Current Medical Diagnosis & Treatment 2015

35

Protozoal & Helminthic Infections

Philip J. Rosenthal, MD

PROTOZOAL INFECTIONS

AFRICAN TRYPANOSOMIASIS (Sleeping Sickness)

 ESSENTIALS OF DIAGNOSIS

 Exposure to tsetse flies; chancre at bite site uncommon.

 Hemolymphatic disease: Irregular fever, headache, joint pain, rash, edema, lymphadenopathy.

 Meningoencephalitic disease: Somnolence, severe headache, progressing to coma.

 Trypanosomes in blood or lymph node aspirates; positive serologic tests.

 Trypanosomes and increased white cells and protein in cerebrospinal fluid.

 General Considerations

African trypanosomiasis is caused by the hemoflagellates Trypanosoma brucei rhodesiense and Trypanosoma brucei gambiense. The organisms are transmitted by bites of tsetse flies (genus Glossina), which inhabit shaded areas along streams and rivers. Trypanosomes ingested in a blood meal develop over 18–35 days in the fly; when the fly feeds again on a mammalian host, the infective stage is injected. Human disease occurs in rural areas of sub-Saharan Africa from south of the Sahara to about 30 degrees south latitude. T b gambiense causes West African trypanosomiasis, and is transmitted in the moist sub-Saharan savannas and forests of west and central Africa. T b rhodesiense causes East African trypanosomiasis, and is transmitted in the savannas of east and southeast Africa.

T b rhodesiense infection is primarily a zoonosis of game animals and cattle; humans are infected sporadically. Humans are the principal mammalian host for T b gambiense, but domestic animals can be infected. The largest number of cases is in the Democratic Republic of the Congo. The incidence of trypanosomiasis is probably decreasing, with estimates of 50,000–70,000 cases and 48,000 deaths annually, the large majority due to T b gambiense, leading to the loss of 1.5 million disability-adjusted life years. Infections are rare among travelers, including visitors to game parks.

 Clinical Findings

  1. Symptoms and Signs
  2. West African trypanosomiasis—Chancres at the site of the bite are uncommon. After an asymptomatic period that may last for months,hemolymphatic diseasepresents with fever, headache, myalgias, arthralgias, weight loss, and lymphadenopathy, with discrete, nontender, rubbery nodes, referred to as Winterbottom sign when in a posterior cervical distribution. Other common signs are mild splenomegaly, transient edema, and a pruritic erythematous rash. Febrile episodes may be broken by afebrile periods of up to several weeks. The hemolymphatic stage progresses over months tomeningoencephalitic disease, with somnolence, irritability, personality changes, severe headache, and parkinsonian symptoms progressing to coma and death.
  3. East African trypanosomiasis—Chancres at the bite site are more commonly recognized withT b rhodesienseinfection, with a painful lesion of 3–10 cm and regional lymphadenopathy that appears about 48 hours after the tsetse fly bite and lasts 2–4 weeks. East African disease follows a much more acute course, with the onset of symptoms usually within a few days of the insect bite. The hemolymphatic stage includes intermittent fever and rash, but lymphadenopathy is less common than with West African disease. Myocarditis can cause tachycardia and death due to arrhythmias or heart failure. If untreated, East African trypanosomiasis progresses over weeks to months to meningoencephalitic disease, somnolence, coma, and death.
  4. Laboratory Findings

Diagnosis can be difficult, and definitive diagnosis requires identification of trypanosomes. Microscopic examination of fluid expressed from a chancre or lymph node may show motile trypanosomes or, in fixed specimens, parasites stained with Giemsa. During the hemolymphatic stage, detection of parasites in Giemsa-stained blood smears is common in East African disease but difficult in West African disease. Serial specimens should be examined, since parasitemias vary greatly over time. Meningoencephalitic (or second stage) disease is defined by the World Health Organization (WHO) as cerebrospinal fluid (CSF) showing at least five mononuclear cells per microliter, elevated protein, or presence of trypanosomes. Concentration techniques can aid identification of parasites in blood or CSF. Serologic tests are also available. The simple card agglutination test for trypanosomes (CATT) has excellent sensitivity and specificity for West African disease and can be performed in the field; however, the diagnosis should be confirmed by identification of the parasites. Polymerase chain reaction (PCR) and related molecular diagnostic tests appear to have excellent sensitivity and specificity, but these are not yet standardized or routinely available.

 Treatment

Detection of trypanosomes is a prerequisite for treatment of African trypanosomiasis because of the significant toxicity of most available therapies. Treatment recommendations depend on the type of trypanosomiasis (Table 35–1), which is determined by geography, and stage of disease, which requires examination of CSF.

Table 35–1. Treatment of African trypanosomiasis.

  1. West African Trypanosomiasis
  2. Early stage infection—Pentamidine (4 mg/kg intramuscularly or intravenously every day or every other day for 7 days) is used to treat infection that does not involve the central nervous system (CNS). The side effects of pentamidine include immediate hypotension; tachycardia; gastrointestinal symptoms during administration; sterile abscesses; and pancreatic (hypoglycemia), liver, and kidney abnormalities. An alternate drug is eflornithine (100 mg/kg/d intravenously every 6 hours for 14 days).
  3. Late stage infection—Eflornithine is the drug of choice for infection that involves the CNS; the dosage is the same as that used to treat early disease. Eflornithine has less toxicity than older trypanocidal drugs, but it can cause gastrointestinal symptoms and bone marrow suppression and is limited by lack of availability and the need for infusions four times daily. Alternative therapies are melarsoprol (see below) or nifurtimox (5 mg/kg orally three times per day for 14 days), and drug combinations (eg, oral nifurtimox plus twice-daily eflornithine) may offer improved efficacy over monotherapies, with simplified regimens and decreased toxicity. Some authorities now consider nifurtimox-eflornithine combination therapy to be the standard of care for late-stage West African trypanosomiasis.
  4. East African Trypanosomiasis

Pentamidine and eflornithine are not reliably effective, and early disease is treated with suramin. The dosing regimens of suramin vary (eg, 100–200 mg test dose, then 20 mg/kg [maximum 1 g] intravenously on days 1, 3, 7, 14, and 21 or weekly for 5 doses). Suramin toxicities include vomiting and, rarely, seizures and shock during infusions as well as subsequent fever, rash, headache, neuropathy, and kidney and bone marrow dysfunction.

Suramin does not enter the CNS, so East African trypanosomiasis involving the CNS is treated with melarsoprol (three series of 3.6 mg/kg/d intravenously for 3 days, with 7-day breaks between the series or a 10-day intravenous course with 0.6 mg/kg on day 1, 1.2 mg/kg on day 2, and 1.8 mg/kg on days 3–10). Melarsoprol also acts against West African disease, but eflornithine is preferred due to its lower toxicity. Immediate side effects of melarsoprol include fever and gastrointestinal symptoms. The most important side effect is a reactive encephalopathy that can progress to seizures, coma, and death. To help avoid this side effect, corticosteroids are coadministered (recommended regimens include dexamethasone 1 mg/kg/d intravenously for 2–3 days or oral prednisolone 1 mg/kg/d for 5 days, and then 0.5 mg/kg/d until treatment completion). In addition, increasing resistance to melarsoprol is a serious concern. Suramin and melarsoprol are available in the United States from the CDC Drug Service (www.cdc.gov/laboratory/drugservice).

 Prevention & Control

Individual prevention in endemic areas should include long sleeves and pants, insect repellents, and mosquito nets. Control programs focusing on vector elimination and treatment of infected persons and animals have shown good success in many areas but suffer from limited resources.

Barrett MP et al. Management of trypanosomiasis and leishmaniasis. Br Med Bull. 2012;104:175–96. [PMID: 23137768]

Brun R et al. Human African trypanosomiasis. Infect Dis Clin North Am. 2012 Jun;26(2):261–73. [PMID: 22632638]

Kennedy PG. Clinical features, diagnosis, and treatment of human African trypanosomiasis (sleeping sickness). Lancet Neurol. 2013 Feb;12(2):186–94. [PMID: 23260189]

AMERICAN TRYPANOSOMIASIS (Chagas Disease)

 ESSENTIALS OF DIAGNOSIS

Acute stage

 Inflammatory lesion at inoculation site.

 Fever.

 Hepatosplenomegaly; lymphadenopathy.

 Myocarditis.

 Parasites in blood is diagnostic.

Chronic stage

 Heart failure, cardiac arrhythmias.

 Thromboembolism.

 Megaesophagus; megacolon.

 Serologic tests are usually diagnostic.

 General Considerations

Chagas disease is caused by Trypanosoma cruzi, a protozoan parasite found only in the Americas; it infects wild animals and to a lesser extent humans from southern South America to the southern United States. An estimated 8–10 million people are infected, mostly in rural areas. Control efforts in endemic countries have decreased disease incidence to about 40,000 new infections and 12,500 deaths per year. The disease is often acquired in childhood. In many countries in South America, Chagas disease is the most important cause of heart disease. In the United States, the vector is found, some animals are infected, and a few instances of local transmission 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 and infective forms are eliminated in feces. Infection in humans occurs when the parasite penetrates the skin through the bite wound, mucous membranes, or the conjunctiva. Transmission can also occur by blood transfusion, organ or bone marrow transplantation, congenital transfer, or ingestion of food contaminated with vector feces. From the bloodstream, T cruzi invades many cell types but has a predilection for myocardium, smooth muscle, and CNS glial cells. Multiplication causes cellular destruction, inflammation, and fibrosis, with progressive disease over decades.

 Clinical Findings

  1. Symptoms and Signs

As many as 70% of infected persons remain asymptomatic. The acute stage is seen principally in children and lasts 1–2 months. The earliest findings are at the site of inoculation either in the eye—Romaña sign (unilateral edema, conjunctivitis, and lymphadenopathy)—or in the skin—a chagoma (swelling with local lymphadenopathy). Subsequent findings include fever, malaise, headache, mild hepatosplenomegaly, and generalized lymphadenopathy. Acute myocarditis and meningoencephalitis are rare but can be fatal.

An asymptomatic latent period (indeterminate phase) may last for life, but symptomatic disease develops in 10–30% of infected individuals, commonly many years after infection.

Chronic Chagas disease generally manifests as abnormalities in cardiac and smooth muscle. Cardiac disease includes arrhythmias, heart failure, and embolic disease. Smooth muscle abnormalities lead to mega-esophagus and megacolon, with dysphagia, regurgitation, aspiration, constipation, and abdominal pain. These findings can be complicated by superinfections. In immunosuppressed persons, including AIDS patients and transplant recipients, latent Chagas disease may reactivate; findings have included brain abscesses and meningoencephalitis.

  1. Diagnostic Testing

Diagnosis should be considered in persons with suggestive findings who have resided in an endemic area. The diagnosis is made by detecting parasites. With acute infection, evaluation of fresh blood or buffy coats may show motile trypanosomes, and fixed preparations may show Giemsa-stained parasites. Trypanosomes may be identified in lymph nodes, bone marrow, or pericardial or spinal fluid. When initial tests are unrevealing in a suspicious case, xenodiagnosis using laboratory vectors, laboratory culture, or animal inoculation may provide a diagnosis, but these methods are expensive and slow.

Chronic Chagas disease is usually diagnosed serologically. Many different serologic assays are available, but sensitivity and specificity are not ideal, so confirmatory assays are advised after an initial positive test, as is standard for blood bank testing in South America. PCR may offer an important new modality for diagnosis, but assays are not standardized, and reliability and sensitivity of assays has been disappointing.

 Treatment

Treatment is inadequate because the two drugs used, benznidazole and nifurtimox, often cause severe side effects, must be used for long periods, and are ineffective against chronic infection. In acute and congenital infections, the drugs can reduce the duration and severity of infection, but cure is achieved in only about 70% of patients. During the chronic phase of infection, although parasitemia may disappear in up to 70% of patients, treatment does not clearly alter the progression of the disease. Nevertheless, there is general consensus that treatment should be considered in all T cruzi-infected persons regardless of clinical status or time since infection. In particular, treatment is recommended for acute, congenital, and reactivated infections and for children and young adults with chronic disease. Both benznidazole and nifurtimox are available in the United States from the CDC Drug Service (www.cdc.gov/laboratory/drugservice).

Benznidazole is generally preferred due to better efficacy and safety profiles; problems with drug availability have been resolved. It is given orally at a dosage of 5 mg/kg/d in two divided doses for 60 days. Its side effects include granulocytopenia, rash, and peripheral neuropathy. Nifurtimox is given orally in daily doses of 8–10 mg/kg in four divided doses after meals for 90–120 days. Side effects include gastrointestinal (anorexia, vomiting) and neurologic (headaches, ataxia, insomnia, seizures) symptoms, which appear to be reversible and to lessen with dosage reduction. Patients with chronic Chagas disease may also benefit from antiarrhythmic therapy, standard therapy for heart failure, and conservative and surgical management of megaesophagus and megacolon.

 Prevention & Control

In South America, a major eradication program based on improved housing, use of residual pyrethroid insecticides and pyrethroid-impregnated bed curtains, and screening of blood donors has achieved striking reductions in new infections. In endemic areas and ideally in donors from endemic areas, blood should not be used for transfusion unless at least two serologic tests are negative.

Bern C. Antitrypanosomal therapy for chronic Chagas’ disease. N Engl J Med. 2011 Jun 30;364(26):2527–34. [PMID: 21714649]

Rassi A Jr et al. American trypanosomiasis (Chagas disease). Infect Dis Clin North Am. 2012 Jun;26(2):275–91. [PMID: 22632639]

Ribeiro AL et al. Diagnosis and management of Chagas disease and cardiomyopathy. Nat Rev Cardiol. 2012 Oct;9(10):576–89. [PMID: 22847166]

LEISHMANIASIS

 ESSENTIALS OF DIAGNOSIS

 Sand fly bite in an endemic area.

 Visceral leishmaniasis: irregular fever, progressive hepatosplenomegaly, pancytopenia, wasting.

 Cutaneous leishmaniasis: chronic, painless, moist ulcers or dry nodules.

 Mucocutaneous leishmaniasis: destructive nasopharyngeal lesions.

 Amastigotes in macrophages in aspirates, touch preparations, or biopsies.

 Positive culture, serologic tests, PCR, or skin test.

 General Considerations

Leishmaniasis is a zoonosis transmitted by bites of sand flies of the genus Lutzomyia in the Americas and Phlebotomus elsewhere. When sand flies feed on an infected host, the parasitized cells are ingested with the blood meal. Leishmaniasis is caused by about 20 species of Leishmania; taxonomy is complex. Clinical syndromes are generally dictated by the infecting species, but some species can cause more than one syndrome.

An estimated 350 million persons are at risk for leishmaniasis. The estimated annual incidence of disease is 1–1.5 million new cases of cutaneous and 500,000 cases of visceral disease, leading to an estimated 50,000–60,000 deaths. The incidence of disease is increasing in many areas.

Visceral leishmaniasis (kala azar) is caused mainly by Leishmania donovani in the Indian subcontinent and East Africa; Leishmania infantum in the Mediterranean, Middle East, China, parts of Asia, and Horn of Africa; and Leishmania chagasi in South and Central America. Other species may occasionally cause visceral disease. Over 90% of cases occur in five countries: India, Bangladesh, Nepal, Sudan, and Brazil. In each locale, the disease has particular clinical and epidemiologic features. 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%.

Old World cutaneous leishmaniasis is caused mainly by Leishmania tropicaLeishmania major, and Leishmania aethiopica in the Mediterranean, Middle East, Africa, Central Asia, and Indian subcontinent. New World cutaneous leishmaniasis is caused by Leishmania mexicana, Leishmania amazonensis, and the species listed below for mucocutaneous disease in Central and South America.Mucocutaneous leishmaniasis (espundia) occurs in lowland forest areas of the Americas and is caused by Leishmania braziliensis, Leishmania panamensis, and Leishmania peruviana.

