures on contact with water. Intermittently over 2–3 weeks, whenever the ulcer comes in contact with water, the uterus discharges great numbers of larvae, which are ingested by copepods. Most adult worms are gradually extruded; some worms retract and reemerge; and others die in the tissues, disintegrate, and may provoke a severe inflammatory reaction. Infection does not induce protective immunity.

Clinical Findings

A. Symptoms and Signs

Infection may be at several sites. Patients are asymptomatic during the 9- to 14-month incubation period except in the last 1–2 weeks, when the worm reaches and becomes palpable in the skin and a blister develops around its anterior end. Several hours before the head appears at the skin surface, local erythema, burning, pruritus, and tenderness often develop at the site of emergence. There may also be a 24-hour systemic allergic reaction (pruritus, fever, nausea and vomiting, dyspnea, periorbital edema, and urticaria). After rupture, the tissues surrounding the ulceration frequently become indurated, reddened, and tender. Because most lesions appear on the leg or foot, patients often must give up walking and working for days to several months. Uninfected ulcers heal in 4–6 weeks. The worm rarely reaches ectopic sites.

Secondary infections, including tetanus, are common. Deep “cold” abscesses may result at the sites of dying, nonemergent worms. Ankle and knee joint infections with resultant deformity are common complications.

B. Laboratory Findings

When an emerging adult worm is not visible in the ulcer or under the skin, the diagnosis may be made by detection of larvae in smears from discharging sinuses. Immersion of an ulcer in cold water stimulates larval expulsion. Eosinophilia is usually present. Skin and serologic tests are not useful. Calcified worms can be recognized on radiographs.


All persons in an endemic area should be actively immunized against tetanus.

A. General Measures

The patient should be at bed rest with the affected part elevated. Cleanse the lesion, control secondary infection with topical antibiotics, and change dressings twice daily.

B. Manual Extraction

Traditional extraction of emerging worms by gradually rolling them out a few centimeters each day on a small stick is still useful, especially when done along with chemotherapy and use of aseptic dressings. The process appears to be facilitated by placing the affected part in water several times a day. If the worm is broken during removal, however, secondary infection almost always results, leading to cellulitis, abscess formation, or septicemia.

C. Anthelmintic Therapy

The following drugs have an anti-inflammatory effect but do not kill the adults or the larvae. This effect may alleviate symptoms, reduce duration of infection, facilitate worm removal, or expedite their spontaneous extrusion.

  • Metronidazole, 250 mg orally three times daily for 10 days, causes only minimal toxicity. (See under Amebiasis.)

  • Mebendazole, 400–800 mg orally daily for 6 days, can be tried.

D. Surgical Removal

Preemergent female worms can sometimes be surgically removed intact under local anesthesia if not firmly embedded in deep fascia or around tendons.

Prevention & Control

The disease is prevented by use of only noncontaminated drinking water. This can be accomplished either by (1) preventing contamination of community water supplies through use of tube wells, hand pumps, or cisterns or treating water sources with the larvicide temephos; or (2) filtering water through finely woven cloth (eg, nylon nets of 100-mcm pore size); or (3) boiling water.

Centers for Disease Control and Prevention (CDC): Progress toward global eradication of dracunculiasis, January 2004-July 2005. MMWR Morb Mortal Wkly Rep 2005;54:1075.

Greenaway C: Dracunculiasis (guinea worm disease). CMAJ 2004;170:495.

Enterobiasis (Pinworm Infection)

Essentials of Diagnosis

  • Nocturnal perianal and vulvar pruritus, insomnia, irritability, restlessness.

  • Vague gastrointestinal symptoms.

  • Eggs demonstrable by cellulose tape test; worms visible on perianal skin or in stool.


General Considerations

Enterobius vermicularis (8–13 × 0.5 mm) is common worldwide and is the most prevalent nematode infection in the United States. Humans, the only host, can harbor a few to hundreds of worms. Young children are affected more often than adults, and multiple infections occur in households and institutions with young children. High rates have been recorded in homosexual men, but the infection does not become opportunistic in HIV.

The adult worms inhabit the cecum and adjacent bowel areas, lying loosely attached to the mucosa. Gravid females migrate through the anus to the perianal skin and deposit eggs in large numbers. The eggs become infective in a few hours and may then infect others or be autoinfective if transferred to the mouth by contaminated food, drink, fomites, or hands. After being swallowed, the eggs hatch in the duodenum, and the larvae migrate down to the cecum. Retroinfection occasionally occurs when the eggs hatch on the perianal skin and the larvae migrate through the anus into the large intestine. The development of a mature ovipositing female from an ingested egg requires about 3–4 weeks. Eggs remain viable for 2–3 weeks outside the host. The life span of the worm is 30–45 days.

Clinical Findings

A. Symptoms and Signs

Many patients are asymptomatic. The most common and important symptom is perianal pruritus (particularly at night), due to the presence of the female worms or deposited eggs. Insomnia, restlessness, enuresis, and irritability are common symptoms, particularly in children. Many mild gastrointestinal symptoms have also been attributed to enterobiasis, but the association is difficult to prove. Perianal scratching may result in excoriation and impetigo. Adults sometimes report a “crawling” sensation in the anal area. Rarely, worm migration—including migration through the female genital tract or into the urethra—results in ectopic inflammation (vulvovaginitis, diverticulitis, appendicitis, cystitis) or granulomatous reactions (colon, genital tract, peritoneum, and elsewhere). Colonic ulceration and eosinophilic colitis have been reported.

B. Laboratory Findings

Diagnosis is made by finding eggs on the perianal skin (eggs are seldom found on stool examination). The most reliable method is by applying a short strip of sealing cellulose pressure-sensitive tape (eg, Scotch Tape) to the perianal skin and then spreading the tape on a slide for low-power microscopic study; toluene is used to clear the preparation. Three such preparations made on consecutive mornings before bathing or defecation will establish the diagnosis in about 90% of cases. Before the diagnosis can be ruled out, five to seven such examinations are necessary. Nocturnal examination of the perianal area or gross examination of stools may reveal adult worms, which should be placed in preservative, alcohol, or saline for laboratory examination. The worms can sometimes be seen on anoscopy. Eosinophilia is rare.

Differential Diagnosis

Pinworm pruritus must be distinguished from similar pruritus due to mycotic infections, allergies, hemorrhoids, proctitis, fissures, strongyloidiasis, and other conditions.


A. General Measures

Symptomatic patients should be treated, and in some situations all members of the patient's household should be treated concurrently, since for each overt case there are usually several inapparent cases. Careful washing of hands with soap and water after defecation and again before meals is important. Fingernails should be kept trimmed close and clean and scratching of the perianal area avoided. Ordinary washing of bedding will usually kill pinworm eggs; some workers recommend daily washing.

B. Specific Measures

Albendazole, mebendazole, and pyrantel pamoate are the drugs of choice and can be given with or without food. The dosage should be repeated at 2 and 4 weeks to avoid potential reinfection from infective eggs in the household environment. Albendazole and mebendazole should not be used in pregnancy. Piperazine, although effective, is not recommended because treatment requires 1 week.

  • Albendazole, available in the United States though not approved for this indication, is given as a single oral 400 mg dose. Abdominal pain and diarrhea are rare.

  • Mebendazole is given as a single 100 mg oral dose.

  • Pyrantel pamoate is administered as a 10 mg (base)/kg (maximum, 1 g) dose. Infrequent side effects include vomiting, diarrhea, headache, dizziness, and drowsiness. In the United States, pyrantel is available as self-medication for pinworm infection.


Although annoying, the infection is usually benign. Reinfection is common, especially in children, because of continued exposure outside the home.

Horton J: Albendazole: a broad spectrum anthelminthic for treatment of individuals and populations. Curr Opin Infect Dis 2002;15:5998.

Nackley AC et al: Appendiceal enterobius vermicularis infestation associated with right-sided chronic pelvic pain. JSLS 2004;8:171.

Petro M et al: Unusual endoscopic and microscopic view of Enterobius vermicularis: a case report with a review of the literature. South Med J 2005;98:927.


Tandan T et al: Pelvic inflammatory disease associated with Enterobius vermicularis. Arch Dis Child 2002;86:439.


Essentials of Diagnosis

  • History of residence in an endemic area (much of the tropics and subtropics between 40°N and 30°S).

  • Episodic attacks of lymphangitis, lymphadenitis, and fever.

  • Hydrocele; chyluria; acute or chronic lymphedema; or elephantiasis of arms, legs, genitalia, or breasts.

  • Microfilariae in blood, chyluria, or hydrocele fluid; positive serology; circulating antigens.

More than 120 million people are infected with lymphatic filariasis in 83 tropical and subtropical countries, 40 million are disfigured, and an estimated 1 million new persons, mainly children, are infected yearly. The disease is caused by three filarial nematodes: Wuchereria bancrofti, Brugia malayi, and Brugia timori. The filarial diseases are among the most important infections worldwide that cause a high degree of disability. W bancrofti is widely distributed in the tropics and subtropics of both hemispheres and on Pacific islands and is transmitted by culex, aedes, and anopheles mosquitoes. B malayi is transmitted by mansonia and anopheles mosquitoes of South India, Sri Lanka, Southeast Asia, South China, the northern coastal areas of China, and South Korea. B timori is found on the southeastern islands of Indonesia.