 Clinical Findings

  1. Symptoms and Signs
  2. Visceral leishmaniasis (kala azar)—Most infections are subclinical, but a small number progress to full-blown disease. A local nonulcerating nodule at the site of the sand fly bite may precede systemic manifestations but usually is inapparent. The onset of illness may be acute, within 2 weeks of infection, or insidious. Symptoms and signs include fever, chills, sweats, weakness, anorexia, weight loss, cough, and diarrhea. The spleen progressively becomes greatly enlarged, firm, and nontender. The liver is somewhat enlarged, and generalized lymphadenopathy may occur. Hyperpigmentation of skin can be seen, leading to the name kala azar (“black fever”). Other signs include skin lesions, petechiae, gingival bleeding, jaundice, edema, and ascites. As the disease progresses, severe wasting and malnutrition are seen; death eventually occurs, often due to secondary infections, within months to a few years. Post-kala azar dermal leishmaniasis may appear after apparent cure in the Indian subcontinent and Sudan. It may simulate leprosy, with hypopigmented macules or nodules developing on preexisting lesions. Viscerotropic leishmaniasis has been reported in small numbers of American military personnel in the Middle East, with mild systemic febrile illnesses afterL tropicainfections.
  3. Old World and New World cutaneous leishmaniasis—Cutaneous swellings appear 2 weeks to several months after sand fly bites and can be single or multiple. Characteristics of lesions and courses of disease vary 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 (Figure 35–1). Satellite lesions may be present. The lesions are painless unless secondarily infected. Local lymph nodes may be enlarged. Systemic symptoms are uncommon, but fever, constitutional symptoms, and regional lymphadenopathy may be seen. For most species, healing occurs spontaneously in months to a few years, but scarring is common.

 Figure 35–1. Skin ulcer due to cutaneous leishmaniasis. (From D. S. Martin, Public Health Image Library, CDC.)

Leishmaniasis recidivans is a relapsing form of L tropica infection associated with hypersensitivity, in which the primary lesion heals centrally, but spreads laterally, with extensive scarring. Diffuse cutaneous leishmaniasis involves spread from a central lesion to local dissemination of nodules and a protracted course. Disseminated cutaneous leishmaniasis involves multiple nodular or ulcerated lesions, often with mucosal involvement.

  1. Mucocutaneous leishmaniasis (espundia)—In Latin America, mucosal lesions develop in a small percentage of persons infected withL braziliensisand some other species, usually months to years after resolution of a cutaneous lesion. Nasal congestion is followed by ulceration of the nasal mucosa and septum, progressing to involvement of the mouth, lips, palate, pharynx, and larynx. Extensive destruction can occur, and secondary bacterial infection is common.
  2. Infections in patients with AIDS—Leishmaniasis is an opportunistic infection in persons with AIDS seen in southern Europe and other areas. Visceral leishmaniasis can present late in the course of HIV infection, with fever, hepatosplenomegaly, and pancytopenia. The gastrointestinal tract, respiratory tract, and skin may also be involved.
  3. Laboratory Findings

Identifying amastigotes within macrophages in tissue samples provides a definitive diagnosis. In visceral leishmaniasis, fine-needle aspiration of the spleen for culture and tissue evaluation is generally safe, and yields a diagnosis in over 95% of cases. Bone marrow aspiration is less sensitive but safer and diagnostic in most cases, and Giemsa-stained buffy coat of peripheral blood may occasionally show organisms. Cultures with media available from the CDC will grow promastigotes within a few days to weeks. PCR can also identify the infection. Serologic tests may facilitate diagnosis, but none are sufficiently sensitive or specific to be used alone. Numerous antibody-based rapid diagnostic tests are available; these have shown good specificity but limitations in sensitivity outside of India. Forcutaneous lesions, biopsies should be taken from the raised border of a skin lesion, with samples for histopathology, touch preparation, and culture. The histopathology shows inflammation with mononuclear cells. Macrophages filled with amastigotes may be present, especially early in infection. An intradermal leishmanin (Montenegro) skin test is positive in most individuals with cutaneous disease but negative in those with progressive visceral or diffuse cutaneous disease; this test is not approved in the United States. In mucocutaneous leishmaniasis, diagnosis is established by detecting amastigotes in scrapings, biopsy preparations, or aspirated tissue fluid, but organisms may be rare. Cultures from these samples may grow organisms. Serologic studies are often negative, but the leishmanin skin test is usually positive.

 Treatment

  1. Visceral Leishmaniasis

The treatment of choice for visceral leishmaniasis is liposomal amphotericin B (approved by the FDA), which is generally effective and well tolerated but very expensive. Standard dosing is 3 mg/kg/d intravenously on days 1–5, 14, and 21. Conventional amphotericin B deoxycholate, which is much less expensive, is also highly effective but with more toxicity. It is administered as a slow intravenous infusion of 1 mg/kg/d for 15–20 days or 0.5–1 mg/kg every second day for up to 8 weeks. Infusion-related side effects with conventional or liposomal amphotericin B include gastrointestinal symptoms, fever, chills, dyspnea, hypotension, and hepatic and renal toxicity.

Pentavalent antimonials remain the most commonly used drugs to treat leishmaniasis in most areas. Response rates are good outside India, but in India, resistance is a major problem. Two preparations are available, sodium stibogluconate in the United States and many other areas and meglumine antimonate in Latin America and francophone countries; the compounds appear to have comparable activities. In the United States, sodium stibogluconate can be obtained from the CDC Drug Service (www.cdc.gov/laboratory/drugservice).

Treatment with either antimonial is given once daily at a dose of 20 mg/kg/d intravenously (preferred) or intramuscularly for 20 days for cutaneous leishmaniasis and 28 days for visceral or mucocutaneous disease. Toxicity increases over time, with development of gastrointestinal symptoms, fever, headache, myalgias, arthralgias, pancreatitis, and rash. Intramuscular injections can cause sterile abscesses. Monitoring should include serial ECGs, and changes are indications for discontinuation to avoid progression to serious arrhythmias.

Miltefosine is the first oral drug for the treatment of leishmaniasis, and it is registered in India for this indication. It has demonstrated excellent results in India, but after a decade of use, efficacy may be decreasing. It can be administered at a daily oral dose of 2.5 mg/kg in two divided doses for 28 days. A 28-day course of miltefosine (2.5 mg/kg/d) is also effective for the treatment of New World cutaneous leishmaniasis. Vomiting, diarrhea, and elevations in transaminases and kidney function studies are common, but generally short-lived, side effects.

The aminoglycoside paromomycin (11 mg/kg/d intramuscularly for 21 days) was shown to be similarly efficacious to amphotericin B for the treatment of visceral disease in India, where it is approved for this indication. It is much less expensive than liposomal amphotericin B or miltefosine. Paromomycin has shown relatively poor efficacy in Africa. The drug is well tolerated; side effects include ototoxicity and reversible elevations in liver enzymes.

The use of drug combinations to improve treatment efficacy, shorten treatment courses, and reduce the selection of resistant parasites has been actively studied. In India, compared to a standard 30-day (treatment on alternate days) course of amphotericin, noninferior efficacy and decreased adverse events were seen with a single dose of liposomal amphotericin plus a 7-day course of miltefosine, a single dose of liposomal amphotericin plus a 10-day course of paromomycin, or a 10-day course of miltefosine plus paromomycin. In East Africa, compared to a standard 30-day course of sodium stibogluconate, similar efficacy was seen with a 17-day course of sodium stibogluconate plus paromomycin.

  1. Cutaneous Leishmaniasis

In the Old World, cutaneous leishmaniasis is generally self-healing over some months and does not metastasize to the mucosa, so it may be justified to withhold treatment in regions without mucocutaneous disease if lesions are small and cosmetically unimportant. Lesions on the face or hands are generally treated. New World leishmaniasis has a greater risk of progression to mucocutaneous disease, so treatment is more often warranted. Standard therapy is with pentavalent antimonials for 20 days, as described above. Other treatments include those discussed above for visceral disease, azole antifungals, and allopurinol. In studies in South America, a 28-day course of miltefosine was superior to a 20-day course of meglumine antimoniate, and oral fluconazole also showed good efficacy. In Tunisia, topical paromomycin for 20 days showed good efficacy. Topical therapy has included intralesional antimony, paromomycin ointment, cryotherapy, local heat, and surgical removal. Diffuse cutaneous leishmaniasis and related chronic skin processes generally respond poorly to therapy.

  1. Mucocutaneous Leishmaniasis

Cutaneous infections from regions where parasites include those that cause mucocutaneous disease (eg, L braziliensis in parts of Latin America) should all be treated to help prevent disease progression. Treatment of mucocutaneous disease with antimonials is disappointing, with responses in only about 60% in Brazil. Other therapies listed above for visceral leishmaniasis may also be used, although they have not been well studied for this indication.

 Prevention & Control

Personal protection measures for avoidance of sand fly bites include use of insect repellants, fine-mesh insect netting, long sleeves and pants, and avoidance of warm shaded areas where flies are common. Disease control measures include destruction of animal reservoir hosts, mass treatment of humans in disease-prevalent areas, residual insecticide spraying in dwellings, limiting contact with dogs and other domesticated animals, and use of permethrin-impregnated collars for dogs.

Ben Salah A et al. Topical paromomycin with or without gentamicin for cutaneous leishmaniasis. N Engl J Med. 2013 Feb 7;368(6):524–32. [PMID: 23388004]

Goto H et al. Cutaneous and mucocutaneous leishmaniasis. Infect Dis Clin North Am. 2012 Jun;26(2):293–307. [PMID: 22632640]

Murray HW. Leishmaniasis in the United States: treatment in 2012. Am J Trop Med Hyg. 2012 Mar;86(3):434–40. [PMID: 22403313]

Musa A et al. Sodium stibogluconate (SSG) & paromomycin combination compared to SSG for visceral leishmaniasis in East Africa: a randomised controlled trial. PLoS Negl Trop Dis. 2012;6(6):e1674. [PMID: 22724029]

Rubiano LC et al. Noninferiority of miltefosine versus meglumine antimoniate for cutaneous leishmaniasis in children. J Infect Dis. 2012 Feb 15;205(4):684–92. [PMID: 22238470]

Sundar S et al. Efficacy of miltefosine in the treatment of visceral leishmaniasis in India after a decade of use. Clin Infect Dis. 2012 Aug;55(4):543–50. [PMID: 22573856]

van Griensven J et al. Visceral leishmaniasis. Infect Dis Clin North Am. 2012 Jun;26(2):309–22. [PMID: 22632641]

MALARIA

 ESSENTIALS OF DIAGNOSIS

 Residence or exposure in a malaria-endemic area.

 Intermittent attacks of chills, fever, and sweating.

 Headache, myalgia, vomiting, splenomegaly; anemia, thrombocytopenia.

 Intraerythrocytic parasites identified in thick or thin blood smears.

 Complications of falciparum malaria: cerebral malaria, severe anemia, hypotension, noncardiogenic pulmonary edema, acute kidney injury, hypoglycemia, acidosis, and hemolysis.

 General Considerations

Malaria is the most important parasitic disease of humans, causing hundreds of millions of illnesses and nearly a million deaths each year. The disease is endemic in most of the tropics, including much of South and Central America, Africa, the Middle East, the Indian subcontinent, Southeast Asia, and Oceania. Transmission, morbidity, and mortality are greatest in Africa, where most deaths from malaria are in young children. Malaria is also common in travelers from nonendemic areas to the tropics.

Four species of the genus Plasmodium classically cause human malaria. Plasmodium falciparum is responsible for nearly all severe disease. It is endemic in most malarious areas and is by far the predominant species in Africa. Plasmodium vivax is about as common as P falciparum, except in Africa. P vivax uncommonly causes severe disease, although this outcome may be more common than previously appreciated. Plasmodium ovale and Plasmodium malariae are much less common causes of disease, and generally do not cause severe illness. Plasmodium knowlesi, a parasite of macaque monkeys, is now recognized to cause occasional illnesses, including some severe disease, in humans in Southeast Asia.

Malaria is transmitted by the bite of infected female anopheline mosquitoes. During feeding, mosquitoes inject sporozoites, which circulate to the liver, and rapidly infect hepatocytes, causing asymptomatic liver infection. Merozoites are subsequently released from the liver, and they rapidly infect erythrocytes to begin the asexual erythrocytic stage of infection that is responsible for human disease. Multiple rounds of erythrocytic development, with production of merozoites that invade additional erythrocytes, lead to large numbers of circulating parasites and clinical illness. Some erythrocytic parasites also develop into sexual gametocytes, which are infectious to mosquitoes, allowing completion of the life cycle and infection of others.

Malaria may uncommonly be transmitted from mother to infant (congenital malaria), by blood transfusion, and in nonendemic areas by mosquitoes infected after biting infected immigrants or travelers. In P vivax and P ovale, parasites also form dormant liver hypnozoites, which are not killed by most drugs, allowing subsequent relapses of illness after initial elimination of erythrocytic infections. For all plasmodial species, parasites may recrudesce following initial clinical improvement after suboptimal therapy.

In highly endemic regions, where people are infected repeatedly, antimalarial immunity prevents severe disease in most older children and adults. However, young children, who are relatively nonimmune, are at high risk for severe disease from P falciparum infection, and this population is responsible for most deaths from malaria. Pregnant women are also at increased risk for severe falciparum malaria. In areas with lower endemicity, individuals of all ages commonly present with uncomplicated or severe malaria. Travelers, who are generally nonimmune, are at high risk for severe disease from falciparum malaria at any age.

 Clinical Findings

  1. Symptoms and Signs

An acute attack of malaria typically begins with a prodrome of headache and fatigue, followed by fever. A classic malarial paroxysm includes chills, high fever, and then sweats. Patients may appear to be remarkably well between febrile episodes. Fevers are usually irregular, especially early in the illness, but without therapy may become regular, with 48- (P vivax and P ovale) or 72-hour (P malariae) cycles, especially with non-falciparum disease. Headache, malaise, myalgias, arthralgias, cough, chest pain, abdominal pain, anorexia, nausea, vomiting, and diarrhea are common. Seizures may represent simple febrile convulsions or evidence of severe neurologic disease. Physical findings may be absent or include signs of anemia, jaundice, splenomegaly, and mild hepatomegaly. Rash and lymphadenopathy are not typical in malaria, and thus suggestive of another cause of fever.

In the developed world, it is imperative that all persons with suggestive symptoms, in particular fever, who have traveled in an endemic area be evaluated for malaria. The risk for falciparum malaria is greatest within 2 months of return from travel; other species may cause disease many months—and occasionally more than a year—after return from an endemic area.

Severe malaria is characterized by signs of severe illness, organ dysfunction, or a high parasite load (peripheral parasitemia > 5% or > 200,000 parasites/mcL). It is principally a result of P falciparuminfection because this species uniquely infects erythrocytes of all ages and mediates the sequestration of infected erythrocytes in small blood vessels, thereby evading clearance of infected erythrocytes by the spleen.

Severe falciparum malaria can include dysfunction of any organ system, including neurologic abnormalities progressing to alterations in consciousness, repeated seizures, and coma (cerebral malaria); severe anemia; hypotension and shock; noncardiogenic pulmonary edema and the acute respiratory distress syndrome; acute kidney injury due to acute tubular necrosis or, less commonly, severe hemolysis; hypoglycemia; acidosis; hemolysis with jaundice; hepatic dysfunction; retinal hemorrhages and other fundoscopic abnormalities; bleeding abnormalities, including disseminated intravascular coagulation; and secondary bacterial infections, including pneumonia and Salmonella bacteremia. In the developing world, severe malaria and deaths from the disease are mostly in young children, in particular from cerebral malaria and severe anemia. Cerebral malaria is a consequence of a single severe infection while severe anemia follows multiple malarial infections, intestinal helminths, and nutritional deficiencies. In a large trial of African children, acidosis, impaired consciousness, convulsions, renal impairment, and underlying chronic illness were associated with poor outcome.