No animal reservoir hosts are known for W bancrofti or B timori; cats, monkeys, and other animals may harbor B malayi. Mosquitoes become infected by ingesting microfilariae with a blood meal; at subsequent feedings, they can infect new susceptible hosts. Over months, adult worms (females, 8–9 cm × 0.2–0.3 mm) mature and live (up to 2 decades) in or near superficial and deep lymphatics and lymph nodes and produce large numbers of viviparous circulating microfilariae.

Pathologic changes in lymph vessels are due to host immunologic reactions to developing and mature worms; also implicated are bacterial and fungal superinfections. An abscess may form at the site of a dying worm. Living microfilariae generally cause no lesions, except in tropical pulmonary eosinophilia. Rapid death of microfilariae, however, does produce findings.

Dirofilariasis, infections by Dirofilaria immitis and Dirofilaria repens (from dogs) and Dirofilaria tenuis (from raccoons) have been reported in the United States, Japan, Australia, and elsewhere. Nodules have been found in the periphery of the lungs as solitary “coin” lesions (1–4.5 cm), in the skin, or in other tissues. The parasites die in the larval stage, cause few symptoms, and rarely calcify. The serologic test for filariasis is positive, but there is no microfilaremia. Eosinophilia is seen in 15% of patients.

Several other species of filarial worms infect humans but usually without causing important findings: microfilariae of Mansonella ozzardi and Mansonella streptocerca appear in the skin, Mansonella perstans appears in the blood.

Clinical Findings

A. Symptoms and Signs

Many infections remain symptomatic, with or without microfilariae; if they do appear, it is 6–12 months after infection. The incubation period for symptoms is generally 8–16 months in expatriates but may be longer in indigenous persons. Many infections remain asymptomatic, with or without microfilariae.

1. Acute disease

Episodes of fever (filarial fever), with or without inflammation of lymphatics and nodes, occur at irregular intervals and last for several days. Characteristically, the adenolymphangitis presents as retrograde extension from the affected node (unlike ascending bacterial lymphangitis). With disease progression, epididymitis and orchitis as well as involvement of pelvic, abdominal, or retroperitoneal lymphatics may also occur intermittently. Lymph node enlargement may persist. In travelers, allergic-like findings (hives, rashes, eosinophilia) as well as lymphangitis and lymphadenitis are likely to be present.

2. Chronic disease

Obstructive phenomena that occur as a result of interference with normal lymphatic flow include hydrocele; scrotal lymphedema; lymphatic varices; and elephantiasis, particularly of the extremities, genitals, and breasts. Chyluria may result from rupture of distended lymphatics into the urinary tract. Manifestations seen in some patients include lymphadenopathy or moderate hepatomegaly or splenomegaly.

3. Occult disease

A small proportion of infected persons develop occult disease, in which the classic clinical manifestations and microfilaremia are not present but microfilariae are present in the tissues.

In tropical pulmonary eosinophilia, microfilariae of W bancrofti or B malayi are sequestered in the lungs but are not found in the blood. The condition, usually in young males, is characterized by episodic nocturnal coughing or wheezing, dyspnea, low-grade fever, scant expectoration, hypereosinophilia, high filarial antibody titers and IgE levels, diffuse miliary lesions or increased bronchovascular markings on chest films, and a rapid response to diethylcarbamazine treatment (6 mg/kg daily for 21 days). Relapses (in 20%) require re-treatment with up to 12 mg/kg daily for up to 30 days. If untreated, the condition can progress to chronic pulmonary fibrosis.

B. Laboratory Findings

Diagnosis of active infection is made by finding microfilariae in blood (or hydrocele fluid), a positive antigen test


(only available for W bancrofti), or by ultrasound. In indigenous persons, microfilariae are rare in the first 2–3 years, abundant as the disease progresses, and again rare in the obstructive stage. Thus, amicrofilaremia does not exclude presence of the infection. In addition, there is no correlation between microfilarial density and disease severity. In nonindigenous persons, inflammatory reactions may be prominent in the absence of microfilariae. Microfilariae of W bancrofti are found in the blood chiefly at night (nocturnal periodicity 10 pm to 2 am), except for a nonperiodic variety in the South Pacific. B malayi microfilariae are usually nocturnally periodic but in Southeast Asia may be present at all times, with a slight nocturnal rise. Anticoagulated blood specimens are collected at times that relate to the periodicity of the local strain. Specimens may be stored at ambient temperatures until examined in the morning by wet film for motile larvae and by Giemsa-stained smears—thick for sensitivity and thin for specific morphology to distinguish species. A formalin-anionic detergent preservative can also be used. If these are negative, the blood specimens should be concentrated by the membrane filtration technique or Knott concentration. Where available, testing for antigens of W bancrofti, which circulate throughout the day, should be done and can replace microscopy. ELISA and a rapid (5 min) immunochromatographic card test are sensitive (96–100%) and specific (nearly 100%) and thus are particularly useful for amicrofilaremic persons and for daytime examination of blood. A rapid dipstick test has shown a 97% sensitivity and 99% specificity for B malayi, and a PCR assay has been developed for both W bancrofti and B malayi. Other serologic tests may also be helpful in screening; negative tests usually rule out present or past infection, but false-positive tests occur with other filarial and helminthic infections, including ascariasis. An indirect hemagglutination titer of 1:128 and a bentonite flocculation titer of 1:5 in combination are considered the minimum significant titers. Eosinophil counts may be elevated. Live adult worms can be detected by high-frequency ultrasound of the scrotum (up to 80% of infected men) and of the female breast. In differential diagnosis, lymphangiography (potentially damaging to the lymphatics) and radionuclide lymphoscintigraphy may be useful lymphatic imaging methods.


A. Drug Treatment

Diethylcarbamazine is the drug of choice for treatment of individual patients. A mass drug treatment program involving 83 countries is underway to reduce lymphatic filariasis disability and to achieve worldwide eradication by 2020. Infected persons are given five consecutive annual doses. In most of the world, diethylcarbamazine plus albendazole is used, but in Africa, where persons may have concurrent onchocerciasis or loiasis infections, ivermectin plus albendazole is used.

1. Diethylcarbamazine

Diethylcarbamazine rapidly kills blood microfilariae; however it kills adults worms slowly and incompletely (20%). Treatment requires multiple 14-day courses (2 mg/kg orally three times a day after meals, starting with small doses and gradually increasing over 3–4 days). At this dose, direct drug-induced toxicity is rare. However, adverse immunologic reactions—more common in bancroftian filariasis—occur due to dying parasites. Reactions to dying microfilariae are frequent, rapid, and sometimes severe and include fever, headache, myalgia, dizziness, malaise, and other allergic responses; reactions to dying adult worms are slow and local and include lymphadenitis and abscess. Antipyretics and analgesics may be helpful. In areas where onchocerciasis or loiasis is also prevalent, the use of diethylcarbamazine is commonly contraindicated because of the potential for severe reactions to dying microfilariae of those parasites; instead, in Africa, ivermectin plus albendazole can be used. Diethylcarbamazine availability in the United States is only from the Parasitic Diseases Drug Service, Centers for Disease Control and Prevention, Atlanta, GA 30333; phone 404–639-3670.

2. Ivermectin

Effective only as a microfilaricide, ivermectin is given as a single oral 200 mcg/kg dose and repeated at 6-month intervals. The side effects of ivermectin against microfilariae are rapid and similar to that of diethylcarbamazine. Ivermectin should not be used in early pregnancy, although specific fetal problems have not been recognized. To kill the adult worms, diethylcarbamazine must also be given.

3. Albendazole

Albendazole continues under evaluation as a microfilaricide (a single oral dose of 400 mg) and as a macrofilaricide (400 mg twice daily for 3 weeks) but increasing findings suggest poor efficacy. The drug is free of significant side effects but is generally contraindicated in pregnancy.

B. Other Treatments

During acute inflammatory episodes, it is controversial whether to treat and whether drug usage will shorten the attack. General measures include rest, antipyretics, analgesics, antibiotics for secondary infections, use of postural drainage, elastic stockings and pressure bandages for leg edema, and suspensory bandaging for orchitis and epididymitis.

Hydroceles may benefit from repeated drainage, a locally injected sclerosing agent, or surgery. To manage elephantiasis, lymphovenous shunt procedures may be useful, combined with antibiotics to treat superinfections. Reconstructive surgery on limbs is controversial.

The search for an effective macrofilaricide continues. Under evaluation is the finding that Wolbachia bacteria are obligate intracellular infections of filarial parasites. Doxycycline treatment of patients (100–200 mg/d for 4–6 weeks) leads to bacterial death followed by the slow death of the adult parasites. The bacteria have also been implicated in some of the chronic morbidity of filariasis.



The prognosis is good with treatment of early and mild cases (including low-grade lymphedema, chyluria, small hydrocele), but in advanced infection the prognosis is poor.

Critchley J et al: Albendazole for the control and elimination of lymphatic filariasis: systematic review. Trop Med Int Health 2005;10:818.

Kvelem D et al: Short communication: Impact of long-term (14 years) bi-annual ivermectin treatment on Wuchereria bancrofti microfilaraemia. Trop Med Int Health 2005;10:1002.

Simonsen PE et al: The effect of eight half-yearly single-dose treatments with DEC on Wuchereria bancrofti circulating antigenaemia. Trans R Soc Trop Med Hyg 2005;99:541.

Theis JH: Public health aspects of dirofilariasis in the United States. Vet Parasitol 2005;133:157.

Tisch DJ et al: Mass chemotherapy options to control lymphatic filariasis: a systematic review. Lancet Infect Dis 2005;5:514.


Gnathostomiasis, due for the most part to infection by the larval stage of the nematode Gnathostoma spinigerum, is rarely caused by other Gnathostoma species. Infection is most common in Thailand and Japan but is also reported from Southeast Asia, China, India, Central and South America, Israel, and East Africa. In Mexico, where the Gnathostoma species has not been identified, the number of cases is increasing; more than 1000 have been reported in recent years, commonly associated with increased eating of raw fresh-water fish, especially sushi, sashimi, and a preparation called ceviche. In the United States, though G spinigerum has rarely been seen in minks, it has not been reported in humans. Eggs passed in feces of the definitive hosts, wild and domestic dogs and cats, are infective for copepods (water fleas). Ingestion of copepods by secondary hosts results in encysted larvae in their tissues; humans are infected when these larvae are ingested in raw, marinated, or inadequately cooked freshwater fish, shrimp, crab, crayfish, chicken or other fowl, frogs, or pork. Infection has also been attributed to ingestion of infected copepods in water.

Within 24–48 hours, larval migration through the intestinal wall can cause acute epigastric pain, vomiting, urticaria, and eosinophilia. The worm then migrates to subcutaneous and other tissues but is unable to mature. Most common is a pruritic subcutaneous swelling up to 25 cm across, occasionally accompanied by stabbing pain. Over weeks to years, the swelling may remain in one area for days or weeks, move continuously, or there may be an absence of physical signs between episodes. Occasionally the worm becomes visible under the skin.

Internal organs and the eye (pain, anterior uveitis, increased intraocular pressure, vitreous hemorrhage, and eventually blindness) may also be invaded. Spontaneous pneumothorax, leukorrhea, hematemesis, hematuria, hemoptysis, paroxysmal coughing, and edema of the pharynx with dyspnea have been reported as complications. Invasion of the brain can result in an eosinophilic meningoencephalitis or subarachnoid hemorrhage. Spinal cord invasion can lead to myelitis or radiculopathy.

Definitive diagnosis is sometimes possible by surgical removal of the worm when it appears close to the skin. Although common, marked eosinophilia may be absent, especially for parasites in the central nervous system. Serodiagnosis is by immunoblot assay (high sensitivity and specificity) or ELISA of blood or cerebrospinal fluid. Skin and other serologic tests are unsatisfactory.

Treatment is with ivermectin (200 mcg/kg orally daily for 2 days) or with albendazole (400 mg orally twice daily for 21 days). Larval death appears to occur slowly and a second course of treatment may be necessary; cure rates may reach 95%. Courses of prednisolone have provided temporary relief of symptoms. Lesions in the eye or brain should probably not be treated with an anthelmintic because of the potential for edema resulting from release of antigens from the dying worm.

Kraivichian K et al: Treatment of cutaneous gnathostomiasis with ivermectin. Am J Trop Med Hyg 2004;71:623.

Lingon BL: Gnathostomiasis: a review of a previously localized zoonosis now crossing numerous geographical boundaries. Semin Pediatr Infec Dis 2005;16:137.

Magana M et al: Gnathostomiasis: clinicopathologic study. Am J Dermatopathol 2004;26:91.

Moore DA et al: Gnathostomiasis: an emerging imported disease. Emerg Infect Dis 2003;9:647.

Hookworm Disease

Essentials of Diagnosis

Early findings (not commonly recognized):

  • Dermatitis: pruritic, erythematous, papulovesicular eruption at site of larval invasion, often of the feet.

  • Pulmonary migration of larvae: transient episodes of coughing, asthma, fever, blood-tinged sputum, marked eosinophilia.

Later findings:

  • Intestinal symptoms: anorexia, diarrhea, abdominal discomfort.

  • Anemia (iron deficiency): fatigue, pallor, dyspnea on exertion, poikilonychia, heart failure.

  • Characteristic eggs and occult blood in the stool.


General Considerations

Hookworm disease, widespread in the moist tropics and subtropics and sporadically in southeastern United States, is caused by Ancylostoma duodenale and Necator americanus. Probably a quarter of the world's population is infected, and in many areas the infection is a major cause of debility, retardation of growth and development of children, and increased susceptibility to infection. Prevalence rates can reach 80% in the humid tropics under unsanitary conditions.

Although in the Western Hemisphere and tropical Africa, Necator was the prevailing species, and in the Far East, India, China, and the Mediterranean area, Ancylostoma was prevalent, both species have now become widely distributed. Infection is rare in regions with less than 40 inches of rainfall annually. Humans are the only host for both species.

The adult worms are approximately 1 cm long. Eggs produced by females are passed in the stool and must fall on warm, moist soil if hatching followed by larval development is to take place. Larvae remain infective for hours to about a week, depending on environmental conditions. Following skin penetration, often of the feet, the larvae migrate in the bloodstream to the pulmonary capillaries, break into alveoli, and then are carried by ciliary action upward to the bronchi, trachea, and mouth. After being swallowed, they reach and attach to the mucosa of the upper small bowel; maturation and release of eggs occur in 6–8 weeks. Ancylostoma infection can also be acquired by ingestion of the larvae in food or water. Adult ancylostoma worms survive about a year; necator, about 3–5 years.

The worms suck blood at their attachment sites. Blood loss is proportionate to the worm burden. A light infection is approximately 1000 eggs per gram of feces (equivalent to about 11 ancylostoma and 32 necator adults); a moderate worm load is 2000–8000 eggs per gram of feces. Iron loss with moderate infection is 1.1 mg/d for N americanus and 2.3 mg/d for A duodenale. Over years—and depending on the host's dietary intake of iron—iron reserves can be depleted and severe anemia can result from moderate infections with 30 or more ancylostoma or 100 or more necator worms. Accompanying the anemia is loss of protein that can lead to hypoalbuminemia.

Clinical Findings

A. Symptoms and Signs

The first manifestation of infection is a pruritic erythematous dermatitis, either maculopapular or vesicular, that follows skin penetration of the infective larvae. Severity is a function of the number of invading larvae and host sensitivity. Scratching may result in secondary infection. Strongyloidiasis and cutaneous larva migrans must be considered in the differential diagnosis at this stage.

The pulmonary stage, in which there is larval migration through the lungs, may show dry cough, wheezing, blood-tinged sputum, and low-grade fever. The pulmonary migration of ascaris and strongyloides larvae can produce similar findings.

After 2 or more weeks, maturing worms attach to the mucosa of the duodenum and upper jejunum. In heavy infections, worms may reach the ileum. Patients who have light infections and adequate iron intake often remain asymptomatic. In heavy infections, however, there may be anorexia, diarrhea, vague abdominal pain, and ulcer-like epigastric symptoms. Severe anemia may result in pallor, deformed nails, pica, and cardiac decompensation. Marked protein loss may also occur, resulting in hypoalbuminemia, with edema and ascites. There are conflicting reports of malabsorption in some severe infections.

Reduction in worm loads and symptoms after the first decade of life suggests that a moderate degree of immunity develops.

B. Laboratory Findings

Diagnosis depends on demonstration of characteristic eggs in feces; a concentration method may be needed. The two species cannot be differentiated by the appearance of their eggs. The stool usually contains occult blood. Hypochromic microcytic anemia can be severe, with hemoglobin levels as low as 2 g/dL, a low serum iron and a high iron-binding capacity, and low serum ferritin. Eosinophilia (as high as 30–60% of a total white blood count reaching 17,000/mcL) is usually present in the pulmonary migratory stage of infection but is not marked in the chronic intestinal stage.


A. General Measures

The availability of safe anthelmintics makes it possible to treat all patients initially, irrespective of the intensity of infection; nevertheless, it may not be necessary or beneficial to treat light infections. Heavy infections may need re-treatment at 2-week intervals until the worm burden is reduced to a low level as estimated by semiquantitative egg counts. Eradication of infection is not essential, since light infections do not injure the well-nourished patient and iron loss is replaced if the patient is receiving adequate dietary iron.

If anemia is present, oral ferrous sulfate and a diet high in protein and vitamins are required for at least 3 months after the anemia has been corrected in order to replace iron stores. A dosage schedule for ferrous sulfate or gluconate tablets (200 mg) is one tablet three times daily for 2 months followed by one tablet daily for 4 months. Parenteral iron is rarely indicated. Folic acid (5 mg daily for 1 month) should also be given. Blood transfusion may be necessary if anemia is severe.

B. Specific Measures

Pyrantel, mebendazole, albendazole, and levamisole are highly effective drugs for treatment of both hookworm species; ivermectin is not effective. Mebendazole, pyrantel, or albendazole can be used to treat concurrent


trichuriasis, and all of the drugs can be used to treat concurrent ascariasis. The drugs are given before or after meals, without purges. For these drugs, mild gastrointestinal side effects and headache may occur; none should be used in pregnancy. Albendazole (400 mg) or mebendazole (500 mg) is being used for repeated (up to 3 times yearly) mass treatment of children for intestinal parasites (hookworm, ascariasis, trichuriasis). Improvements have been seen in blood hemoglobin levels and improved growth, even in light infections in young children. However, drug resistance may be emerging.