Uncommon disorders resulting from immunologic responses to chronic infection are massive splenomegaly and, with P malariae infection, immune complex glomerulopathy with nephrotic syndrome. HIV-infected individuals are at increased risk for malaria and for severe disease, in particular with advanced immunodeficiency.

  1. Laboratory Findings

Giemsa-stained blood smears remain the mainstay of diagnosis (Figures 35–2 through 35–5), although other routine stains (eg, Wright stain) will also demonstrate parasites. Thick smears provide efficient evaluation of large volumes of blood, but thin smears are simpler for inexperienced personnel and better for discrimination of parasite species. Single smears are usually positive in infected individuals, although parasitemias may be very low in nonimmune individuals. If illness is suspected, repeating smears in 8- to 24-hour intervals is appropriate. The severity of malaria correlates only loosely with the quantity of infecting parasites, but high parasitemias (especially > 10–20% of erythrocytes infected or > 200,000–500,000 parasites/mcL) or the presence of malarial pigment (a breakdown product of hemoglobin) in > 5% of neutrophils are associated with a particularly poor prognosis.

 Figure 35–2. Thin film Giemsa-stained micrograph with Plasmodium falciparum ring forms. (From Steven Glenn, Laboratory & Consultation Division, Public Health Image Library, CDC.)

Figure 35–3. Thin film Giemsa-stained micrograph with Plasmodium malariae trophozoite. (From Steven Glenn, Laboratory & Consultation Division, Public Health Image Library, CDC.)

Figure 35–4. Thin film Giemsa-stained micrograph with Plasmodium vivax schizont. (From Steven Glenn, Laboratory & Consultation Division, Public Health Image Library, CDC.)

 Figure 35–5. Thin film Giemsa-stained micrograph with Plasmodium ovale trophozoite. (From Steven Glenn, Laboratory & Consultation Division, Public Health Image Library, CDC.)

A second means of diagnosis is rapid diagnostic tests to identify circulating plasmodial antigens with a simple “dipstick” format. These tests are not well standardized but are widely available. At best, they offer sensitivity and specificity near that of high-quality blood smear analysis and are simpler to perform.

Serologic tests indicate history of disease but are not useful for diagnosis of acute infection. PCR is highly sensitive but not available for routine diagnosis. In immune populations, highly sensitive tests, such as PCR, have limited value because subclinical infections, which are of uncertain significance and not routinely treated, are common.

Other diagnostic findings with uncomplicated malaria include thrombocytopenia, anemia, leukocytosis or leukopenia, liver function abnormalities, and hepatosplenomegaly. Severe malaria can present with the laboratory abnormalities expected for the advanced organ dysfunction discussed above.

 Treatment

Malaria is the most common cause of fever in much of the tropics and in travelers seeking medical attention after return from endemic areas. Fevers are often treated presumptively in endemic areas, but ideally, treatment should follow definitive diagnosis, especially in non-immune individuals.

Symptomatic malaria is caused only by the erythrocytic stage of infection. Available antimalarial drugs (Table 35–2) act against this stage, except for primaquine, which acts principally against hepatic parasites.

Table 35–2. Major antimalarial drugs.

  1. Non-Falciparum Malaria

The first-line drug for non-falciparum malaria from most areas remains chloroquine. Due to increasing resistance of P vivax to chloroquine, alternative therapies are recommended when resistance is suspected, particularly for infections acquired in Indonesia, Oceania, and Peru. These infections can be treated with artemisinin-based combination therapies or other first-line regimens for P falciparuminfections as discussed below. For P vivax or P ovale, eradication of erythrocytic parasites with chloroquine should be accompanied by treatment with primaquine (after evaluating for glucose-6-phosphate dehydrogenase [G6PD] deficiency; see below) to eradicate dormant liver stages (hypnozoites), which may lead to relapses with recurrent erythrocytic infection and malaria symptoms after weeks to months if left untreated. P malariae infections need only be treated with chloroquine.

  1. Uncomplicated Falciparum Malaria

P falciparum is resistant to chloroquine and sulfadoxine-pyrimethamine in most areas, with the exceptions of Central America west of the Panama Canal and Hispaniola. Falciparum malaria from other areas should not be treated with these older drugs, and decisions regarding chemoprophylaxis should follow the same geographic considerations.

Artemisinin-based combinations, all including a short-acting artemisinin and longer-acting partner drug, are now first-line therapies in nearly all endemic countries. The WHO currently recommends five artemisinin-based combinations to treat falciparum malaria (Table 35–3), but the efficacy of these regimens varies. Other combination therapies are under development. Quinine generally remains effective for falciparum malaria, but it must be taken for an extended period to cure disease and is poorly tolerated, and should best be reserved for the treatment of severe malaria and for treatment after another regimen has failed (Table 35–4).

Table 35–3. WHO recommendations for the treatment of uncomplicated falciparum malaria.

Table 35–4. Treatment of malaria.

In developed countries, malaria is an uncommon but potentially life-threatening infection of travelers and immigrants, many of whom are nonimmune, so they are at risk for rapid progression to severe disease. Nonimmune individuals with falciparum malaria should generally be admitted to the hospital due to risks of rapid progression of disease. A number of options are available for the treatment of uncomplicated falciparum malaria in the United States (Table 35–4).

  1. Severe Malaria

Severe malaria is a medical emergency. Parenteral treatment is indicated for severe malaria, as defined above, and with inability to take oral drugs. With appropriate prompt therapy and supportive care, rapid recoveries may be seen even in very ill individuals.

Standard therapy for severe malaria has been intravenous quinine in most areas and, in the United States, intravenous quinidine, which is equally effective. However, intravenous artesunate has shown superior efficacy and better tolerability than intravenous quinine for severe malaria in large randomized trials in Asian adults and African children. It is the standard of care for severe malaria, although it is not yet available in much of the developing world, where quinine remains standard therapy. In the United States, intravenous artesunate is available on an investigational basis through the CDC (for enrollment call 770-488-7788); if approved, the drug is provided emergently from CDC Quarantine Stations. The drug is administered in four doses of 2.4 mg/kg over 3 days, every 12 hours on day 1, and then daily. If artesunate cannot be obtained promptly, severe malaria should be treated with intravenous quinine or quinidine. In endemic regions, if parenteral therapy is not available, intrarectal administration of artemether or artesunate is also effective. Patients receiving intravenous quinine or quinidine should receive continuous cardiac monitoring; if QTc prolongation exceeds 25% of baseline, the infusion rate should be reduced. Blood glucose should be monitored every 4–6 hours, and 5–10% dextrose may be coadministered to decrease the likelihood of hypoglycemia.

Appropriate care of severe malaria includes maintenance of fluids and electrolytes; respiratory and hemodynamic support; and consideration of blood transfusions, anticonvulsants, antibiotics for bacterial infections, and hemofiltration or hemodialysis. With high parasitemia (> 5–10%), exchange transfusion has been used, but beneficial effects have not clearly been demonstrated, and it is generally no longer recommended.

  1. Antimalarial Drugs
  2. Chloroquine—Chloroquine remains the drug of choice for the treatment of sensitiveP falciparumand other species of malaria parasites (Table 35–4). Chloroquine is active against erythrocytic parasites of all human malaria species. It does not eradicate hepatic stages, so must be used with primaquine to eradicate P vivax and P ovale infections. Chloroquine-resistant P falciparum is widespread in nearly all areas of the world with falciparum malaria, with the exceptions of Central America west of the Panama Canal, Mexico, and Hispaniola. Chloroquine-resistant P vivax has been reported from a number of areas, most notably Southeast Asia and Oceania.

Chloroquine is the drug of choice for the treatment of non-falciparum and sensitive falciparum malaria. It rapidly terminates fever (in 24–48 hours) and clears parasitemia (in 48–72 hours) caused by sensitive parasites. Chloroquine is also the preferred chemoprophylactic agent in malarious regions without resistant falciparum malaria.

Chloroquine is usually well tolerated, even with prolonged use. Pruritus is common, primarily in Africans. Nausea, vomiting, abdominal pain, headache, anorexia, malaise, blurring of vision, and urticaria are uncommon. Dosing after meals may reduce some adverse events.

  1. Amodiaquine and piperaquine—Amodiaquine is a 4-aminoquinoline that is closely related to chloroquine. Amodiaquine has been widely used to treat malaria because of its low cost, limited toxicity and, in some areas, effectiveness against chloroquine-resistant strains ofP falciparum. Use of amodiaquine decreased after recognition of rare but serious side effects, notably agranulocytosis, aplastic anemia, and hepatotoxicity. However, serious side effects are rare with short-term use, and amodiaquine is a component of a new combination therapy (artesunate-amodiaquine) recommended to treat falciparum malaria (Table 35–3). Chemoprophylaxis with amodiaquine is best avoided because of increased toxicity with long-term use.

Piperaquine is another 4-aminoquinoline that was previously heavily used in China and has been coformulated with dihydroartemisinin in an artemisinin-based therapy. Piperaquine appears to be well tolerated, to have minimal problems with resistance (despite prior reports of resistance in China), and in combination with dihydroartemisinin to offer a highly efficacious therapy for falciparum malaria.

  1. Mefloquine—Mefloquine is effective against many chloroquine-resistant strains ofP falciparumand against other malarial species. Although toxicity is a concern, mefloquine is also a recommended chemoprophylactic drug. Resistance to mefloquine has been reported sporadically from many areas, but it appears to be uncommon except in regions of Southeast Asia with high rates of multidrug resistance (especially border areas of Thailand).

For treatment of uncomplicated malaria, mefloquine can be administered as a single dose or in two doses over 1 day. It is used in combination with artesunate in Southeast Asia, where resistance to mefloquine has been seen but the combination remains effective in most areas. It should be taken with meals and swallowed with a large amount of water. Mefloquine is recommended by the CDC for chemoprophylaxis in all malarious areas except those with no chloroquine resistance (where chloroquine is preferred) and some rural areas of Southeast Asia with a high prevalence of mefloquine resistance. Eradication of P vivax and P ovale requires a course of primaquine.

Adverse effects with weekly dosing of mefloquine for chemoprophylaxis include nausea, vomiting, dizziness, sleep and behavioral disturbances, epigastric pain, diarrhea, abdominal pain, headache, rash and, uncommonly, seizures and psychosis. Concerns about neuropsychiatric toxicity, including possibly rare irreversible effects, led the FDA to add a black box warning for the drug in 2013. Mefloquine should be avoided in persons with histories of psychiatric disease or seizures.

Adverse effects are more common (up to 50% of treatments) with the higher dosages of mefloquine required for treatment. These effects may be lessened by splitting administration into two doses separated by 6–8 hours. Serious neuropsychiatric toxicities (depression, confusion, acute psychosis, or seizures) have been reported in < 1 in 1000 treatments, but some authorities believe that these are more common. Mefloquine can also alter cardiac conduction, and so it should not be coadministered with quinine, quinidine, or halofantrine, and caution is required if these drugs are used to treat malaria after mefloquine chemoprophylaxis. Mefloquine is generally considered safe in young children and pregnant women.

  1. Quinine and quinidine—Quinine dihydrochloride and quinidine gluconate remain first-line therapies for falciparum malaria, especially severe disease, although toxicity concerns complicate therapy (Table 35–4). Quinine acts rapidly against the four species of human malaria parasites. Quinidine, the dextrorotatory stereoisomer of quinine, is at least as effective as quinine in the treatment of severe falciparum malaria.

Resistance of P falciparum to quinine is common in some areas of Southeast Asia, where the drug may fail if used alone to treat falciparum malaria. However, quinine still provides at least a partial therapeutic effect in most patients.

Quinine and quinidine are effective treatments for severe falciparum malaria, although intravenous artesunate is now the standard of care. Quinine can be administered slowly intravenously or, in a dilute solution, intramuscularly, but parenteral quinine is not available in the United States, where quinidine is used. The drugs can be administered in divided doses or by continuous intravenous infusion; treatment should begin with a loading dose to rapidly achieve effective plasma concentrations. Intravenous quinine and quinidine should be administered with cardiac monitoring because of their cardiac toxicity and the relative unpredictability of their pharmacokinetics. Therapy should be changed to an oral agent as soon as the patient has improved and can tolerate oral medications.

In areas without newer combination regimens, oral quinine sulfate is an alternative first-line therapy for uncomplicated falciparum malaria, although poor tolerance may limit compliance. Quinine is commonly used with a second drug (most often doxycycline) to shorten the duration of use (usually to 3 days) and to limit toxicity. Therapeutic dosages of quinine and quinidine commonly cause tinnitus, headache, nausea, dizziness, flushing, and visual disturbances. Hypersensitivity reactions include rash, urticaria, angioedema, and bronchospasm. Hematologic abnormalities include hemolysis (especially with G6PD deficiency), leukopenia, agranulocytosis, and thrombocytopenia. Therapeutic doses may cause hypoglycemia through stimulation of insulin release; this is a particular problem in severe infections and in pregnant patients, who have increased sensitivity to insulin. Overly rapid infusions can cause severe hypotension. ECG abnormalities (QT prolongation) are fairly common, but dangerous arrhythmias are uncommon when the drugs are administered appropriately. Blackwater fever is a rare severe illness, probably due to hypersensitivity, that includes marked hemolysis and hemoglobinuria in the setting of quinine therapy for malaria. Quinine should not be given concurrently with mefloquine and should be used with caution in a patient who has previously received mefloquine.

  1. Primaquine—Primaquine phosphate, a synthetic 8-aminoquinoline, is the drug of choice for the eradication of dormant liver forms ofP vivaxand P ovale (Table 35–4). Primaquine is active against hepatic stages of all human malaria parasites. This action is optimal soon after therapy with chloroquine or quinine. Primaquine also acts against erythrocytic stage parasites, although this activity is too weak for the treatment of active disease, and against gametocytes.

For P vivax and P ovale infections, chloroquine or other drugs are used to eradicate erythrocytic forms, and if the G6PD level is normal, a 14-day course of primaquine (52.6 mg primaquine phosphate [30 mg base] daily) is initiated to eradicate liver hypnozoites and prevent a subsequent relapse. Some strains of P vivax, particularly in New Guinea and Southeast Asia, are relatively resistant to primaquine, and the drug may occasionally fail to eradicate liver forms.

Standard chemoprophylaxis does not prevent a relapse of P vivax or P ovale infections, since liver hypnozoites are not eradicated by chloroquine or other standard treatments. To diminish the likelihood of relapse, some authorities advocate the use of a treatment course of primaquine after the completion of travel to an endemic area. Primaquine can also be used for chemoprophylaxis to prevent P falciparum and P vivax infection in persons with normal levels of G6PD.

Primaquine in recommended doses is generally well tolerated. It infrequently causes nausea, epigastric pain, abdominal cramps, and headache, especially when taken on an empty stomach. Rare adverse effects include leukopenia, agranulocytosis, leukocytosis, and cardiac arrhythmias. Standard doses of primaquine may cause hemolysis or methemoglobinemia (manifested by cyanosis), especially in persons with G6PD deficiency or other hereditary metabolic defects. Patients should be tested for G6PD deficiency before primaquine is prescribed. When a patient is deficient in G6PD, treatment strategies may consist of (1) withholding therapy and treating subsequent relapses, if they occur, with chloroquine; (2) treating patients with standard dosing, paying close attention to their hematologic status; or (3) treating with weekly primaquine (45 mg base) for 8 weeks. G6PD-deficient individuals of Mediterranean and Asian ancestry are most likely to have severe deficiency, while those of African ancestry usually have a milder biochemical defect. This difference can be taken into consideration in choosing a treatment strategy. Primaquine should be discontinued if there is evidence of hemolysis or anemia and should be avoided in pregnancy.

  1. Inhibitors of folate synthesis—Inhibitors of two parasite enzymes involved in folate metabolism, dihydrofolate reductase (DHFR) and dihydropteroate synthase (DHPS), are used, generally in combination regimens, for the treatment and prevention of malaria, although the drugs are rather slow acting and now limited by resistance.