1. Albendazole

Albendazole given orally once only at a dosage of 400 mg results in the cure of 85–95% of patients with Ancylostoma infection and markedly reduces the worm burden in those not cured. Because cure rates for single-dose treatments of Necator infection were 33–90%, treatment should be continued for 2–3 days, especially in heavy infections. Albendazole is available in the United States, though it is not FDA-approved for this indication.

2. Pyrantel pamoate

In A duodenale infections, pyrantel given as a single dose, 10 mg (base)/kg (maximum 1 g), produces cures in 76–98% of cases and a marked reduction in the worm burden in the remainder. Drug resistance has been reported from northwestern Australia. For N americanus infections, a single dose may give a satisfactory cure rate in light infection, but for moderate or heavy infection a 3-day course is necessary. If the species is unknown, treat as for necatoriasis. Mild and transient drowsiness and headache may occur.

3. Mebendazole

When mebendazole is given at a dosage of 100 mg twice daily for 3 days, reported cure rates for both hookworm species range from 35% to 95%. A single 500 mg dose may be sufficient for light infections. Mebendazole sometime stimulates ascarids to emerge from the nose or mouth.

4. Levamisole

Levamisole is given as a single dose of 150 mg. The drug is less effective against N americanus.


If the disease is recognized before serious secondary complications appear, complete recovery is the rule following treatment.

Eosinophilic Enteritis

In Australia, A caninum, the dog hookworm, has been found to cause abdominal pain, diarrhea, and peripheral eosinophilia. Pathologic findings may include iliac ulcerations and regional lymphandenitis. The diagnosis is made by finding an immature adult worm at endoscopy. Treatment with albendazole or mebendazole can be tried.

Brooker S et al: Human hookworm infection in the 21st century. Adv Parasitol 2004;58:197.

Bungiro R et al: Hookworm infection: new developments and prospects for control. Curr Opin Infect Dis 2004;17:421.

Crompton DW et al: Nutritional impact of intestinal helminthiasis during the human life cycle. Annu Rev Nutr 2002;22: 35.

Hotez PJ et al: Hookworm infection. N Engl J Med 2004; 351:799.


Essentials of Diagnosis

  • History of residence in rain forests of tropical Africa.

  • Transitory (Calabar) swellings on various parts of the body.

  • Adult worms noted beneath the skin or under the conjunctival epithelium.

  • Characteristic microfilariae in the blood showing diurnal periodicity; eosinophilia; positive serologic tests.

General Considerations

Loiasis is a chronic filarial disease caused by infection with Loa loa. The infection occurs in humans and monkeys in rain and swamp forest areas of West Africa from Nigeria to Angola and throughout the Congo river watershed of central Africa eastward to southwestern Sudan and western Uganda. An estimated 3–13 million persons are infected.

The adult worms live in the subcutaneous tissues for up to 12 years. Gravid females release microfilariae into the bloodstream, which subsequently are ingested in a blood meal by the vector-intermediate host, female chrysops species, which are day-biting flies. When the fly feeds again, the larval stage can infect a new host or cause superinfection. The time to worm maturity and detection of new microfilariae is 6 months to several years. Unlike the other filarial parasites of humans, L loa does not harbor endosymbiont bacteria.

Clinical Findings

A. Symptoms and Signs

Many infected persons are asymptomatic. In symptomatic persons, the worms (females, 4–7 cm × 0.5 mm) are evidenced by their temporary appearance beneath the skin or conjunctiva, by unilateral edema of an extremity, or by Calabar swellings. The latter are subcutaneous edematous reactions, 3–10 cm in diameter, nonpitting and nonerythematous, and at times associated with low-grade fever, local pain, and pruritus. The swellings or edema may migrate a few centimeters for 2–3 days or stay in place before they subside. At irregular


intervals, they recur at the same or different sites, but only one appears at a time. When near joints, they may be temporarily disabling. Migration across the eye may be asymptomatic or produce pain, intense conjunctivitis, and eyelid edema. Dying adult worms may elicit small nodules or local sterile abscesses, and dead worms may result in radiologically detectable calcification.

Microfilariae in the blood do not induce symptoms. Rarely, however, they enter the central nervous system and may cause encephalitis, myelitis, or jacksonian seizures; the larvae can also induce lesions and complications in the retina, heart, lungs, kidneys, and other tissues.

Natives generally have a mild form of the infection or are asymptomatic but are microfilaremic and serologically positive. The disease among visitors, however, is often characterized by more pronounced immunologically mediated symptoms (frequent and debilitating Calabar swellings, elevated leukocyte and eosinophil counts, hypergammaglobulinemia, increased polyclonal IgE) and frequently a positive serologic test but nondetectable microfilaremia.

B. Laboratory Findings

Specific diagnosis is made by finding characteristic microfilariae in daytime (10 am to 4 pm) blood specimens by concentration methods; in order of increasing sensitivity, they are (1) thick films, (2) Knott's concentration, and (3) Nuclepore filtration. Multiple daily samples may be needed. Presumptive diagnosis that permits treatment is based on Calabar swellings or eye migration, a history of residence in an endemic area, and marked eosinophilia (40% or greater). Serologic tests may be positive, but cross-reactions occur with other filarial diseases and sometimes with other nematode infections. A PCR test, highly sensitive and specific, can detect the organism in some amicrofilaremic persons. Expatriates are usually amicrofilaremic.

Treatment & Prognosis

See specialized sources and references for details on proper use of diethylcarbamazine (drug of choice both as a microfilaricide and macrofilaricide), since side effects to dying microfilariae may be severe, and life-threatening encephalitis can occur rarely. The dosage is 50 mg once (day 1), 50 mg three times daily (day 2), 100 mg three times daily (day 3), and 3 mg/kg three times daily (days 4–21). One course of treatment cures about 50% of patients; three courses, 90%. Reactions are more likely with pretreatment microfilaria counts greater than 25/mcL. Apheresis has been used to reduce parasite loads before starting diethylcarbamazine. Prednisone (40–60 mg/d) is sometimes indicated in heavily infected persons to minimize reactions. Albendazole (200 mg twice daily for 3 weeks) and ivermectin (multiple doses) continue to be evaluated for microfilariae reduction. Albendazole is preferred because of its lower risk of encephalitis. Surgical removal of adult worms from the eye or skin is not recommended.

In the United States, diethylcarbamazine is available only from the Parasitic Diseases Drug Service, Centers for Disease Control and Prevention, Atlanta, GA 30333, telephone 404–639-3670.

Individual protection is facilitated by daytime use of insect repellent and by wearing light-colored clothing with long sleeves and trousers. Diethylcarbamazine prophylaxis, 300 mg weekly, may be useful if the risk of exposure is high. It is not indicated, however, for the casual traveler or for persons who might previously have acquired any of the filarial infections.

Most infections run a benign course, but some are accompanied by severe and temporarily disabling symptoms. The prognosis is excellent with treatment, except for patients with high pretreatment microfilariae counts.

Blum J et al: Encephalopathy following Loa loa treatment with albendazole. Acta Trop 2001;78:63.

Pion SD et al: Loiasis: the individual factors associated with the presence of microfilaraemia. Ann Trop Med Parasitol 2005;99:491.

Tabi TE et al: Human loiasis in a Cameroonian village: a double-blind, placebo-controlled, crossover clinical trial of a three-day albendazole regimen. Am J Trop Med Hyg 2004;71:211.


Essentials of Diagnosis

  • Skin: pruritus, excoriations, pigmentary changes, papular eruptions, atrophy, licenoid thickening.

  • Subcutaneous nodules.

  • Eyes: itching, photophobia, conjunctivitis, punctate and sclerosing keratitis, iridocyclitis, posterior segment lesions; impaired vision to blindness.

  • Microfilariae in skin snips and on slit-lamp examination of cornea or anterior chamber; adult worms in subcutaneous nodules.

  • Positive serologic tests.

General Considerations

Onchocerciasis is a chronic filarial disease caused by Onchocerca volvulus. An estimated 18 million persons are infected, of whom 3–4 million have skin disease, 0.3 million are blinded, and 0.5 million severely visually impaired. In hyperendemic areas, more than 40% of inhabitants over 40 years of age are blind. The infection, predominant in West Africa, also occurs in many other parts of tropical Africa and in localized areas of the southwestern Arabian peninsula, southern Mexico, Guatemala, Venezuela, Colombia, and northwestern Brazil. The West African savanna strain is especially associated with severe blinding eye lesions. In some areas of Africa where blindness is not a severe


problem, cutaneous onchocerciasis can nevertheless be severe and disabling.

Humans are the only important host. The vector and intermediate host are simulium flies, day biters that breed in rivers and fast-flowing streams and become infected by ingesting microfilariae with a human blood meal; at subsequent feedings, they can infect new susceptible hosts.