Fansidar is a fixed combination of sulfadoxine (500 mg) and pyrimethamine (25 mg). The long half-lives of its components allow weekly dosing for chemoprophylaxis, but due to rare serious side effects with long-term dosing, this drug is no longer recommended for this purpose. For treatment, advantages of sulfadoxine-pyrimethamine include ease of administration (a single oral dose) and low cost. However, resistance is now a major problem. In addition, it is not reliably effective in P vivax infections, and its usefulness against P ovale and P malariae infections has not been adequately studied, limiting its utility outside of Africa.

Sulfadoxine-pyrimethamine is a component of two combination regimens for uncomplicated malaria recommended by the WHO (Table 35–3). Sulfadoxine-pyrimethamine plus artesunate has shown efficacy in some areas but is best replaced by more effective combination regimens in most areas. Amodiaquine plus sulfadoxine-pyrimethamine has shown quite good efficacy in Africa, despite increasing resistance to both components. It is recommended for chemoprophylaxis in areas with seasonal malaria transmission and limited drug resistance; for this purpose, the drug is administered to children monthly during the transmission season. Another antifolate combination, trimethoprim-sulfamethoxazole, is widely used to prevent coinfections in patients infected with HIV, and it offers partial protection against malaria. Malarone, a combination of proguanil with atovaquone, is discussed below.

  1. Artemisinins—Artemisinin (qinghaosu) is a sesquiterpene lactone endoperoxide, the active component of an herbal medicine that has been used for various indications in China for over 2000 years. Analogs have been synthesized to increase solubility and improve antimalarial efficacy. The most important of these analogs are artesunate, artemether, and dihydroartemisinin. The WHO is encouraging availability of oral artemisinins only in coformulated combination regimens.

Artemisinins act very rapidly against all erythrocytic-stage human malaria parasites. Of concern, delayed clearance of parasites and some clinical failures have been seen after treatment with artesunate in parts of Southeast Asia, heralding the emergence of artemisinin resistance in this region.

Artemisinins are playing an increasing role in the treatment of malaria, including multidrug-resistant P falciparum malaria. However, due to their short plasma half-lives, recrudescence rates are unacceptably high after short-course therapy, leading to use in conjunction with another agent. Also because of their short-half lives, they are not useful in chemoprophylaxis.

Artemisinins should be used for uncomplicated malaria in combination regimens including a longer-acting partner drug, known as artemisinin-based combination therapy (ACT). The ACTs that are currently most advocated in Africa are artesunate plus amodiaquine (ASAQ) and artemether plus lumefantrine (Coartem), each of which is available as a coformulated product and is the recommended therapy for uncomplicated malaria in a number of countries. Another ACT, artesunate plus mefloquine is used mostly outside of Africa; its efficacy may be declining in parts of Asia. Dihydroartemisinin-piperaquine is a newer ACT that has shown excellent efficacy, and is now the first-line regimen in some countries in Southeast Asia.

In studies of severe malaria, intramuscular artemether was at least as effective as intramuscular quinine, and intravenous artesunate was superior to intravenous quinine in terms of efficacy and tolerability. Thus, the standard of care for severe malaria is intravenous artesunate, when it is available, although parenteral quinine and quinidine remain acceptable alternatives. Artesunate and artemether have also been effective in the treatment of severe malaria when administered rectally, offering a valuable treatment modality when parenteral therapy is not available.

Artemisinins are very well tolerated. The most commonly reported adverse effects have been nausea, vomiting, and diarrhea, which may often be due to acute malaria, rather than drug toxicity. Neutropenia, anemia, hemolysis, and elevated levels of liver enzymes have been noted rarely. Artemisinins are teratogenic in animals, and they should be avoided in the first trimester of pregnancy for uncomplicated malaria. However, for severe malaria, for which all available treatments entail some risk, the WHO endorses the use of intravenous artesunate or quinine while additional data are gathered on artesunate safety.

  1. Atovaquone plus proguanil (Malarone)—Atovaquone, a hydroxynaphthoquinone, is not effective when used alone, due to rapid development of drug resistance. However, Malarone, a fixed combination of atovaquone (250 mg) and the antifolate proguanil (100 mg), is highly effective for both the treatment and chemoprophylaxis of falciparum malaria, and it is approved for both indications in the United States (Table 35–4). It also appears to be active against other species of malaria parasites. Unlike most other antimalarials, Malarone provides activity against both erythrocytic and hepatic stage parasites.

For treatment, Malarone is given at an adult dose of four tablets daily for 3 days. For chemoprophylaxis, Malarone must be taken daily. It has an advantage over mefloquine and doxycycline in requiring shorter durations of treatment before and after the period at risk for malaria transmission, due to activity against liver-stage parasites. It should be taken with food.

Malarone is generally well tolerated. Adverse effects include abdominal pain, nausea, vomiting, diarrhea, headache, and rash, and these are more common with the higher dose required for treatment. Reversible elevations in liver enzymes have been reported. The safety of atovaquone in pregnancy is unknown.

  1. Antibiotics—A number of antibacterials in addition to the folate antagonists and sulfonamides are slow-acting antimalarials. None of the antibiotics should be used as single agents for the treatment of malaria due to their slow rate of action.

Doxycycline is commonly used in the treatment of falciparum malaria in conjunction with quinidine or quinine, allowing a shorter and better-tolerated course of those drugs (Table 35–4). Doxycycline is also a standard chemoprophylactic drug, especially for use in areas of Southeast Asia with high rates of resistance to other antimalarials, including mefloquine. Doxycycline side effects include gastrointestinal symptoms, candidal vaginitis, and photosensitivity. The drug should be taken while upright with a large amount of water to avoid esophageal irritation. Clindamycin can be used in conjunction with quinine or quinidine in those for whom doxycycline is not recommended, such as children and pregnant women (Table 35–4). The most common toxicities with clindamycin are gastrointestinal. Azithromycin also has antimalarial activity and is under study for treatment and chemoprophylaxis.

  1. Halofantrine and lumefantrine—Halofantrine, a phenanthrene-methanol related to quinine, is effective against erythrocytic stages of all four human malaria species. Because of toxicity concerns, it should not be taken with meals, since food enhances absorption. Halofantrine is rapidly effective against most chloroquine-resistant strains ofP falciparum, but its use is now very limited due to risks of serious cardiac toxicity.

Lumefantrine, an aryl alcohol related to halofantrine, is available only as a fixed-dose combination with artemether (Coartem or Riamet). Oral absorption is highly variable and improved when the drug is taken with food. Use of Coartem with a fatty meal is recommended. Coartem is highly effective for the treatment of falciparum malaria, but it is fairly expensive and requires twice-daily dosing. Despite these limitations, due to its reliable efficacy against falciparum malaria, Coartem is the first-line therapy for malaria in many malarious countries. Coartem is well tolerated; side effects include headache, dizziness, loss of appetite, gastrointestinal symptoms, and palpitations. Importantly, Coartem does not generally cause QT prolongation or the serious cardiac toxicity seen with halofantrine.

 Prevention

Malaria is transmitted by night-biting anopheline mosquitoes. Bed nets, in particular nets treated with permethrin insecticides, are heavily promoted as inexpensive means of antimalarial protection, and improvement in mortality rates has been demonstrated. Extensive efforts are also underway to develop a malaria vaccine, and partial protection of African children has been demonstrated, but a vaccine offering complete protection is not anticipated in the near future. The availability of improved modalities to control mosquito vectors and treat and prevent malaria has heightened enthusiasm for malaria elimination, and there have been important gains in some areas; however, control remains very challenging in highly endemic regions, and elimination is not expected in these areas in the foreseeable future.

When travelers from nonendemic to endemic countries are counseled on the prevention of malaria, it is imperative to emphasize measures to prevent mosquito bites (insect repellents, insecticides, and bed nets), since parasites are increasingly resistant to multiple drugs and no chemoprophylactic regimen is fully protective. Chemoprophylaxis is recommended for all travelers from nonendemic regions to endemic areas, although risks vary greatly for different locations, and some tropical areas entail no risk; specific recommendations for travel to different locales are available from the CDC (www.cdc.gov). Current recommendations from the CDC include the use of chloroquine for chemoprophylaxis in the few areas with only chloroquine-sensitive malaria parasites (principally the Caribbean and Central America west of the Panama Canal), mefloquine or Malarone for most other malarious areas, and doxycycline for areas with a high prevalence of multidrug-resistant falciparum malaria (principally parts of Southeast Asia) (Table 35–5). Recommendations should be checked regularly (Phone: 877-FYI-TRIP; Internet: http://wwwnc.cdc.gov/travel) because they may change in response to changing resistance patterns and increasing experience with new drugs. In some circumstances, it may be appropriate for travelers to not use chemoprophylaxis but to carry supplies of drugs with them in case a febrile illness develops and medical attention is unavailable. Regimens for self-treatment include ACTs, Malarone, and quinine. Most authorities do not recommend routine terminal chemoprophylaxis with primaquine to eradicate dormant hepatic stages of P vivax and P ovale after travel, but this may be appropriate in some circumstances, especially for travelers with major exposure to these parasites.

Table 35–5. Drugs for the prevention of malaria in travelers.1

Regular chemoprophylaxis is not a standard management practice in developing world populations due to the expense and potential toxicities of long-term therapy. However, intermittent preventive therapy, whereby at-risk populations (in particular pregnant women and children) receive antimalarial therapy at set intervals, is of increasing interest. This strategy may decrease the incidence of malaria while allowing antimalarial immunity to develop. During pregnancy, intermittent preventive therapy with sulfadoxine-pyrimethamine, provided once during both the second and third trimesters, has improved pregnancy outcomes. In infants, therapy with sulfadoxine-pyrimethamine following standard immunization schedules has offered benefits. With increasing resistance, it is not clear if sulfadoxine-pyrimethamine will retain prophylactic efficacy or if other drugs with shorter half-lives will be effective. In areas with seasonal malaria transmission and limited drug resistance, principally the Sahel region of West Africa, the policy is to administer amodiaquine and sulfadoxine-pyrimethamine to children monthly during the transmission season.

 Prognosis

When treated appropriately, uncomplicated malaria generally responds well, with resolution of fevers within 1–2 days and a mortality of about 0.1%. Severe malaria can commonly progress to death, but many children respond well to therapy. In the developed world, mortality from malaria is mostly in adults, and often follows extended illnesses and secondary complications long after eradication of the malarial infection. Pregnant women are at particular risk during their first pregnancy. Malaria in pregnancy also increases the likelihood of poor pregnancy outcomes, with increased prematurity, low birth weight, and mortality.

 When to Refer

Referral to an expert on infectious diseases or travel medicine is important with all cases of malaria in the United States, and in particular for falciparum malaria; referral should not delay initial diagnosis and therapy, since delays in therapy can lead to severe illness or death.

 When to Admit

  • Admission for non-falciparum malaria is only warranted if a patient presents with specific problems that require hospital management.
  • Patients with falciparum malaria are generally admitted because the disease can progress rapidly to severe illness; exceptions may be made with individuals who are from malaria-endemic areas, and thus expected to have a degree of immunity, who are without evidence of severe disease, and who are judged able to return promptly for medical attention if their disease progresses.

Baird KJ et al. Diagnosis and treatment of Plasmodium vivax malaria. Adv Parasitol. 2012;80:203–70. [PMID: 23199489]

Dondorp AM et al; AQUAMAT Group. Artesunate versus quinine in the treatment of severe falciparum malaria in African children (AQUAMAT): an open-label, randomised trial. Lancet. 2010 Nov 13;376(9753):1647–57. [PMID: 21062666]

Murray CJ et al. Global malaria mortality between 1980 and 2010: a systematic analysis. Lancet. 2012 Feb 4;379(9814):413–31. [PMID: 22305225]

Nadjm B et al. Malaria: an update for physicians. Infect Dis Clin North Am. 2012 Jun;26(2):243–59. [PMID: 22632637]

Olotu A et al. Four-year efficacy of RTS,S/AS01E and its interaction with malaria exposure. N Engl J Med. 2013 Mar 21;368(12):1111–20. [PMID: 23514288]

Phyo AP et al. Emergence of artemisinin-resistant malaria on the western border of Thailand: a longitudinal study. Lancet. 2012 May 26;379(9830):1960–6. [PMID: 22484134]

von Seidlein L et al. Predicting the clinical outcome of severe falciparum malaria in African children: findings from a large randomized trial. Clin Infect Dis. 2012 Apr;54(8):1080–90. [PMID: 22412067]

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World Health Organization. Guidelines for the treatment of malaria, 2nd edition. Geneva, Switzerland, 2010. http://www.who.int/malaria/publications/atoz/9789241547925/en/index.html

BABESIOSIS

 ESSENTIALS OF DIAGNOSIS

 History of tick bite or exposure to ticks.

 Fever, flu-like symptoms, anemia.

 Intraerythrocytic parasites on Giemsa-stained blood smears.

 Positive serologic tests.

 General Considerations

Babesiosis is an uncommon intraerythrocytic infection caused mainly by two Babesia species and transmitted by Ixodes ticks. In Europe, where only a few dozen cases of babesiosis have been reported, infection is caused by Babesia divergens, which also infects cattle. In the United States, hundreds of cases of babesiosis have been reported, and infection is caused by Babesia microti, which also infects wild mammals. Most babesiosis in the United States occurs in the coastal northeast, with some cases also in the upper midwest, following the geographic range of the vector Ixodes scapularis, and Lyme disease and anaplasmosis, which are spread by the same vector. The incidence of the disease appears to be increasing in some areas. Rare episodes of illnesses caused by B microtiB divergens, and other Babesia-like organisms have been reported from other areas. Babesiosis can also be transmitted by blood transfusion.

 Clinical Findings

  1. Symptoms and Signs

With B microti infections, symptoms appear 1 to several weeks after a tick bite; parasitemia is evident after 2–4 weeks. Patients usually do not recall the tick bite. The typical flu-like illness develops gradually and is characterized by fever, fatigue, headache, arthralgia, and myalgia. Other findings may include nausea, vomiting, abdominal pain, sore throat, depression, emotional lability, anemia, thrombocytopenia, and splenomegaly. Parasitemia may continue for months to years, with or without symptoms, and the disease is usually self-limited. Severe complications are most likely to occur in older persons or in those who have had splenectomy. Serious complications include respiratory failure, hemolytic anemia, disseminated intravascular coagulation, heart failure, and acute kidney injury. In a study of hospitalized patients, the mortality rate was 6.5%. Most recognized B divergens infections in Europe have been in patients who have had splenectomy. These infections progress rapidly with high fever, severe hemolytic anemia, jaundice, hemoglobinuria, and acute kidney injury, with death rates over 40%.

  1. Laboratory Findings

Identification of the intraerythrocytic parasite on Giemsa-stained blood smears establishes the diagnosis (Figure 35–6). These can be confused with malaria parasites, but the morphology is distinctive. Repeated smears are often necessary because well under 1% of erythrocytes may be infected, especially early in infection, although parasitemias can exceed 10%. An indirect immunofluorescent antibody test for B microti is available from the CDC; antibody is detectable within 2–4 weeks after the onset of symptoms and persists for months. Diagnosis can also be made by PCR or by inoculation of hamsters or gerbils.

 Figure 35–6. Blood smear showing Babesia spp. rings with basophilic stippling. (From Dr. Mae Melvin, Public Health Image Library, CDC.)

 Treatment

Most patients have a mild illness and recover without therapy. Standard therapy is a 7-day course of quinine (650 mg orally three times daily) plus clindamycin (600 mg orally three times daily). An alternative is a 7-day course of atovaquone (750 mg orally every 12 hours) plus azithromycin (600 mg orally once daily). Exchange transfusion has been used successfully in severely ill asplenic patients and those with parasitemia > 10%.

Herwaldt BL et al. Transfusion-associated babesiosis in the United States: a description of cases. Ann Intern Med. 2011 Oct 18;155(8):509–19. [PMID: 21893613]

Vannier E et al. Human babesiosis. N Engl J Med. 2012 Jun 21;366(25):2397–407. [PMID: 22716978]

TOXOPLASMOSIS

 ESSENTIALS OF DIAGNOSIS

 Infection confirmed by isolation of Toxoplasma gondii or identification of tachyzoites in tissue or body fluids.

Primary infection

 Fever, malaise, headache, sore throat.

 Lymphadenopathy.

 Positive IgG and IgM serologic tests.

Congenital infection

 Follows acute infection of seronegative mothers and leads to CNS abnormalities and retinochoroiditis.

Infection in immunocompromised persons

 Reactivation leads to encephalitis, retinochoroiditis, pneumonitis, myocarditis.

 Positive IgG but negative IgM serologic tests.

 General Considerations

T gondii, an obligate intracellular protozoan, is found worldwide in humans and in many species of mammals and birds. The definitive hosts are cats. Humans are infected after ingestion of cysts in raw or undercooked meat, ingestion of oocysts in food or water contaminated by cats, transplacental transmission of trophozoites or, rarely, direct inoculation of trophozoites via blood transfusion or organ transplantation. Toxoplasma seroprevalence varies widely. It has decreased in the United States to about 20–30%, but it is much higher in other countries in both the developed and developing worlds, where it may exceed 80%.

 Clinical Findings

  1. Symptoms and Signs

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

  1. Primary infection in the immunocompetent person—After ingestion,T gondiiinfection progresses from the gastrointestinal tract to lymphatics, and then dissemination. Most acute infections are asymptomatic. About 10–20% are symptomatic after an incubation period of 1–2 weeks. Acute infections in immunocompetent persons typically present as mild, febrile illnesses that resemble infectious mononucleosis. Nontender cervical or diffuse lymphadenopathy may persist for weeks to months. Systemic findings may include fever, malaise, headache, sore throat, rash, myalgias, hepatosplenomegaly, and atypical lymphocytosis. Rare severe manifestations are pneumonitis, meningoencephalitis, hepatitis, myocarditis, polymyositis, and retinochoroiditis. Symptoms may fluctuate, but most patients recover spontaneously within at most a few months.
  2. Congenital infection—Congenital transmission occurs as a result of infection, which may be symptomatic or asymptomatic, in a nonimmune woman during pregnancy. Fetal infection follows maternal infection in 30–50% of cases, but this risk varies by trimester: 10–25% during the first, 30–50% during the second, and 60% or higher during the third trimester. In the United States, an estimated 400 to 4000 congenital infections occur yearly. While the risk of fetal infection increases, the risk of severe fetal disease decreases over the course of pregnancy. Early fetal infections commonly lead to spontaneous abortion, stillbirths, or severe neonatal disease, including neurologic manifestations. Neurologic findings can include seizures, psychomotor retardation, deafness, and hydrocephalus. Retinochoroiditis and other sight-threatening eye lesions may develop. Systemic findings include fever or hypothermia, jaundice, vomiting, diarrhea, hepatosplenomegaly, pneumonitis, myocarditis, and rash. Infections later in pregnancy less commonly lead to major fetal problems. Most infants appear normal at birth, but they may have subtle abnormalities and progress to symptoms and signs of congenital toxoplasmosis later in life. Hepatosplenomegaly and lymphadenopathy may develop in the first few months of life; CNS and eye disease often present later. The most common late presentation of congenital toxoplasmosis is retinochoroiditis.
  3. Retinochoroiditis—This manifestation of congenital toxoplasmosis presents weeks to years after congenital infection, commonly in teenagers or young adults. Retinochoroiditis also is seen in persons who acquire infection early in life, and these patients more often present with unilateral disease. Uveitis is also seen. Disease presents with pain, photophobia, and visual changes, usually without systemic symptoms. Signs and symptoms eventually improve, but visual defects may persist. Rarely, progression may result in glaucoma and blindness.
  4. Disease in the immunocompromised person—Reactivated toxoplasmosis occurs in patients with AIDS, cancer, or those given immunosuppressive drugs. In patients with advanced AIDS, the most common manifestation is encephalitis, with multiple necrotizing brain lesions. The encephalitis usually presents subacutely, with fever, headache, altered mental status, focal neurologic findings, and other evidence of brain lesions. Less common manifestations of toxoplasmosis in patients with AIDS are chorioretinitis and pneumonitis. Chorioretinitis presents with ocular pain and alterations in vision. Pneumonitis presents with fever, cough, and dyspnea. Toxoplasmosis can develop in seronegative recipients of solid organ or bone marrow transplants due to reactivation or, more rarely, transmission of infection. Reactivation also can occur in those with hematologic malignancies or treated with immunosuppressive drugs. With primary or reactivated disease in those with immunodeficiency due to malignancy or immunosuppressive drugs, toxoplasmosis is similar to that in individuals with AIDS, but pneumonitis and myocarditis are more common.
  5. Diagnostic Testing
  6. Identification of parasites—Organisms can be seen in tissue or body fluids, although they may be difficult to identify; special staining techniques can facilitate identification. The demonstration of tachyzoites indicates acute infection; cysts may represent either acute or chronic infection. With lymphadenopathy due to toxoplasmosis, examination of lymph nodes usually does not show organisms. Parasite identification can also be made by inoculation of tissue culture or mice. PCR can be used for sensitive identification of organisms in amniotic fluid, blood, CSF, aqueous humor, and bronchoalveolar lavage fluid.
  7. Serologic diagnosis—Multiple serologic methods are used, including the Sabin-Feldman dye test, enzyme-linked immunosorbent assay (ELISA), indirect fluorescent antibody test, and agglutination tests. IgG antibodies are seen within 1–2 weeks of infection, and usually persist for life. IgM antibodies peak earlier than IgG and decline more rapidly, although they may persist for years. In immunocompromised individuals in whom reactivation is suspected, a positive IgG assay indicates distant infection, and thus the potential for reactivated disease; a negative IgG argues strongly against reactivation toxoplasmosis. With reactivation in immunocompromised persons, IgM tests are generally negative.
  8. During pregnancy and in newborns—Conversion from a negative to positive serologic test or rising titers are suggestive of acute infection, but tests are not routinely performed during pregnancy. When pregnant women are screened, negative IgG and IgM assays exclude active infection, but indicate the risk of infection during the pregnancy. The pattern of positive IgG with negative IgM is highly suggestive of chronic infection, with no risk of congenital disease unless the mother is severely immunocompromised. A positive IgM test is concerning for new infection because of the risk of congenital disease. Confirmatory testing should be performed before consideration of treatment or possible termination of pregnancy due to the limitations of available tests. Tests of the avidity of anti-IgG antibodies can be helpful, but a battery of tests is needed for confirmation of acute infection during pregnancy. When acute infection during pregnancy is suspected, PCR of amniotic fluid offers a sensitive assessment for congenital disease; this test should optimally be performed at 18 weeks of gestation. In newborns, positive IgM or IgA antibody tests are indicative of congenital infection, although the diagnosis is not ruled out by a negative test. Positive IgG assays may represent transfer of maternal antibodies without infection of the infant. Organisms may be identified by PCR; smears; or culture of blood, CSF, or tissue.
  9. In immunocompetent individuals—Individuals with a suggestive clinical syndrome should be tested for IgG andIgM antibodies. Seroconversion, a 16-fold rise in antibody titer, or an IgM titer > 1:64 are suggestive of acute infection, although false-positive results may occur. Acute infection can also be diagnosed by detection of tachyzoites in tissue, culture of organisms, or PCR of blood or body fluids. Histologic evaluation of lymph nodes can show characteristic morphology, with or without organisms.
  10. In immunodeficient individuals—A presentation consistent with toxoplasmic encephalitis warrants imaging of the brain. CT and MRI scans typically show multiple ring-enhancing cerebral lesions, most commonly involving the corticomedullary junction and basal ganglia. MRI is the more sensitive imaging modality. In AIDS patients with a positive IgG serologic test and no recent antitoxoplasma or antiviral therapy, the predictive value of a typical imaging study is about 80%. The other common diagnosis in this setting is CNS lymphoma, which more typically causes a single brain lesion. The differential diagnosis also includes tuberculoma, bacterial brain abscess, fungal abscess, and carcinoma. Diagnosis of CNS toxoplasmosis is most typically made after a therapeutic trial, with clinical and radiologic improvement expected within 2–3 weeks. Definitive diagnosis requires brain biopsy and search for organisms and typical histology. In retinochoroiditis, funduscopic examination shows vitreous inflammatory reaction, white retinal lesions, and pigmented scars. Diagnosis of other clinical entities in immunocompromised individuals is generally based on histology.

 Treatment

  1. Approach to Treatment

Therapy is generally not necessary in immunocompetent persons, since primary illness is self-limited. However, for severe, persistent, or visceral disease, treatment for 2–4 weeks may be considered. Treatment is appropriate for primary infection during pregnancy because the risk of fetal transmission or the severity of congenital disease may be reduced. For retinochoroiditis, most episodes are self-limited, and opinions vary on indications for treatment. Treatment is often advocated for episodes with decreases in visual acuity, multiple or large lesions, macular lesions, significant inflammation, or persistence for over a month. Immunocompromised patients with active infection must be treated. For those with transient immunodeficiency, therapy can be continued for 4–6 weeks after cessation of symptoms. For those with persistent immunodeficiency, such as AIDS patients, full therapy for 4–6 weeks is followed by maintenance therapy with lower doses of drugs. Immunodeficient patients who are asymptomatic but have a positive IgG serologic test should receive long-term chemoprophylaxis.

  1. Medications

Drugs for toxoplasmosis are active only against tachyzoites, so they do not eradicate infection. Standard therapy is the combination of pyrimethamine (200 mg loading dose, then 50–75 mg [1 mg/kg] orally once daily) plus sulfadiazine (1–1.5 g orally four times daily), with folinic acid (10–20 mg orally once daily) 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. Pyrimethamine side effects include headache and gastrointestinal symptoms. Even with folinic acid therapy, bone marrow suppression may occur; platelet and white blood cell counts should be monitored at least weekly. A first-line alternative to sulfadiazine is clindamycin (600 mg orally four times daily). Other possible alternatives are trimethoprim-sulfamethoxazole or combining pyrimethamine with atovaquone, clarithromycin, azithromycin, or dapsone. Pyrimethamine is not used during the first trimester of pregnancy due to its teratogenicity. Standard therapy for the treatment of acute toxoplasmosis during pregnancy is with spiramycin (1 g orally three times daily until delivery). This therapy is used only to decrease the risk of fetal infection; it reduces the frequency of transmission to the fetus by about 60%. Spiramycin does not cross the placenta, so when fetal infection is documented or for acute infections late in pregnancy (which commonly lead to fetal transmission) treatment with combination regimens as described above is indicated.

 Prevention

Prevention of primary infection centers on avoidance of undercooked meat or contact with material contaminated by cat feces, particularly for seronegative pregnant women and immunocompromised persons. For meat, irradiation, cooking to 66°C, or freezing to –20°C kills tissue cysts. Thorough cleaning of hands and surfaces is needed after contact with raw meat or areas contaminated by cats. Oocysts passed in cat feces can remain infective for a year or more, but fresh oocysts are not infective for 48 hours. For best protection, litter boxes should be changed daily and soaked in boiling water for 5 minutes. In addition, gloves should be worn when gardening, fruits and vegetables should be thoroughly washed, and ingestion of dried meat should be avoided.

Universal screening of pregnant women for T gondii antibodies is conducted in some countries but not the United States. Pregnant women should ideally have their serum examined for IgG and IgM antibody, and those with negative titers should adhere to the prevention measures described above. Seronegative women who continue to have environmental exposure should undergo repeat serologic screening several times during pregnancy.

For immunocompromised individuals, chemoprophylaxis to prevent primary or reactivated infection is warranted. For transplant recipients, pyrimethamine (25 mg daily orally for 6 weeks) has been used. For advanced AIDS patients and others, chemoprophylaxis with trimethoprim-sulfamethoxazole (one double-strength tablet daily or two tablets three times weekly), used primarily for protection against Pneumocystis, is also effective against T gondii. Alternatives are pyrimethamine plus either sulfadoxine or dapsone (various regimens). In AIDS patients, chemoprophylaxis can be discontinued if antiretroviral therapy leads to immune reconstitution.

Fernà ndez-Sabé N et al. Risk factors, clinical features, and outcomes of toxoplasmosis in solid-organ transplant recipients: a matched case-control study. Clin Infect Dis. 2012 Feb 1;54(3):355–61. [PMID: 22075795]

Montoya JG et al. Management of Toxoplasma gondii infection during pregnancy. Clin Infect Dis. 2008 Aug 15;47(4):554–66. [PMID: 18624630]

Robert-Gangneux F et al. Epidemiology of and diagnostic strategies for toxoplasmosis. Clin Microbiol Rev. 2012 Apr;25(2):264–96. [PMID: 22491772]

AMEBIASIS

 ESSENTIALS OF DIAGNOSIS

 Organisms or antigen present in stools or abscess aspirate.

 Positive serologic tests with colitis or hepatic abscess, but these may represent prior infections.

 Mild to moderate colitis with recurrent diarrhea.

 Severe colitis including bloody diarrhea, fever, and abdominal pain, with potential progression to hemorrhage or perforation.

 Hepatic abscess with fever, hepatomegaly, and abdominal pain.

 General Considerations

The Entamoeba complex contains three morphologically identical species: Entamoeba dispar and Entamoeba moshkovskii, which are avirulent, and Entamoeba histolytica, which may be an avirulent intestinal commensal or lead to serious disease. Disease follows penetration of the intestinal wall, resulting in diarrhea, and with severe involvement, dysentery or extraintestinal disease, most commonly liver abscess.

E histolytica infections are present worldwide but are most prevalent in subtropical and tropical areas under conditions of crowding, poor sanitation, and poor nutrition. Of the estimated 500 million persons worldwide infected with Entamoeba, most are infected with E dispar and an estimated 10% with E histolytica. The prevalence of E moshkovskii is unknown. Mortality from invasive E histolyticainfections is estimated at 100,000 per year.

Humans are the only established E histolytica host. Transmission occurs through ingestion of cysts from fecally contaminated food or water, facilitated by person-to-person spread, flies and other arthropods as mechanical vectors, and use of human excrement as fertilizer. Urban outbreaks have occurred because of common-source water contamination.

 Clinical Findings

  1. Symptoms and Signs
  2. Intestinal amebiasis—In most infected persons, the organism lives as a commensal, and the carrier is without symptoms. With symptomatic disease, diarrhea may begin within a week of infection, although an incubation period of 2–4 weeks is more common, with gradual onset of abdominal pain and diarrhea. Fever is uncommon. Periods of remission and recurrence may last days to weeks or longer. Abdominal examination may show distention, tenderness, hyperperistalsis, and hepatomegaly. Microscopic hematochezia is common. More severe presentations include colitis and dysentery, with more extensive diarrhea (10–20 stools per day) and bloody stools. With dysentery, physical findings include high fevers, prostration, vomiting, abdominal pain and tenderness, hepatic enlargement, and hypotension. Severe presentations are more common in young children, pregnant women, those who are malnourished, and those receiving corticosteroids. Thus, in endemic regions, corticosteroids should not be started for presumed inflammatory bowel disease without first ruling out amebiasis. Fulminant amebic colitis can progress to necrotizing colitis, intestinal perforation, mucosal sloughing, and severe hemorrhage, with mortality rates over 40%. More chronic complications of intestinal amebiasis include chronic diarrhea with weight loss, which may last for months to years; bowel ulcerations; and amebic appendicitis. Localized granulomatous lesions (amebomas) can present after either dysentery or chronic intestinal infection. Clinical findings include pain, obstructive symptoms, and hemorrhage and may suggest intestinal carcinoma.
  3. Extraintestinal amebiasis—The most common extraintestinal manifestation is amebic liver abscess. This can occur with colitis, but more frequently presents without history of prior intestinal symptoms. Patients present with the acute or gradual onset of abdominal pain, fever, an enlarged and tender liver, anorexia, and weight loss. Diarrhea is present in a small number of patients. Physical examination may show intercostal tenderness. Abscesses are most commonly single and in the right lobe of the liver, and they are much more common in men. Without prompt treatment, amebic abscesses may rupture into the pleural, peritoneal, or pericardial space, which is often fatal. Amebic infections may rarely occur throughout the body, including the lungs, brain, and genitourinary system.
  4. Laboratory Findings

Laboratory studies with intestinal amebiasis show leukocytosis and hematochezia, with fecal leukocytes not present in all cases. With extraintestinal amebiasis, leukocytosis and elevated liver function studies are seen.