The skin and eye changes are the result of dead or dying microfilariae. However, recent findings suggest that the predominant corneal changes may be due to endoxins from Wolbachia bacteria, which are obligate intracellular organisms in the worms.

The advent of the safe drug ivermectin has led to effective individual treatment and to mass control programs. In target communities, mass treatment yearly in Africa and twice yearly in the Americas combined with anti-vector measures has resulted in a dramatic decrease in the prevalence of skin and eye disease. The drug has been provided free by the manufacturer, Merck & Co.

Clinical Findings

A. Symptoms and Signs

Adult worms, which can live for up to 15 years, typically are contained in fibrous subcutaneous nodules that cause insignificant pathology and are painless, freely movable, and 0.5–1 cm in diameter. Many nodules, however, are deep in the connective and muscular tissues. The interval from exposure to onset of symptoms can be as long as 1–3 years. Female worms release motile microfilariae into the skin, subcutaneous tissues, lymphatics, and eyes; microfilariae are occasionally seen in the urine but rarely in blood or cerebrospinal fluid. Skin manifestations are localized or cover large areas. Pruritus may be severe, leading to skin excoriation and lichenification; other findings include pigmentary changes, papules, scaling, atrophy, pendulous skin, and acute inflammation. Pruritus may occur in the absence of skin lesions. There may be marked enlargement of femoral and inguinal nodes and generalized lymph node enlargement. Microfilariae in the eye may lead to visual impairment and blindness; findings include itching, photophobia, anterior segment changes (limbitis, punctate and sclerosing keratitis, iritis, secondary glaucoma, cataract), and posterior segment changes (optic neuritis, optic atrophy, chorioretinitis, and other retinal and choroidal findings). Infected expatriates, as compared with indigenous persons, may show more prominent dermatitis and eosinophilia but have a low to nondetectable microfiladerma or eosinophilia and an absence of nodules and eye disease.

B. Laboratory Findings

Diagnosis is by demonstrating microfilariae in skin snips (usually obtained with a punch biopsy instrument), identifying them in the cornea or anterior chamber by slit-lamp examination (after the patient has sat with head lowered between knees for 2 minutes), in nodule aspirates, or sometimes in the urine. The preferred site for skin snips is the iliac crest in Africa and the deltoid and scapula areas in the Americas. Skin snips placed in saline are incubated for 2–4 hours before examination, or overnight for low-intensity infections. Where available, the PCR test done on skin snips and urine has a high sensitivity and specificity; it is positive only in active infection. Adult worms may be recovered in excised nodules, whereas ultrasound has been used to detect nonpalpable onchocercomas and to distinguish them from other lesions (lipomas, fibromas, lymph nodes, foreign body granulomas). Traditional serologic tests are usually positive, but cross-reactions occur with other forms of filariasis, and the tests do not distinguish current from past infection. The use of recombinant antigens has resulted in the development of the highly sensitive and specific ELISA and rapid-format card tests. Methods to detect circulating antigen are being evaluated but appear less useful. Eosinophilia (15–50%), polyclonal hypergammaglobulinemia, and elevated IgE levels are common. The Mazzotti oral test, done only if the above tests are negative, is based on the ingestion of diethylcarbamazine (0.5 to 1.0 mg/kg); a skin reaction or pruritus within several hours is highly suggestive of the infection. The Mazzotti skin test is no longer recommended because of the potential for dangerous reactions.

Treatment & Prognosis

Drug treatment is with ivermectin (a microfilaricide) as a single oral dose of 150 mcg/kg given with water on an empty stomach; the patient should remain fasting for 2 more hours. The number of microfilariae in the skin diminishes markedly within 2–3 days, remains low for about 6 months, and then gradually increases; the number of microfilariae in the anterior chamber of the eye, however, decrease slowly over months, eventually disappear, and then gradually return. The optimum frequency of treatment to control symptoms and prevent disease progression remains to be determined. To initiate treatment, three schedules have been proposed: (1) an initial and repeat dose at 6 months, (2) repeated doses at 3-month intervals for a year, or (3) repeated doses at monthly intervals for a total of three doses. Treatment is repeated at intervals of 6 months for 2 years and yearly thereafter until the patient is asymptomatic or until the worms have died normally (12–15 years). Although ivermectin is not effective in killing adult worms, evidence suggests that the drug has a limited effect on intrauterine embryogenesis. Adverse reactions, which are more marked with the first dose, are mild in 9% of patients and severe in 0.2%; these include edema (face and limbs), fever, pruritus, lymphadenitis, malaise, and hypotension. Ivermectin does not, however, cause a severe reaction in the eyes or skin as occurs with diethylcarbamazine. With the initial treatment only, patients with microfilariae in the cornea or anterior chamber may benefit from several days of prednisone treatment (1 mg/kg/d) to avoid inflammatory eye reactions. Ivermectin should not be used in the presence of concurrent


L loa infections, in early pregnancy (no adverse events have been reported), or in patients with central nervous system diseases in which increased penetration of ivermectin may occur into the central nervous system. Safety in children under 15 kg has not been established. The possibility of drug resistance is emerging. In Latin America only, nodulectomy continues to be used for nodules on or near the head.

Diethylcarbamazine is no longer recommended in onchocerciasis therapy because of its potential for severe reactions and because it was no more effective than ivermectin in reducing microfilariae loads. For selected patients in whom repeated ivermectin treatments do not control symptoms, suramin can be given for its macrofilaricidal action; however, because of suramin's toxicity and complex administration, it should only be administered by experts. Amocarzine is under evaluation for its macrofilaricidal and microfilaricidal actions. Albendazole does not kill microfilariae but interferes with early embryogenesis; the drug is not macrofilarialcidal. Doxycycline has potential as a chemotherapeutic agent based on findings that a 6–8 week course of treatment has a long-term sterilizing effect through the drug's action on Wolbachia bacteria, which are obligate intracellular organisms in onchocerca adults and microfilariae.

With treatment, some skin and ocular lesions improve and ocular progression is prevented. The prognosis is unfavorable only for those patients who are seen for the first time with already far-advanced ocular onchocerciasis.

Fobi G et al: A randomized, double-blind, controlled trial of the effects of ivermectin at normal and high doses, given annually or three-monthly, against Onchocerca volvulus: ophthalmological results. Trans R Soc Trop Med Hyg 2005;99:279.

Hoerauf A et al: Onchocerciasis. BMJ 2003;326:207.

Hopkins DR et al: Whither onchocerciasis control in Africa? Am J Trop Med Hyg 2005;72:1.

Kamgno J et al: Adverse systemic reactions to treatment of onchocerciasis with ivermectin at normal and high doses given annually or three-monthly. Trans R Soc Trop Med Hyg 2004;98:496.

Tielsch JM et al: Impact of ivermectin on illness and disability associated with onchocerciasis. Trop Med Int Hlth 2004;9: A45.

Twum-Danso NA et al: Variation in incidence of serious adverse events after onchocerciasis treatment with ivermectin in areas of Cameroon co-endemic for loiasis. Trop Med Int Health 2003;8:820.


Essentials of Diagnosis

  • Pruritic dermatitis at sites of larval penetration.

  • Diarrhea, epigastric pain, nausea, malaise, weight loss.

  • Cough, rales, transient pulmonary infiltrates.

  • Hyperinfection syndrome: Severe diarrhea, bronchopneumonia, ileus, septicemia.

  • Positive serology (useful for screening); eosinophilia; larvae detected in stool, especially by the agar plate culture method.

General Considerations

Strongyloidiasis is caused by infection with Strongyloides stercoralis (2–2.5 mm × 30–50 mcm). Major symptoms result from adult parasitism, principally in the duodenum and jejunum, or from larval migration through pulmonary and cutaneous tissues. The primary host is humans, but dogs, cats, and primates have been found infected with strains indistinguishable from those of humans. Human infections with Strongyloides fulleborni have been encountered in Papua New Guinea and parts of Africa.

Strongyloidiasis is endemic in tropical and subtropical regions. Although prevalence is generally low, in some areas disease rates exceed 25%. In temperate areas, the disease occurs sporadically. In the United States, highest infection rates are found in immigrants from endemic areas, in parts of Appalachia, and in the Southeast. Puerto Rico is also an endemic area. Multiple infections in households are common, and prevalence may be high in institutions, particularly mental institutions (2–4%). The infection is also prevalent among immunocompromised persons (see below).

The parasite is uniquely capable of maintaining its life cycle both within the human host and in soil. Infection occurs when filariform larvae in soil penetrate the skin, enter the bloodstream, and are carried to the lungs, where they escape from capillaries into alveoli and ascend the bronchial tree to the glottis. The larvae are then swallowed and carried to the duodenum and upper jejunum, where maturation to the adult stage takes place. The parasitic female, generally held to be parthenogenetic, matures and lives embedded in the muscosa for up to 5 years. Eggs hatch to free noninfectious larvae (rhabditform) that pass to the ground via the feces.

In moist soil, these larvae metamorphose into the infective (filariform) larvae. However, the parasite also has a free-living cycle in soil, in which some rhabditiform larvae develop into adults that produce eggs from which rhabditiform larvae emerge to continue the life cycle.