  1. Diagnostic Testing

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

  1. Intestinal amebiasis—Diagnosis is most commonly made by identifying organisms in the stool.E histolyticaand E dispar cannot be distinguished, but the identification of amebic trophozoites or cysts in a symptomatic patient is highly suggestive of amebiasis. Stool evaluation for organisms is not highly sensitive (~30–50% for amebic colitis), and at least three stool specimens should be evaluated afterconcentration and staining. Multiple serologic assays are available; these tests are fairly sensitive, although sensitivity is lower (~70% in colitis) early in illness, and they cannot distinguish recent and old disease, as they remain positive for years after infection. A commercially available stool antigen test (TechLab II) offers improved sensitivity (> 90% for colitis); it requires fresh or frozen (not preserved) stool specimens. PCR-based tests are available but not used routinely. Colonoscopy of uncleansed bowel typically shows no specific findings in mild intestinal disease; in severe disease, ulcers may be found with intact intervening friable mucosa, resembling inflammatory bowel disease (Figure 35–7). Examination of fresh ulcer exudate for motile trophozoites and for E histolytica antigen may yield a diagnosis.

 Figure 35–7. Gross pathology showing intestinal ulcers due to amebiasis. (From Dr. Mae Melvin, Public Health Image Library, CDC.)

  1. Hepatic abscess—Serologic tests for anti-amebic antibodies are almost always positive, except very early in the infection. Thus, a negative test in a suspicious case should be repeated in about a week. The TechLab II antigen test can be used to test serum, with good sensitivity if used before the initiation of therapy. Examination of stools for organisms or antigen is frequently negative; the antigen test is positive in ~40% of cases. As imaging studies cannot distinguish amebic and pyogenic abscesses, when a diagnosis is not available from serologic studies, percutaneous aspiration may be indicated, ideally with an image-guided needle. Aspiration typically yields brown or yellow fluid. Detection of organisms in the aspirate is uncommon, but detection ofE histolyticaantigen is very sensitive and diagnostic. The key risk of aspiration is peritoneal spillage leading to peritonitis from amebas or other (pyogenic or echinococcal) organisms.
  2. Imaging

Liver abscesses can be identified by ultrasonography, CT, or MRI, typically with round or oval low-density nonhomogeneous lesions, with abrupt transition from normal liver to the lesion, and hypoechoic centers. Abscesses are most commonly single, but more than one may be present. The right lobe is usually involved.

 Treatment

Treatment of amebiasis generally entails the use of metronidazole or tinidazole to eradicate tissue trophozoites and a luminal amebicide to eradicate intestinal cysts (Table 35–6). Asymptomatic infection with E dispar does not require therapy. This organism cannot be differentiated morphologically from E histolytica, but with negative serology E dispar colonization is likely, and treatment is not indicated. Colonization with E histolytica is generally treated with a luminal agent. Effective luminal agents are diloxanide furoate (500 mg orally three times daily with meals for 10 days), iodoquinol (diiodohydroxyquin; 650 mg orally three times daily for 21 days), and paromomycin (30 mg/kg base orally, maximum 3 g, in three divided doses after meals daily for 7 days). Side effects associated with luminal agents are flatulence with diloxanide furoate, mild diarrhea with iodoquinol, and gastrointestinal symptoms with paromomycin. Relative contraindications are thyroid disease for iodoquinol and kidney disease for iodoquinol or paromomycin.

Table 35–6. Treatment of amebiasis.1

Treatment of intestinal amebiasis requires metronidazole (750 mg orally three times daily for 10 days) or tinidazole (2 g orally once daily for 3 days for mild disease and 5 days for serious disease) plus a luminal agent (Table 35–6). Metronidazole has most commonly been used in the United States, but tinidazole offers simpler dosing and less side effects. Metronidazole often induces transient nausea, vomiting, epigastric discomfort, headache, or a metallic taste. A disulfiram-like reaction may occur if alcohol is coingested. Metronidazole should be avoided in pregnant or nursing mothers if possible. The same toxicities and concerns probably apply for tinidazole, although it appears to be better tolerated. Fluid and electrolyte replacement is also important for patients with significant diarrhea. Surgical management of acute complications of intestinal amebiasis is best avoided whenever possible. Successful therapy of severe amebic colitis may be followed by postdysenteric colitis, with continued diarrhea without persistent infection; this syndrome generally resolves in weeks to months.

Alternatives for the treatment of intestinal amebiasis are tetracycline (250–500 mg orally four times daily for 10 days) plus chloroquine (500 mg orally daily for 7 days). Emetine or dehydroemetine, which are not available in the United States, can be given subcutaneously or intramuscularly in a dose of 1–1.5 mg/kg/d; the maximum daily dose is 90 mg for dehydroemetine and 65 mg for emetine). These agents are effective but cardiotoxic with a narrow therapeutic range and should be used only until severe disease is controlled. They cause nausea, vomiting, and pain at the injection site.

Amebic liver abscess is also treated with metronidazole or tinidazole plus a luminal agent (even if intestinal infection is not documented; Table 35–6). Metronidazole can be used intravenously when necessary. With failure of initial response to metronidazole or tinidazole, chloroquine, emetine or dehydroemetine may be added. Needle aspiration may be helpful for large abscesses (over 5–10 cm), in particular if the diagnosis remains uncertain, if there is an initial lack of response, or if a patient is very ill, suggesting imminent abscess rupture. With successful therapy, abscesses disappear slowly (over months).

 Prevention & Control

Prevention requires safe water supplies; sanitary disposal of human feces; adequate cooking of food; protection of food from fly contamination; handwashing; and, in endemic areas, avoidance of fruits and vegetables that cannot be cooked or peeled. Water supplies can be boiled, treated with iodine (0.5 mL tincture of iodine per liter for 20 minutes; cysts are resistant to standard concentrations of chlorine), or filtered.

Gonzales ML et al. Antiamoebic drugs for treating amoebic colitis. Cochrane Database Syst Rev. 2009 Apr 15;(2):CD006085.[PMID: 19370624]

Pritt BS et al. Amebiasis. Mayo Clin Proc. 2008 Oct;83(10):1154–9. [PMID: 18828976]

Wright SG. Protozoan infections of the gastrointestinal tract. Infect Dis Clin North Am. 2012 Jun;26(2):323–39. [PMID: 22632642]

INFECTIONS WITH PATHOGENIC FREE-LIVING AMEBAS

 ESSENTIALS OF DIAGNOSIS

 Acute meningoencephalitis or chronic granulomatous encephalitis after contact with warm fresh water.

 Keratitis, particularly in contact lens users.

The free-living amebas that cause disease in humans are of the genera Acanthamoeba, NaegleriaBalamuthia, and Sappinia. The organisms are widely distributed in soil and fresh and brackish water.Acanthamoeba and Naegleria species have been found to harbor LegionellaVibrio 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 Naegleria fowleri, but also Balamuthia mandrillaris and Acanthamoeba species. 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 warm fresh water. The incubation period varies from 2 to 15 days. Early symptoms include headache, fever, stiff neck, 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. CSF shows hundreds to thousands of leukocytes and erythrocytes per cubic millimeter. Protein is usually elevated, and glucose is normal or moderately reduced. A fresh wet mount of the CSF may show motile trophozoites. Staining with Giemsa or Wright stain will identify the trophozoites. Species identification is based on morphology and immunologic methods. Primary amebic meningoencephalitis is nearly always fatal. Amphotericin B appears to be the drug of choice; one survivor was treated with intravenous and intrathecal amphotericin B, intravenous miconazole, and oral rifampin.

  1. Granulomatous Amebic Encephalitis

Acanthamoeba species and B mandrillaris can cause an encephalitis that is more chronic in nature than primary amebic meningoencephalitis. One case of encephalitis caused by Sappinia has also been described. Neurologic disease may be preceded by skin lesions, including ulcers and nodules. After an uncertain incubation period neurologic symptoms develop slowly, with headache, meningismus, nausea, vomiting, lethargy, and low-grade fevers progressing over weeks to months to focal neurologic findings, mental status abnormalities, and eventually coma and death. CT and MRI show single or multiple nonspecific lesions. Lumbar puncture is dangerous due to increased intracranial pressure. CSF shows a lymphocytic pleocytosis with elevated protein; amebas are not typically seen. Diagnosis can be made by biopsy of skin or brain lesions. Information on the treatment of granulomatous amebic encephalitis is limited. Some patients have been successfully treated with various combinations of flucytosine, pentamidine, fluconazole or itraconazole, sulfadiazine, trimethoprim-sulfamethoxazole, and azithromycin.

  1. Acanthamoeba Keratitis

Acanthamoeba keratitis is a painful, sight-threatening corneal infection. It is associated with corneal trauma, most commonly after use of contact lenses and contaminated saline solution. Symptoms include severe eye pain, photophobia, tearing, and blurred vision. The keratitis progresses slowly, with waxing and waning clinical findings over months, and can progress to blindness. Lack of response to antibacterial, antifungal, and antiviral topical treatments and potential use of contaminated contact lens solution are suggestive of the diagnosis. Ocular examination shows corneal ring infiltrates, but these can also be caused by other pathogens. The diagnosis can be made by examination or culture of corneal scrapings. Available diagnostic techniques include examination of a wet preparation for cysts and motile trophozoites, examination of stained specimens, evaluation with immunofluorescent reagents, culture of organisms, and PCR.

Acanthamoeba keratitis can be cured with local therapy. Topical propamidine isethionate (0.1%), chlorhexidine digluconate (0.02%), polyhexamethylene biguanide, neomycin-polymyxin B-gramicidin, miconazole, and combinations of these agents have been used successfully. Oral itraconazole or ketoconazole can be added for deep keratitis. Drug resistance has been reported. Use of corticosteroid therapy is controversial. In some cases, debridement and penetrating keratoplasty have been performed in addition to medical therapy. Corneal grafting can be done after the amebic infection has been eradicated.

Bravo FG et al. Balamuthia mandrillar is infection of the skin and central nervous system: an emerging disease of concern to many specialties in medicine. Curr Opin Infect Dis. 2011 Apr;24(2):112–7. [PMID: 21192259]

Dart JK et al. Acanthamoeba keratitis: diagnosis and treatment update, 2009. Am J Ophthalmol. 2009 Oct;148(4):487–499.e2. [PMID: 19660733]

Visvesvara GS. Amebic meningoencephalitides and keratitis: challenges in diagnosis and treatment. Curr Opin Infect Dis. 2010 Dec;23(6):590–4. [PMID: 20802332]

COCCIDIOSIS (Cryptosporidiosis, Isosporiasis, Cyclosporiasis, Sarcocystosis) & Microsporidiosis

 ESSENTIALS OF DIAGNOSIS

 Acute diarrhea, especially in children in developing countries.

 Outbreaks of diarrhea secondary to contaminated water or food.

 Prolonged diarrhea in immunocompromised persons.

 Diagnosis mostly by identifying organisms in specially stained stool specimens.

 General Considerations

The causes of coccidiosis are Cryptosporidium species (C parvumC hominis, and others)Isospora belli; Cyclospora cayetanensis; and Sarcocystis species. Microsporidiosis is caused by at least 14 species, most commonly Enterocytozoon bieneusi and Encephalitozoon intestinalis. These infections occur worldwide, particularly in the tropics and in regions where hygiene is poor. They are causes of endemic childhood gastroenteritis (particularly in malnourished children in developing countries); institutional and community outbreaks of diarrhea; traveler’s diarrhea; and acute and chronic diarrhea in immunosuppressed patients, in particular those with AIDS. They are all notable for the potential to cause prolonged diarrhea, often lasting for a number of weeks. Clustering occurs in households, day care centers, and among sexual partners.

The infectious agents are oocysts (coccidiosis) or spores (microsporidiosis) transmitted 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. Coccidian oocysts and microsporidian cysts can remain viable in the environment for years.

I belli and C cayetanensis appear to infect only humans. C cayetanensis has caused a number of food-borne outbreaks in the United States in recent years, most commonly associated with imported fresh produce. Sarcocystis infects many species; humans are intermediate hosts (infected by ingestion of fecal sporocysts) for some species but definitive hosts for Sarcocystis bovihominis and Sarcocystis suihominis (infected by ingestion of tissue cysts in undercooked beef and pork, respectively).

Cryptosporidiosis is a zoonosis (C parvum principally infects cattle), but most human infections are acquired from humans, in particular with C hominus. Cryptosporidia are highly infectious and readily transmitted in day care settings and households. They have caused large community outbreaks due to contaminated water supplies (causing ~400,000 illnesses in Milwaukee in 1993) and are the leading cause of recreational water–associated outbreaks of gastroenteritis. Of note, coccidia and microsporidians will generally be missed on routine evaluations of stool for ova and parasites, as they require special staining techniques for identification.

 Clinical Findings

  1. Symptoms and Signs
  2. Cryptosporidiosis—The incubation period appears to be 1–14 days. In developing countries, disease is primarily in children under 5 years of age, causing 5–10% of childhood diarrhea. Presenting symptoms in children include acute watery diarrhea, abdominal pain, and cramps, with rapid resolution in most patients; however, symptoms quite commonly persist for 2 weeks or more. In developed countries, most patients are adults. Diarrhea in immunocompetent individuals typically lasts from 5 to 10 days. It is usually watery, with accompanying abdominal pain and cramps, nausea, vomiting, and fever. Relapses may follow initial resolution of symptoms. Mild illness and asymptomatic infection are also common.

Cryptosporidiosis is a well-characterized cause of diarrhea in those with AIDS. It was common before the advent of highly active antiretroviral therapy, particularly with advanced immunosuppression. Clinical manifestations are variable, but patients commonly have chronic diarrhea with frequent foul smelling stools, malabsorption, and weight loss. Severe, life-threatening watery diarrhea may be seen. Cryptosporidiosis also causes extraintestinal disease with AIDS, including pulmonary infiltrates with dyspnea and biliary tract infection with sclerosing cholangitis and AIDS cholangiopathy.