Autoinfection in humans, which probably occurs at a low rate in most infections, is an important factor in determining worm burden and is responsible for the persistence of infections up to decades. Autoinfection takes place in the lower bowel when some rhabditiform larvae develop into filariform larvae that can penetrate the intestinal mucosa, enter the intestinal lymphatic and portal circulation, are carried to the lungs, and return to the small bowel to complete the cycle. This process is accelerated by achlorhydria, constipation, diverticula, and other conditions that reduce


bowel motility. In addition, an external autoinfection cycle can occur as a result of fecal contamination of the perianal area.

The hyperinfection syndrome occurs when autoinfection greatly increases; a marked rise in the worm burden occurs with massive dissemination of filariform larvae to the lungs and other tissues. Local inflammatory reactions may follow, and occasionally larvae metamorphose into adults. Hyperinfection—as well as recrudescence of chronic asymptomatic infection—is generally initiated as a result of depressed host cellular immunity, especially associated with use of an immunosuppressive drug, debilitation, malnourishment, radiotherapy, diabetic ketoacidosis, alcohol abuse, or malignancy. Although hyperinfection is infrequent in AIDS, recrudescence and a protracted, difficult-to-cure course may occur. Human T-cell lymphotropic virus, type 1 (HTLV1) infection is highly associated with strongyloidiasis, especially with hyperinfection.

Clinical Findings

A. Symptoms and Signs

Up to 30% of infected persons are asymptomatic. The time from larval penetration of the skin by filariform larvae until their appearance in the feces is 3–4 weeks. An acute syndrome can sometimes be recognized in which cutaneous symptoms, usually of the feet, are followed by pulmonary and then intestinal symptoms. Patients usually present, however, with chronic symptoms (continuous or with irregular exacerbations) that can persist for years or for life. Immigrants from endemic areas should be screened for Strongyloides infection if they are to be treated with an immunosuppressive drug.

1. Cutaneous manifestations

In acute infection in sensitized patients, there may be focal edema, inflammation, petechiae, serpiginous or urticarial tracts, and intense itching. In chronic infections, both stationary urticaria and larva currens occur, the latter characterized by transient eruptions that migrate in serpiginous tracts.

2. Intestinal manifestations

Symptoms range from mild to severe, the most common being diarrhea, abdominal pain, and flatulence. Anorexia, nausea, vomiting, epigastric tenderness, and pruritus ani may be present; with increasing severity, fever and malaise may appear. Diarrhea may alternate with constipation, and in severe cases the feces contain mucus and blood. The pain is often epigastric in location and may mimic a duodenal ulcer. Malabsorption or a protein-losing enteropathy can result from a large intestinal worm burden.

3. Pulmonary manifestations

With migration of larvae through the lungs, bronchi, and trachea, symptoms may be limited to a dry cough and throat irritation, or low-grade fever, dyspnea, wheezing, and hemoptysis may occur; asthma is rare. Bronchopneumonia, bronchitis, pleural effusion, progressive dyspnea, and miliary abscesses can develop; the cough may become productive of an odorless, mucopurulent sputum.

4. Hyperinfection syndrome

Intense dissemination of filariform larvae to the lungs and other tissues can result in additional complications, including pleural effusion, pericarditis and myocarditis, hepatic granulomas, cholecystitis, purpura, ulcerating lesions at all levels of the gastrointestinal tract, central nervous system involvement, paralytic ileus, perforation and peritonitis, polymicrobial sepsis, and meningitis (due to larval carriage of enterobacteria from the colon), cachexia, shock, and death. Nephrotic syndrome is encountered on rare occasions.

B. Laboratory Findings

1. Detection of eggs and larvae

Eggs are seldom found in feces. Diagnosis, which may be difficult, requires finding the larval stages in feces or duodenal fluid. Rhabditiform larvae may be found in recently passed stool specimens; filariform larvae, however, will be present in specimens held in the laboratory for some hours. Four to six specimens, some unpreserved, should be collected at 2-day intervals or longer (the number of larvae in feces varies from day to day). Since the sensitivity of direct microscopic examination of one specimen is about 30%, it is essential that half of the specimens be processed, unpreserved by a more sensitive method, either agar plate culture (the most sensitive, up to 90%), Baermann concentration, or Harda-Mori filtration.

The diagnosis can sometimes be made by finding rhabditiform larvae or ova in mucus obtained by means of the duodenal string test or by duodenal intubation and aspiration. Duodenal biopsy is seldom indicated but will confirm the diagnosis in most patients. Rarely, filariform or rhabditiform larvae can be detected in urine or in sputum or bronchial washings during the pulmonary phase of the disease.

2. Serologic and hematologic findings

For screening, the ELISA is sensitive (84–95%) and specific (84–92%), but cross-reactions can occur with filarial and other helminthic infections. A newly developed dot blot test appears to have fewer cross-reactions. A positive test indicates current or past infection. These IgG antibodies remain detectable in immunocompromised patients.

In chronic low-grade intestinal strongyloidiasis, the white blood cell count is often normal, with a normal or slightly elevated percentage of eosinophils. However, with increasing larval migration, eosinophilia may reach 50% and leukocytosis 20,000/mcL. In immunocompromised patients, eosinophilia may not be seen. Mild anemia may be present.

3. Hyperinfection

Findings may include hypoproteinemia, malabsorption, abnormal liver function, extensive pulmonary infiltrates, and multiple organ failures. Filariform larvae may appear in the urine. Eosinopenia, when present, is thought to be an unfavorable prognostic sign.

C. Imaging

Small bowel x-rays may show inflammation, irritability, and prominent mucosal folds; there may also be


bowel dilation, delayed emptying, and ulcerative duodenitis. In chronic infections, the findings can resemble those in nontropical and tropical sprue, or there may be narrowing, rigidity, and diminished peristalsis. During pulmonary migration of larvae, chest films are normal or show fine miliary nodules or irregular changing patches of pneumonitis, abscess, or pleural effusion.

Differential Diagnosis

Because of varied signs and symptoms, the diagnosis of strongyloidiasis is often difficult. Eosinophilia plus one or more of the following factors should further enhance consideration of the diagnosis: endemic area exposure, duodenal ulcer-like pain, persistent or recurrent diarrhea, malabsorption, recurrent coughing or wheezing, and transient pulmonary infiltrates. The duodenitis and jejunitis of strongyloidiasis can also mimic giardiasis, cholecystitis, and pancreatitis. Transient pulmonary infiltrates must be differentiated from tropical pulmonary eosinophilia and Löffler's syndrome. The diagnosis should be considered among the many causes of malabsorption in the tropics; in the differential diagnosis of ulcerative colitis; and in immunocompromised persons, including HIV-infected patients.


Since Strongyloides can multiply in humans, treatment should continue until the parasite is eradicated. In follow-up, multiple stool examinations should be done at weekly intervals, preferably by the agar plate culture method. Patients receiving immunosuppressive therapy should be examined for strongyloidiasis before and at intervals during that treatment. Patients with strongyloidiasis infections who are resistant to treatment should be evaluated for AIDS. In concurrent infection with strongyloidiasis and ascariasis or hookworm (which is common), eradicate the latter infections first.

The drug of choice in treatment is ivermectin, which appears to be equal in effectiveness to thiabendazole but has far fewer side effects.

A. Ivermectin

The dosage is 200 mcg/kg orally followed by a second dose within several days (cure rates range from 82% to 98%). An enema preparation is being evaluated for patients unable to take oral medication. A parenteral formulation of ivermectin is available in some countries but is licensed only for veterinary use. In the hyperinfection syndrome in immunocompromised patients with or without AIDS, it may be necessary to prolong treatment or change to thiabendazole.

B. Albendazole

Albendazole is given at a dosage of 400 mg twice daily for 3–7 days and repeated in 1 week; cure rates in several studies ranged from 38% to 95%. In comparative studies, albendazole is less effective than ivermectin.

C. Thiabendazole

An oral dose of 25 mg/kg (maximum, 1.5 g per dose) is given after meals twice daily for 2–3 days. Repeat the course in 2 weeks. A 7-day (or longer) course is needed for disseminated infections. Tablet and liquid formulations are available; tablets should be chewed. Side effects, including headache, weakness, vomiting, vertigo, and decreased mental alertness, occur in as many as 30% of patients and may be severe, particularly if given for more than 2 days. Other potentially serious side effects occur rarely. Erythema multiforme and the Stevens-Johnson syndrome have been associated with thiabendazole therapy; several fatalities have occurred in children. The drug is not available in the United States.


The prognosis is favorable except in the hyperinfection syndrome and in infections associated with malnutrition, advanced liver disease, immunologic disorders, or the use of immunosuppressive drugs. In selected instances, to control infections that cannot be eradicated, once-monthly treatments can be tried with a 1-day dose of ivermectin or 2-day course of thiabendazole.

Concha R et al: Intestinal strongyloidiasis: recognition, management, and determinants of outcome. J Clin Gastroenterol 2005;39:2031.

Lanzafam M et al: Strongyloidiasis in an HIV-1-infected patient after highly active antiretroviral therapy-induced immune restoration. J Infect Dis 2005;191:1027.

Lim S et al: Complicated and fatal Strongyloides infection in Canadians: risk factors, diagnosis and management. CMAJ 2004;171:479.

Nuesch R et al: Imported strongyloidosis: a longitudinal analysis of 31 cases. J Travel Med 2005;12:80.