  1. Isosporiasis—The incubation period forI belliis about 1 week. In immunocompetent persons, it usually causes a self-limited watery diarrhea lasting 2–3 weeks, with abdominal cramps, anorexia, malaise, and weight loss. Fever is unusual. Chronic symptoms may persist for months. In immunocompromised patients, isosporiasis more commonly causes severe and chronic diarrhea, with complications including marked dehydration, malnutrition, and hemorrhagic colitis. Extraintestinal disease has been reported rarely.
  2. Cyclosporiasis—C cayetanensisoocysts must undergo a period of sporulation of 7 days or more after shedding before they become infectious. Therefore, person-to-person spread is unlikely, and spread has typically been due to contaminated food (especially fresh produce) and water. The incubation period is 1–11 days. Infections can be asymptomatic. Cyclosporiasis causes an illness similar to that described for the other pathogens described in this section, with watery diarrhea, abdominal cramps, nausea, fatigue, and anorexia. Fever is seen in 25% of cases. Symptoms typically continue for 2 weeks or longer and may persist for months. Relapses of diarrhea are common. Diarrhea may be preceded by a flu-like prodrome and followed by persistent fatigue. In immunocompromised patients, cyclosporiasis is typically more severe and prolonged, with chronic fulminant watery diarrhea and weight loss.
  3. Sarcocystosis—Sarcocystisinfection may be common in some developing countries, but it is usually asymptomatic. Infection appears to most commonly follow the ingestion of undercooked beef or pork, leading to the development of cysts in muscle, with myalgias, fever, bronchospasm, pruritic rash, lymphadenopathy, and subcutaneous nodules. Ingestion of fecal sporocysts may lead to gastrointestinal symptoms.
  4. Microsporidiosis—Microsporidia are obligate intracellular protozoans that cause a wide spectrum of diseases. Many infections are of zoonotic origin, but human-to-human transmission has been documented. Infection is mainly by ingestion of spores, but also by direct inoculation of the eyes. In immunocompetent hosts, microsporidian infections most commonly present as self-limited diarrhea. Ocular infections have also been described. Disease from microsporidia is seen mainly in immunocompromised persons, particularly those with AIDS. Infections in AIDS patients are most commonly withE bieneusiandE intestinalis. They cause chronic diarrhea, with anorexia, bloating, weight loss, and wasting, especially in those with advanced immunodeficiency. Fever is usually not seen. Other illnesses in immunocompromised persons associated with microsporidians (including the genera Enterocytozoon, Encephalitozoon, Brachiola, Vittaforma, Pleistophora, Trachipleistophora, and Microsporidium) include biliary tract disease (AIDS cholangiopathy), genitourinary infection with cystitis, kidney disease, hepatitis, peritonitis, myositis, respiratory infections including sinusitis, central nervous system infections including granulomatous encephalitis, and disseminated infections. Ocular infections with Encephalitozoon species cause conjunctivitis and keratitis, presenting as redness, photophobia, and loss of visual acuity.
  5. Laboratory Findings
  6. Cryptosporidiosis—Typically, stool is without blood or leukocytes. Diagnosis is traditionally made by detecting the organism in stool using a modified acid-fast stain; this technique is relatively insensitive, and multiple specimens should be evaluated before ruling out the diagnosis. Of note, routine evaluation for ova and parasites typically does not include a modified acid-fast stain, so this must be specifically requested in many laboratories. Antigen detection offers improved sensitivity and specificity, both of which are well over 90% with a number of available assays, and these methods may now be considered the optimal means of diagnosis.
  7. Isosporiasis—Diagnosis of isosporiasis is by examination of stool wet mounts or after modified acid-fast staining, in which the organism is clearly distinguishable fromother parasites. Other stains also show the organism. Shedding of oocysts may be intermittent, so the sensitivity of stool evaluation is not high, and multiple samples should be examined. The organism may also be identified in duodenal aspirates or small bowel biopsies.
  8. Cyclosporiasis—Diagnosis is made by examination of stool wet mounts or after modified acid-fast staining. Multiple specimens may need to be examined to make a diagnosis. The organism can also be identified in small bowel aspirates or biopsy specimens.
  9. Sarcocystosis—Eosinophilia and elevated creatine kinase may be seen. Diagnosis is by identification of the acid-fast organisms in stool or by identification of trophozoites or bradyzoites in tissue biopsies.
  10. Microsporidiosis—Diagnosis can be made by identification of organisms in specially stained stool, fluid, or tissue specimens, for example with Weber chromotrope-based stain. Electron microscopy is helpful for confirmation of the diagnosis and speciation. PCR and culture techniques are available but not used routinely.

 Treatment

Most acute infections with these pathogens 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 some cases, parenteral nutrition.

  1. Cryptosporidiosis—Treatment of cryptosporidiosis is challenging. No agent is clearly effective. Modest benefits have been seen in some (but not other) studies with paromomycin, a non-absorbed aminoglycoside (25–35 mg/kg orally for 14 days has been used), and nitazoxanide (500 mg–1 g orally twice daily for 3 days in nonimmunocompromised and 2–8 weeks in advanced AIDS patients), which is approved in the United States for this indication. It can cause mild gastrointestinal toxicity. Other agents that have been used with mixed success in AIDS patients with cryptosporidiosis include azithromycin, spiramycin, bovine hyperimmune colostrum, and octreotide. Reversing immunodeficiency with effective antiretroviral therapy is of greatest importance.
  2. Isosporiasis—Isosporiasis is effectively treated in immunocompetent and immunosuppressed persons with trimethoprim-sulfamethoxazole (160 mg/800 mg orally two to four times daily for 10 days, with the higher dosage for patients with AIDS). An alternative therapy is pyrimethamine (75 mg orally in four divided doses) with folinic acid (10–25 mg/d orally). Maintenance therapy with low-dose trimethoprim-sulfamethoxazole (160 mg/800 mg daily or three times per week) or Fansidar (1 tablet weekly) prevents relapse in those with persistent immunosuppression.
  3. Cyclosporiasis—Cyclosporiasis is also treated with trimethoprim-sulfamethoxazole (dosing as for isosporiasis). With AIDS, long-term maintenance therapy (160 mg/800 mg three times weekly) helps prevent relapse. For patients intolerant of trimethoprim-sulfamethoxazole, ciprofloxacin (500 mg orally twice daily for 7 days) showed efficacy, albeit with less ability to clear the organism than trimethoprim-sulfamethoxazole.
  4. Sarcocystosis—For sarcocystosis, no specific treatment is established, but sulfadiazine cleared intestinal cysts in one study.
  5. Microsporidiosis—Treatment of microsporidiosis is complex. Infections with most species, including those causing gastrointestinal and other manifestations, should be treated with albendazole (400 mg orally twice daily for 2–4 weeks), which has activity against a number of species, but relatively poor efficacy (about 50%) againstE bieneusi, the most common microsporidial cause of diarrhea in AIDS patients. Fumagillin, which is used to treat honeybees and fish with microsporidian infections, has shown benefit in clinical trials at a dose of 20 mg three times per day for 14 days; treatment was accompanied by reversible thrombocytopenia. As with cryptosporidiosis, the best means of controlling microsporidiosis in AIDS patients is to restore immune function with effective antiretroviral therapy. Ocular microsporidiosis can be treated with fumagillin solution (3 mg/mL); this probably should be given with concurrent systemic therapy with albendazole. Adjunctive management may include corticosteroids to decrease inflammation and keratoplasty.

 Prevention

Water purification is important for control of these infections. Chlorine disinfection is not effective against cryptosporidial oocysts, so other purification measures are needed. Immunocompromised patients should boil or filter drinking water and should consider avoidance of lakes and swimming pools. Routine precautions (handwashing, gloves, disinfection) should prevent institutional patient-to-patient spread. Optimal means of preventing microsporidial infections are not well understood, but water purification and body substance precautions for immunocompromised and hospitalized individuals are likely effective.

Didier ES et al. Microsporidiosis: not just in AIDS patients. Curr Opin Infect Dis. 2011 Oct;24(5):490–5. [PMID: 21844802]

Marcos LA et al. Intestinal protozoan infections in the immunocompromised host. Curr Opin Infect Dis. 2013 Aug;26(4):295–301. [PMID: 23806893]

O’Connor RM et al. Cryptosporidiosis in patients with HIV/AIDS. AIDS. 2011 Mar 13;25(5):549–60. [PMID: 21160413]

Shirley DA et al. Burden of disease from cryptosporidiosis. Curr Opin Infect Dis. 2012 Oct;25(5):555–63. [PMID: 22907279]

GIARDIASIS

 ESSENTIALS OF DIAGNOSIS

 Acute diarrhea; may be profuse and watery.

 Chronic diarrhea with greasy, malodorous stools.

 Abdominal cramps, distention, flatulence, and malaise.

 Cysts or trophozoites in stools.

 General Considerations

Giardiasis is a protozoal infection of the upper small intestine caused by the flagellate Giardia lamblia (also called Giardia intestinalis and Giardia duodenalis). The parasite occurs worldwide, most abundantly in areas with poor sanitation. In developing countries, young children are very commonly infected. In the United States and Europe, the infection is the most common intestinal protozoal pathogen; the US estimate is 100,000 to 2.5 million new infections leading to 5000 hospital admissions yearly. Groups at special risk include travelers to Giardia-endemic areas, those who swallow contaminated water during recreation or wilderness travel, men who have sex with men, and persons with impaired immunity. Outbreaks are common in households, children’s day care centers, and residential facilities, and may occur as a result of contamination of water supplies.

The organism occurs in feces as a flagellated trophozoite and as a cyst. Only the cyst form is infectious by the oral route; trophozoites are destroyed by gastric acidity. Humans are a reservoir for the pathogen; dogs, cats, beavers, and other mammals have been implicated but not confirmed as reservoirs. Under suitable moist, cool conditions, cysts can survive in the environment for weeks to months. Cysts are transmitted as a result of fecal contamination of water or food, by person-to-person contact, or by anal-oral sexual contact. The infectious dose is low, requiring as few as ten cysts. After the cysts are ingested, trophozoites emerge in the duodenum and jejunum. Epithelial damage and mucosal invasion are uncommon. Hypogammaglobulinemia, low secretory IgA levels in the gut, achlorhydria, and malnutrition favor the development of infection.

 Clinical Findings

  1. Symptoms and Signs

It is estimated that about 50% of infected persons have no discernable infection, about 10% become asymptomatic cyst passers, and 25–50% develop an acute diarrheal syndrome. Acute diarrhea may clear spontaneously but is commonly followed by chronic diarrhea. The incubation period is usually 1–3 weeks but may be longer. The illness may begin gradually or suddenly. Cysts may not be detected in the stool at the onset of the illness. The acute phase may last days or weeks, and is usually self-limited, although cyst excretion may be prolonged. The initial illness may include profuse watery diarrhea, and hospitalization may be required due to dehydration, particularly in young children. Typical symptoms of chronic disease are abdominal cramps, bloating, flatulence, nausea, malaise, and anorexia. Fever and vomiting are uncommon. Diarrhea is usually not severe in the chronic stage of infection; stools are greasy or frothy and foul smelling, without blood, pus, or mucus. The diarrhea may be daily or recurrent; intervening periods may include constipation. Symptoms can persist for weeks to months. Weight loss is frequent. Chronic disease can include malabsorption, including fat-and protein-losing enteropathy and vitamin deficiencies.

  1. Laboratory Findings

Most patients seek medical attention after having been ill for over a week, commonly with weight loss of 5 kg or more. Stool is generally without blood or leukocytes. Diagnosis is traditionally made by the identification of trophozoites or cysts in stool. A wet mount of liquid stool may identify motile trophozoites. Stained fixed specimens may show cysts or trophozoites. Sensitivity of stool analysis is not ideal, estimated at 50–80% for a single specimen and over 90% for three specimens. Sampling of duodenal contents with a string test or biopsy is no longer generally recommended, but biopsies may be helpful in very ill or immunocompromised patients. When giardiasis is suspected, antigen assays may be simpler and cheaper than repeated stool examinations, but these tests will not identify other stool pathogens. Multiple tests, which identify antigens of trophozoites or cysts, are available. They are generally quite sensitive (85–98%) and specific (90–100%).

 Treatment

The treatments of choice for giardiasis are metronidazole (250 mg orally three times daily for 5–7 days) or tinidazole (2 g orally once). The drugs are not universally effective; cure rates for single courses are typically about 80–95%. Toxicities are as described for treatment of amebiasis, but the lower dosages used for giardiasis limit side effects. A meta-analysis showed albendazole (400 mg orally once daily for 5 days) to have equivalent efficacy and fewer side effects compared with metronidazole, and so it may be considered another first-line agent for giardiasis. Nitazoxanide (500 mg orally twice daily for 3 days) is generally well tolerated but may cause mild gastrointestinal side effects. Other drugs with activity against Giardia include furazolidone (100 mg orally four times a day for 7 days), which is about as effective as the other named drugs but causes gastrointestinal side effects, and paromomycin (500 mg orally three times a day for 7 days), which appears to have somewhat lower efficacy but unlike metronidazole, tinidazole, and furazolidone is safe in pregnancy. Symptomatic giardiasis should always be treated. Treatment of asymptomatic patients should be considered, since they can transmit the infection. With a suggestive presentation but negative diagnostic studies, an empiric course of treatment may be appropriate. Household or day care contacts with an index case should be tested and treated if infected.

 Prevention

Community chlorination (0.4 mg/L) of water is relatively ineffective for inactivating cysts, so filtration is required. For wilderness or international travelers, bringing water to a boil for 1 minute or filtration with a pore size < 1 mcm are adequate. In day care centers, appropriate disposal of diapers and frequent handwashing are essential.

Granados CE et al. Drugs for treating giardiasis. Cochrane Database Syst Rev. 2012 Dec 12;12:CD007787. [PMID: 23235648]

Solaymani-Mohammadi S et al. A meta-analysis of the effectiveness of albendazole compared with metronidazole as treatments for infections with Giardia duodenalis. PLoS Negl Trop Dis. 2010 May 11;4(5):e682. [PMID: 20485492]

TRICHOMONIASIS

 ESSENTIALS OF DIAGNOSIS

 Copious vaginal discharge in women.

 Nongonococcal urethritis in men.

 Motile trichomonads on wet mounts.

 General Considerations

Trichomoniasis is caused by the protozoan Trichomonas vaginalis and is among the most common sexually transmitted diseases, causing vaginitis in women and nongonococcal urethritis in men. It can also occasionally be acquired by other means, since it can survive in moist environments for several hours.

 Clinical Findings

  1. Symptoms and Signs

T vaginalis is often harbored asymptomatically. For women with symptomatic disease, after an incubation period of 5 days to 4 weeks, a vaginal discharge develops, often with vulvovaginal discomfort, pruritus, dysuria, dyspareunia, or abdominal pain. Examination shows a copious discharge, which is usually not foul smelling but is often frothy and yellow or green in color. Inflammation of the vaginal walls and cervix with punctate hemorrhages are common. Most men infected with T vaginalis are asymptomatic, but it can be isolated from about 10% of men with nongonococcal urethritis. In men with trichomonal urethritis, the urethral discharge is generally more scanty than with other causes of urethritis.

  1. Diagnostic Testing

Diagnosis is typically made by identifying the organism in vaginal or urethral secretions. Examination of wet mounts will show motile organisms. Tests for bacterial vaginosis (pH > 4.5, fishy odor after addition of potassium hydroxide) are often positive with trichomoniasis. Newer diagnostic tests include point-of-care antigen tests and nucleic acid amplification assays, both of which offer improved sensitivity compared to wet mount microscopy and excellent specificity.

 Treatment

The treatment of choice is tinidazole or metronidazole, each as a 2 g single oral dose. Tinidazole may be better tolerated and active against some resistant parasites. Toxicities of these drugs are discussed in the section on amebiasis. If the large single dose cannot be tolerated, an alternative metronidazole dosage is 500 mg orally twice daily for 1 week. All infected persons should be treated, even if asymptomatic, to prevent subsequent symptomatic disease and limit spread. Treatment failure suggests reinfection, but metronidazole-resistant organisms have been reported. These may be treated with tinidazole, longer courses of metronidazole, furazolidone, or other experimental therapies (see Chapter 18).

Bachmann LH et al. Trichomonas vaginalis genital infections: progress and challenges. Clin Infect Dis. 2011 Dec;53(Suppl 3):S160–72. [PMID: 22080269]

Hobbs MM et al. Modern diagnosis of Trichomonas vaginalis infection. Sex Transm Infect. 2013 Sep;89(6):434–8. [PMID: 23633669]

HELMINTHIC INFECTIONS

TREMATODE (FLUKE) INFECTIONS

SCHISTOSOMIASIS (Bilharziasis)

 ESSENTIALS OF DIAGNOSIS

 History of fresh water exposure in an endemic area.

 Acute schistosomiasis: fever, headache, myalgias, cough, urticaria, diarrhea, and eosinophilia.

 Intestinal schistosomiasis: abdominal pain, diarrhea, and hepatomegaly, progressing to anorexia, weight loss, and features of portal hypertension.