Pacanowski J et al: Subcutaneous ivermectin as a safe salvage therapy in Strongyloides stercoralis hyperinfection syndrome: a case report. Am J Trop Med Hyg 2005;73:122.

Pornsuriyasak P et al: Disseminated stronglyloidiasis successfully treated with extended duration ivermectin combined with albendazole: a case report of intractable strongyloidiasis. Southeast Asian J Trop Med Public Health 2004;35:531.

Trichinosis (Trichinelliosis, Trichinellosis)

Essentials of Diagnosis

  • History of ingestion of raw or inadequately cooked pork, boar, or bear.

  • First week: diarrhea, cramps, malaise.

  • Second week to 1–2 months: muscle pain and tenderness, fever, periorbital and facial edema, conjunctivitis, systemic toxicity.

  • Eosinophilia and elevated serum enzymes; positive serologic tests; larvae in muscle biopsy.


General Considerations

Trichinosis is caused worldwide by Trichinella spiralis. The disease is present wherever pork is eaten but is a greater problem in many temperate areas than in the tropics. Four other species of Trichinella have been recognized in humans: T nativa appears to be restricted to Arctic and sub-Arctic regions (including Alaska) and T nelsoni to tropical Africa. T pseudospiralis, reported rarely worldwide, occurs as a persistent muscular infection accompanied by prolonged myalgia, muscular weakness and swelling, elevated muscle enzymes, and asthenia. T britovi occurs in palaearctic areas of Europe and Asia.

Human infections occur sporadically or in outbreaks. Infection is usually acquired by eating viable encysted larvae in raw or uncooked pork or pork products. Ground beef has also been a source of infection when adulterated with pork or inadvertently contaminated in a common meat grinder. In some cases, the source of infection is the flesh of dogs (East Asia), horses (France), or wild animals, particularly bears, walruses, bush pigs, foxes, or cougars. In the United States, there has been a marked reduction in prevalence in pigs (rates in commercial pork are nil to 0.007%). As a result, only about fifty human infections have been reported yearly, 60% in association with eating wild game, mainly bear.

Gastric juices liberate the encysted larvae. They rapidly mature and mate, and the adult female then burrows into the mucosa of the small intestine. Within 4–5 days, the female begins to discharge viviparous larvae (100 × 6 mcm) that are disseminated via the lymphatics and bloodstream to most body tissues. Larvae that reach striated muscle encyst and remain viable for months to years; those that reach other tissues are rapidly destroyed. The adult worms (2–3.6 mm × 75–90 mcm) survive for up to about 6 weeks.

In the natural cycle, larvae develop into adult worms in the intestines when a carnivore or omnivore ingests parasitized muscle. Pigs generally become infected by feeding on uncooked food scraps or, less often, by eating infected rats. Other reservoir hosts include swine, dogs, cats, rats, and many wild animals, including the wolf, bear, and boar; marine animals in the Arctic; and the hyena, jackal, and lion in the tropics.

Clinical Findings

A. Symptoms and Signs

The incubation period is 2–7 days (range: 12 hours to 28 days). Severity depends on intensity of infection, tissues invaded, immune status and age of the host (children have less severe infections), and perhaps the strain of the parasite. Findings range from asymptomatic to a mild febrile illness with short-lasting symptoms to a severe progressive illness with multiple system involvement that in rare cases is fatal.

1. Intestinal stage

When present, intestinal symptoms persist for 1–7 days: diarrhea, abdominal cramps, and malaise are the major findings; nausea and vomiting occur less frequently; and constipation is uncommon. Fever, eosinophilia, and leukocytosis are rare during the first week.

2. Muscle invasion stage

This begins at the end of the first week and lasts about 6 weeks. Parasitized muscles show an intense inflammatory reaction. Findings include fever (low-grade to marked); muscle pain and tenderness, edema, and spasm; periorbital and facial edema; sweating; photophobia and conjunctivitis; weakness or prostration; pain on swallowing; dyspnea, coughing, and hoarseness; subconjunctival, retinal, and nail splinter hemorrhages; and rashes and formication. The most frequently parasitized muscles and sites of findings are the masseters, tongue, diaphragm, intercostals, extraocular, laryngeal, paravertebral, nuchal, deltoid, pectoral, gluteus, biceps, and gastrocnemius. Inflammatory reactions around larvae that reach tissues other than muscle may result in a broad range of findings, including the development of meningitis, encephalitis, myocarditis, bronchopneumonia, nephritis, and peripheral and cranial nerve disorders.

3. Convalescent stage

This generally begins in the second month but in severe infections may not begin before 3 months or longer. Vague muscle pains and malaise may persist for several more months. Permanent muscular atrophy has been reported.

B. Laboratory Findings

The diagnosis is supported by findings of eosinophilia, elevated serum muscle enzymes (creatine kinase, lactate dehydrogenase, aspartate aminotransferase), and positive serologic tests. There may be a marked hypergammaglobulinemia with reversal of the albumin-globulin ratio. Absence of an elevated sedimentation rate is a useful diagnostic clue. Confirmation of the diagnosis is by detection of larvae in muscle biopsy specimens.

Leukocytosis and eosinophilia appear during the second week. The proportion of eosinophils rises to a maximum of 20–90% in the third or fourth week and then slowly declines to normal over the next few months.

Serologic tests can detect most clinically manifest cases but are not sufficiently sensitive to detect low-level infections (ie, a few larvae per gram of ingested muscle). More than one antibody test should be used and then repeated to observe for seroconversion or for a rising titer. Seropositivity may not appear for 3–5 weeks, peak in 2–3 months, and remain detectable for 2–3 years. The ELISA becomes positive in 80–100% of symptomatic persons. The bentonite flocculation (BF) test (positive titer > 1:5) is highly sensitive and specific. The immunofluorescent test (positive titer > 16) may become positive in the second week. IgM and IgE antibodies may also appear but are less sensitive


indicators of infection than IgG. Testing by immunoblot is also available. Circulating antigen—now being evaluated—can be detected about 2 weeks after infection in heavily infected persons and in 3–4 weeks in light infections. The intradermal test is no longer recommended, as it may remain positive for years and batches of antigen vary in potency.

Adult worms may be looked for in feces, though they are seldom found. In the second week, there are occasional larvae in blood, duodenal washings, and, rarely, in centrifuged spinal fluid. In the third to fourth weeks, biopsy of skeletal muscle (approximately 1 cm3) may be definitive (particularly gastrocnemius and pectoralis), preferably at a site of swelling or tenderness or near tendinous insertions. Portions of the specimen should be examined microscopically by compression between glass slides, by digestion, and by preparation of multiple histologic sections. If the biopsy is done too early, larvae may not be detectable. Myositis even in the absence of larvae is a significant finding.

C. Imaging

Chest films during the acute phase may show disseminated or localized infiltrates. Late calcification of muscle cysts cannot be detected radiologically.


The more important complications are granulomatous pneumonitis, encephalitis, and cardiac failure.

Differential Diagnosis

Because of its protean manifestations, trichinosis may resemble many other diseases. Eosinophilia, muscle pain and tenderness, and fever should lead the physician to consider collagen vascular disorders such as dermatomyositis or polyarteritis nodosa, which is generally accompanied by an elevated sedimentation rate.


Treatment is principally supportive, since in most cases recovery is spontaneous without sequelae.

A. Intestinal Phase

Though supporting evidence for efficacy is limited, albendazole, because of its relatively high absorption and freedom from adverse reactions, is proposed as the drug of choice in a dosage of 400 mg orally twice daily for 10–15 days. Mebendazole is an alternative drug at a dosage of 200–400 mg orally three times daily for 3 days, followed by 400–500 mg three times daily for 10–15 days. Corticosteroids are contraindicated in the intestinal phase.

B. Muscle Invasion Phase

In this stage, severe infections require hospitalization and high doses of corticosteroids (40–60 mg/d for 1–2 days), followed by lower doses for several days or weeks to control symptoms. However, because corticosteroids may suppress the inflammatory response to adult worms, they should be used only when symptoms are severe. Although drug treatment has not been shown to be effective in the muscle invasion stage, albendazole or mebendazole can be tried.


The frequency and intensity of infection in the United States and other countries have been significantly reduced by public health measures to prevent feeding of uncooked garbage to hogs and by animal inspection (not in the United States). The chief safeguard against trichinosis is adequate cooking of pork to 160°F (71°C) or by freezing meat at -17°C for 20 days (longer if meat is over 15 cm thick). T nativa in game is often relatively resistant to freezing. Low doses of gamma irradiation are also effective in killing larvae.


Death is rare—sometimes within 2–3 weeks in overwhelming infections, more often in 4–8 weeks from a major complication such as cardiac failure or pneumonia.

Centers for Disease Control and Prevention (CDC): Trichinellosis associated with bear meat—New York and Tennessee, 2003. MMWR Morb Mortal Wkly Rep 2004;53:606.

Pozio E et al: Clinical aspects, diagnosis and treatment of trichinellosis. Expert Rev Anti Infect Ther 2003;1:471.

Puljiz I et al: Electrocardiographic changes and myocarditis in trichinellosis: a retrospective study of 154 patients. Ann Trop Med Parasitol 2005;99:403.

Watt G et al: Areas of uncertainty in the management of human trichinellosis: a clinical perspective. Expert Rev Anti Infect Ther 2004;2:649.

Trichuriasis (Trichocephaliasis, Whipworm)

Trichuris trichiura is a common intestinal parasite of humans throughout the world, particularly in the subtropics and tropics. Persons of all ages are affected, but infection is heaviest and most frequent in children. The slender worms, 30–50 mm in length, attach by means of their anterior whip-like end to the mucosa of the large intestine, particularly to the cecum. Eggs are passed in the feces but require 2–4 weeks for larval development after reaching the soil before becoming infective; thus, person-to-person transmission is not possible. Infections are acquired by ingestion of the infective egg. The larvae hatch in the small intestine and mature in the large bowel but do not migrate through the tissues.

Clinical Findings

A. Symptoms and Signs

Light (fewer than 10,000 eggs per gram of feces) to moderate infections rarely cause symptoms. Heavy


infections (30,000 or more eggs per gram of feces) may be accompanied by abdominal cramps, tenesmus, diarrhea, distention, flatulence, and nausea and vomiting. With persistent dysentery and blood loss into the stool, the trichuris dysentery syndrome can appear—particularly in malnourished young children—which is accompanied by anemia, rectal prolapse, clubbing of fingers, growth stunting, and possibly cognitive defects. Adult worms are sometimes seen in stools. Invasion of the appendix, with resulting appendicitis, is rare.

B. Laboratory Findings

Diagnosis is by identification of characteristic eggs and, sometimes, adult worms in stools. Eosinophilia (5–20%) is common with all but light infections. Charcot-Leyden crystals may be seen in stool. Severe iron deficiency anemia may be present with heavy infections. Adult worms are seen at colonoscopy.


Patients with asymptomatic light infections do not require treatment. For those with heavier or symptomatic infections, give mebendazole or albendazole. Thiabendazole should not be used because it is not effective and because it is potentially toxic. Iron replacement may be needed for anemia.

A. Albendazole

Albendazole, given orally at a single dose of 400 mg, has resulted in cure rates of 33–90%, with marked reduction in egg counts in those not cured. For persons with heavy infections, treatment should continue for 3 days. Albendazole should not be used in pregnancy.

B. Mebendazole

A dosage of 100 mg orally twice daily before or after meals for 3 days results in cure rates of 60–80%, with marked reduction in ovum counts in the remaining patients. It may be therapeutically advantageous for the tablets to be chewed before swallowing. In mild disease, a 500-mg dose may be sufficient, whereas in severe trichuriasis, a longer course of treatment (up to 6 days) or a repeat course will often be necessary. Gastrointestinal side effects from the drug are rare. The drug is contraindicated in pregnancy.

Adams VJ et al: Efficacy of albendazole against the whipworm Trichuris trichiura—a randomized, controlled trial. S Afr Med J 2004;94:972.

Elsayed S et al: Trichuris trichiura worm infection. Gastrointest Endosc 2004;60:990.

Nascimento-Carvalho CM et al: Prolonged treatment with albendazole for massive trichuriasis infection. Pediatr Infect Dis J 2004;23:1070.

Sirivichayakul C et al: The effectiveness of 3, 5 or 7 days of albendazole for the treatment of Trichuris trichiura infection. Ann Trop Med Parasitol 2003;97:847.

Visceral Larva Migrans (Toxocariasis)

Essentials of Diagnosis

  • Usually in children under age 5 with history of eating soil in association with puppies.

  • Fever, hepatomegaly, transient pulmonary infiltrates.

  • Moderate to high leukocytosis with persistent eosinophilia hypergammaglobulinemia, high titer anti-A and anti-B isehemagglutinins, positive serologic tests; larvae occasionally in liver biopsy.

General Considerations

Most visceral larva migrans cases are due to Toxocara canis, an ascarid of dogs and other canids; Toxocara cati in domestic cats has occasionally been implicated and rarely Belascaris procyonis of raccoons. The adult worms live in the intestinal tracts of their respective hosts and release large numbers of eggs in the stool.

The reservoir mechanism for T canis is latent infection in female dogs, which is reactivated during pregnancy. Transmission from mother to puppies is via the placenta and milk. Most eggs passed to the environment are from puppies (2 weeks to 6 months) and lactating bitches (up to 6 months after parturition). The life cycle of T cati is similar, but transplacental transmission does not occur.

Human infections are sporadic and probably occur worldwide. In the United States, antibody seroprevalence is 5–7%. Infection is generally in dirt-eating young children who ingest T canis or T cati eggs from soil or sand contaminated with animal feces, most often from puppies. Direct contact with infected animals does not produce infection, as the eggs require a 3- to 4-week extrinsic incubation period to become infective; thereafter, eggs in soil remain infective for months to years.

In humans, hatched larvae are unable to mature but continue to migrate through the tissues for up to 6 months. Eventually they lodge in various organs, particularly the lungs and liver and less often the brain, eyes, and other tissues, where they produce eosinophilic granulomas up to 1 cm in diameter.

Clinical & Laboratory Findings

A. Acute Infection

Migrating larvae may induce fever, cough, urticaria, wheezing, hepatosplenomegaly, and lymphadenopathy. A variety of other findings may occur when other organs are invaded, including myelitis, encephalitis,


and carditis. The acute phase may last 2–3 weeks, but resolution of all physical and laboratory findings may take up to 18 months.

Leukocytosis is marked (may exceed 100,000/mcL), with 30–80% due to eosinophils. Hyperglobulinemia occurs when the liver is extensively invaded and is a useful clue in diagnosis. Nonspecific isohemagglutinin titers (anti-A and anti-B) are usually greater than 1:1024. Chest radiographs may show infiltrates. Ultrasonography may detect 1-cm hypoechoic lesions in the liver, each with a thread-like hyperechoic line. With central nervous system involvement, the cerebrospinal fluid may show a marked eosinophilic pleocytosis. No parasitic forms can be found by stool examination.

Antibody detection is generally the only way to confirm a clinical diagnosis. The ELISA, the most specific (92%) and sensitive (78%) test, may permit a presumptive diagnosis, though it does not distinguish acute from prior infection. However, rising or falling titers with twofold differences are consistent with acute disease. IgE levels are also increased. Definitive diagnosis is by percutaneous liver biopsy or by direct biopsy of a granuloma at laparoscopy (mixed inflammatory infiltrate with numerous eosinophils), but these procedures are seldom justified and may not yield larvae.

B. Ocular Toxocariasis

Most cases occur in children, most commonly 5–10 years old, who present with visual impairment in one eye and sometimes leukocoria, squint, and red eye. The principal pathologic entity is eosinophilic granuloma of the retina that resembles retinoblastoma. Until the recent development of the Toxocara ELISA test, this resulted in the enucleation of many eyes. Other common clinical findings are peripheral retinochoroiditis, a diffuse, painless endophthalmitis; posterior pole granuloma; and a peripheral inflammatory mass. Uncommonly seen are an iris nodule, optic nerve granuloma, uniocular pars planitis, and a migrating retinal nematode. Ocular toxocariasis, which is generally recognized years after the acute infection, is generally not associated with peripheral eosinophilia, hypergammaglobulinemia, or isohemagglutinin elevation. Serum ELISA tests may be positive, but a negative test does not rule out the diagnosis. If doubt exists about whether a patient with a positive serum ELISA test has toxocariasis or retinoblastoma, the vitreous humor should be examined for ELISA antibody (specificity has been reported as greater than 90% at a titer of 1:32 or higher) and eosinophils. High-resolution CT scanning of the orbit should be done.

Prevention, Treatment, & Prognosis

Disease in humans is best prevented by preventing defecation by dogs and cats in areas where children play and by periodic treatment of puppies, kittens, and nursing dog and cat mothers, starting at 2 weeks postpartum, repeating at weekly intervals for 3 weeks and then every 6 months.

A. Acute Infection

Treatment of symptomatic persons is primarily supportive. Although there is no proved specific treatment, the following drugs can be tried: albendazole (400 mg orally twice daily for 21 days), mebendazole (200 mg orally twice daily for 21 days), or ivermectin. Theoretically, release of antigens from dying parasites may exacerbate clinical and laboratory findings. Corticosteroids, antibiotics, antihistamines, and analgesics may be needed to provide symptomatic relief. Symptoms may persist for months but generally clear within 1–2 years. The ultimate outcome is usually good, but permanent neuropsychological deficits have been seen.

B. Ocular Toxocariasis

Treatment includes oral and subconjunctival corticosteroids, an anthelmintic drug, vitrectomy for vitreous traction, and laser photocoagulation. Partial or total permanent visual impairment is rare.

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Eberhardt O et al: Eosinophilic meningomyelitis in toxocariasis: case report and review of the literature. Clin Neurol Neurosurg 2005;107:423.

Good B et al: Ocular toxocariasis in schoolchildren. Clin Infect Dis 2004;39:173.

Moreira-Silva SF et al: Toxocariasis of the central nervous system: with report of two cases. Rev Soc Bras Med Trop 2004;37: 169.

Vidal JE et al: Eosinophilic meningoencephalitis due to Toxocara canis: case report and review of the literature. Am J Trop Med Hyg 2003;69:341.