 Urinary schistosomiasis: hematuria and dysuria, progressing to hydroureter, hydronephrosis and urinary infections.

 Diagnosis based on characteristic eggs in feces or urine; biopsy of rectal or bladder mucosa; positive serology.

 General Considerations

Schistosomiasis, which affects more than 200 million persons worldwide, leads to severe consequences in 20 million persons and about 100,000 deaths annually. The disease is caused by five species of trematode blood flukes. Four species cause intestinal schistosomiasis, with infection of mesenteric venules: Schistosoma mansoni, which is present in Africa, the Arabian peninsula, South America, and the Caribbean; Schistosoma japonicum, which is endemic in China and Southeast Asia; Schistosoma mekongi, which is endemic near the Mekong River in Southeast Asia; and Schistosoma intercalatum, which occurs in parts of Africa. Schistosoma haematobium causes urinary schistosomiasis, with infection of venules of the urinary tract, and is endemic in Africa and the Middle East. Transmission of schistosomiasis is focal, with greatest prevalence in poor rural areas. Control efforts have diminished transmission significantly in many areas, but high level transmission remains common in sub-Saharan Africa and some other areas. Prevalence of infection and illness typically peaks at about 15–20 years of age.

Humans are infected with schistosomes after contact with fresh water containing cercariae released by infected snails. Infection is initiated by penetration of skin or mucous membranes. After penetration, schistosomulae migrate to the portal circulation, where they rapidly mature. After about 6 weeks, adult worms mate, and migrate to terminal mesenteric or bladder venules, where females deposit their eggs. Some eggs reach the lumen of the bowel or bladder and are passed with feces or urine, while others are retained in the bowel or bladder wall or transported in the circulation to other tissues, in particular the liver. Disease in endemic areas is primarily due to a host response to eggs, with granuloma formation and inflammation, eventually leading to fibrosis. Chronic infection can result in scarring of mesenteric or vesicular blood vessels, leading to portal hypertension and alterations in the urinary tract. In previously uninfected individuals, such as travelers with fresh water contact in endemic regions, acute schistosomiasis may occur, with a febrile illness 2–8 weeks after infection.

 Clinical Findings

  1. Symptoms and Signs
  2. Cercarial dermatitis—Following cercarial penetration, localized erythema develops in some individuals, which can progress to a pruritic maculopapular rash that persists for some days. Dermatitis can be caused by human schistosomes and, in non-tropical areas, by bird schistosomes that cannot complete their life cycle in humans (swimmer’s itch).
  3. Acute schistosomiasis (Katayama syndrome)—A febrile illness may develop 2–8 weeks after exposure in persons without prior infection, most commonly after heavy infection withS mansonior S japonicum. Presenting symptoms and signs include acute onset of fever; headache; myalgias; cough; malaise; urticaria; diarrhea, which may be bloody; hepatosplenomegaly; lymphadenopathy; and pulmonary infiltrates. Localized lesions may occasionally cause severe manifestations, including CNS abnormalities and death. Acute schistosomiasis usually resolves in 2–8 weeks.
  4. Chronic schistosomiasis—Many infected persons have light infections and are asymptomatic, but an estimated 50–60% have symptoms and 5–10% have advanced organ damage. Asymptomatic infected children may suffer from anemia and growth retardation. Symptomatic patients with intestinal schistosomiasis typically experience abdominal pain, fatigue, diarrhea, and hepatomegaly. Over years, anorexia, weight loss, weakness, colonic polyps, and features of portal hypertension develop. Late manifestations include hematemesis from esophageal varices, hepatic failure, and pulmonary hypertension. Urinary schistosomiasis may present within months of infection with hematuria and dysuria, most commonly in children and young adults. Fibrotic changes in the urinary tract can lead to hydroureter, hydronephrosis, bacterial urinary infections and, ultimately, kidney disease or bladder cancer.
  5. Laboratory Findings

Microscopic examination of stool or urine for eggs, evaluation of tissue, or serologic tests establish the diagnosis. Characteristic eggs can be identified on smears of stool or urine, but filtration or concentration techniques can improve yields. Quantitative tests that yield > 400 eggs per gram of feces or 10 mL of urine are indicative of heavy infections with increased risk of complications. Diagnosis can also be made by biopsy of the rectum, colon, liver, or bladder. Serologic tests include an ELISA available from the CDC that is 99% specific for all species. The test is 99% sensitive for S mansoni, 95% sensitive for S haematobium, but < 50% sensitive for S japonicum. Species-specific immunoblots can increase sensitivity. In acute schistosomiasis, leukocytosis and marked eosinophilia may occur; serologic tests may become positive before eggs are seen in stool or urine. After therapy, eggs may be shed in stool or urine for months, and so the identification of eggs in fluids or tissue or positive serologic tests cannot distinguish past or active disease. Tests for egg viability are available. With a diagnosis of schistosomiasis, evaluation for the extent of disease is warranted, including liver function studies and imaging of the liver with intestinal disease and ultrasound or other imaging studies of the urinary system in urinary disease.

 Treatment

Treatment is indicated for all schistosome infections. In areas where recurrent infection is common, treatment is valuable in reducing worm burdens and limiting clinical complications. The drug of choice for schistosomiasis is praziquantel. The drug is administered for 1 day at an oral dose of 40 mg/kg (in one or two doses) for S mansoni, S haematobium, and S intercalatum infections and a dose of 60 mg/kg (in two or three doses) for S japonicum and S mekongi. Cure rates are generally > 80% after a single treatment, and those not cured have marked reduction in the intensity of infection. Praziquantel is active against invading cercariae but not developing schistosomulae. Therefore, the drug may not prevent illness when given after exposure and, for recent infections, a repeat course after a few weeks may be appropriate. Praziquantel may be used during pregnancy. Resistance to praziquantel has been reported. Toxicities include abdominal pain, diarrhea, urticaria, headache, nausea, vomiting, and fever, and may be due both to direct effects of the drug and responses to dying worms. Alternative therapies are oxamniquine for S mansoni infection and metrifonate for S haemotobium infection. Both of these drugs currently have limited availability (they are not available in the United States), and resistance may be a problem. No second-line drug is available for S japonicum infections. The antimalarial drug artemether has activity against schistosomulae and adult worms and may be effective in chemoprophylaxis; however, it is expensive, and long-term use in malarious areas might select for resistant malaria parasites. With severe disease, use of corticosteroids in conjunction with praziquantel may decrease complications. Treatment should be followed by repeat examinations for eggs about every 3 months for 1 year after therapy, with re-treatment if eggs are seen.

 Prevention

Travelers to endemic areas should avoid fresh water exposure. Vigorous toweling after exposure may limit cercarial penetration. Chemoprophylaxis with artemether has shown efficacy but is not standard practice. Community control of schistosomiasis includes improved sanitation and water supplies, elimination of snail habitats, and intermittent treatment to limit worm burdens.

Gray DJ et al. Diagnosis and management of schistosomiasis. BMJ. 2011 May 17;342:d2651. [PMID: 21586478]

Gryseels B. Schistosomiasis. Infect Dis Clin North Am. 2012 Jun;26(2):383–97. [PMID: 22632645]

King CH et al. Utility of repeated praziquantel dosing in the treatment of schistosomiasis in high-risk communities in Africa: a systematic review. PLoS Negl Trop Dis. 2011 Sep;5(9):e1321. [PMID: 21949893]

LIVER, LUNG, & INTESTINAL FLUKES

FASCIOLIASIS

Infection by Fasciola hepatica, the sheep liver fluke, results from ingestion of encysted metacercariae on watercress or other aquatic vegetables. Infection is prevalent in sheep-raising areas in many countries, especially parts of South America, the Middle East, and southern Europe. Fasciola gigantica has a more restricted distribution in Asia and Africa and causes similar findings. Eggs are passed from host feces into fresh water, leading to infection of snails, and then deposition of metacercariae on vegetation. In humans, metacercariae excyst, penetrate into the peritoneum, migrate through the liver, and mature in the bile ducts, where they cause local necrosis and abscess formation.

Two clinical syndromes are seen, related to acute migration of worms and chronic infection of the biliary tract. Symptoms related to migration of larvae present 6–12 weeks after ingestion. Typical findings are abdominal pain, fever, malaise, weight loss, urticaria, eosinophilia, and leukocytosis. Tender hepatomegaly and elevated liver function tests may be seen. Rarely, migration to other organs may lead to localized disease. The symptoms of worm migration subside after 2–4 months, followed by asymptomatic infection by adult worms or intermittent symptoms of biliary obstruction, with biliary colic and, at times, findings of cholangitis. Early diagnosis is difficult, as eggs are not found in the feces during the acute migratory phase of infection. Clinical suspicion should be based on clinical findings and marked eosinophilia in at risk individuals. CT and other imaging studies show hypodense migratory lesions of the liver. Definitive diagnosis is made by the identification of characteristic eggs in stool. Repeated examinations may be necessary. In chronic infection, imaging studies show masses obstructing the extrahepatic biliary tract. Serologic assays have sensitivity and specificity > 90%, but cannot distinguish between past and current infection. Antigen tests with excellent sensitivity and specificity are available in veterinary medicine and may be appropriate for diagnosis in humans.

Fascioliasis is unusual among fluke infections, in that it does not respond well to treatment with praziquantel. The treatment of choice is triclabendazole, which is also used in veterinary medicine, but is not available in the United States. Standard dosing of 10 mg/kg orally in a single dose or two doses over 12 hours achieves a cure rate of about 80%, but repeat dosing is indicated if abnormal radiologic findings or eosinophilia do not resolve. Resistance to triclabendazole has been reported in animal but not human infections. The second-line drug for fascioliasis is bithionol (30–50 mg/kg/d orally in three divided doses on alternate days for 10–15 days); this drug is no longer available in the United States. Treatment with either drug can be accompanied by abdominal pain and other gastrointestinal symptoms. Prevention of fascioliasis involves avoidance of ingestion of raw aquatic plants.

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. Millions of people are affected and, in some communities, prevalence can reach over 80%. Opisthorchiasis is principally caused by Opisthorchis felineus (regions of the former Soviet Union) or Opisthorchis viverrini (Thailand, Laos, Vietnam). Clonorchiasis and opisthorchiasis are clinically indistinguishable. Parasite eggs are shed into water in human or animal feces, where they infect snails, which release cercariae, which infect fish. Human infection follows ingestion of raw, undercooked, or pickled freshwater fish containing metacercariae. These parasites excyst in the duodenum and ascend into the biliary tract, where they mature and remain for many years, shedding eggs in the bile.

Most patients harbor few parasites and are asymptomatic. An acute illness can occur 2–3 weeks after initial infection, with fever, abdominal pain, tender hepatomegaly, urticaria, and eosinophilia. 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 heavy infections, findings include abdominal pain, anorexia, weight loss, and tender hepatomegaly. More serious findings can include recurrent bacterial cholangitis and sepsis, cholecystitis, liver abscess, and pancreatitis. An increased risk of cholangiocarcinoma has been documented.

Early diagnosis is presumptive, based on clinical findings and epidemiology. Subsequent diagnosis is made by finding characteristic eggs in stool or duodenal or biliary contents. Repeated concentration tests of stool may be necessary. Imaging studies show characteristic biliary tract dilatations with filling defects due to flukes. ELISA assays for clonorchiasis with sensitivities of ~90% are used in Asia.

The drug of choice is praziquantel, 25 mg/kg orally three times daily for 2 days, which provides cure rates over 95%. One day of treatment may be sufficient. Re-treatment may be required, especially in some areas with known decreased praziquantel efficacy. The second-line drug is albendazole (400 mg orally twice daily for 7 days), which appears to be somewhat less effective.

PARAGONIMIASIS

Eight species of Paragonimus lung flukes cause human disease. The most important is Paragonimus westermani. Paragonimus species are endemic in East Asia, Oceania, West Africa, and South America, where millions of persons are infected; rare infections have occurred in North America. Eggs are released into fresh water, where parasites infect snails, and then cercariae infect crabs and crayfish. Human infection follows consumption of raw, undercooked, or pickled freshwater shellfish. Metacercariae then excyst, penetrate into the peritoneum, and pass into the lungs, where they mature into adult worms over about 2 months.

Most persons have moderate worm burdens and are asymptomatic. In symptomatic cases, abdominal pain and diarrhea develop 2 days to 2 weeks after infection, followed by fever, cough, chest pain, urticaria, and eosinophilia. Acute symptoms may last for several weeks. Chronic infection can cause cough productive of brown sputum, hemoptysis, dyspnea, and chest pain, with progression to chronic bronchitis, bronchiectasis, bronchopneumonia, lung abscess, and pleural disease. Ectopic infections can cause disease in other organs, most commonly the CNS, where disease can present with seizures, headaches, and focal neurologic findings due to parasite meningitis and to intracerebral lesions.

The diagnosis of paragonimiasis is made by identifying characteristic eggs in sputum or stool or identifying worms in biopsied tissue. Multiple examinations and concentration techniques may be needed. Serologic tests may be helpful; an ELISA available from the CDC has sensitivity and specificity > 95%. Chest radiographs may show varied abnormalities of the lungs or pleura, including infiltrates, nodules, cavities, and fibrosis, and the findings can be confused with those of tuberculosis. With CNS disease, skull radiographs can show clusters of calcified cysts, and CT or MRI can show clusters of ring-enhancing lesions.

Treatment is with praziquantel (25 mg/kg orally three times daily for 2 days), which provides efficacy of at least 90%. Alternative therapies are bithionol and triclabendazole. As with cysticercosis, for cerebral paragonimiasis, praziquantel should generally be used with corticosteroids. Chronic infection may lead to permanent lung dysfunction and pleural disease requiring drainage procedures.

INTESTINAL FLUKES

The large intestinal fluke, Fasciolopsis buski, is a common parasite of pigs and humans in eastern and southern Asia. Eggs shed in stools hatch in fresh water, followed by infection of snails, and release of cercariae that encyst on aquatic plants. Humans are infected by eating uncooked plants, including water chestnuts, bamboo shoots, and watercress. Adult flukes mature in about 3 months and live in the small intestine attached to the mucosa, leading to local inflammation and ulceration. Other intestinal flukes that cause similar syndromes include Heterophyes (North Africa and Turkey) and Metagonimus(East Asia) species; these species are transmitted by undercooked freshwater fish.

Infections with intestinal flukes are often asymptomatic, although eosinophilia may be marked. In symptomatic cases, after an incubation period of 1–2 months, manifestations include epigastric pain and diarrhea. Other gastrointestinal symptoms, ileus, edema, and ascites may be seen uncommonly. Diagnosis is based on identification of characteristic eggs or adult flukes in the stool. In contrast to other fluke infections, illness more than 6 months after travel in an endemic area is unlikely. The drug of choice is praziquantel, 25 mg/kg orally as a single dose. Alternative therapies are triclabendazole and niclosamide (for most species).

Cabada MM et al. New developments in epidemiology, diagnosis, and treatment of fascioliasis. Curr Opin Infect Dis. 2012 Oct;25(5):518–22. [PMID: 22744320]

Fürst T et al. Manifestation, diagnosis, and management of foodborne trematodiasis. BMJ. 2012 Jun 26;344:e4093. [PMID: 22736467]

Hong ST et al. Clonorchis sinensis and clonorchiasis, an update. Parasitol Int. 2012 Mar;61(1):17–24. [PMID: 21741496]

CESTODE INFECTIONS

NONINVASIVE CESTODE INFECTIONS

The four major tapeworms that cause noninvasive infections in humans are the beef tapeworm Taenia saginata, the pork tapeworm Taenia solium, the fish tapeworm Diphyllobothrium latum, each of which can reach many meters in length, and the dwarf tapeworm Hymenolepis nanaTaenia and Hymenolepis species are broadly distributed, especially in the tropics; D latum is most prevalent in temperate regions. Other tapeworms that can cause noninvasive human disease include the rodent tapeworm Hymenolepis diminuta, the dog tapeworm Dipylidium caninum, and other Taenia and Diphyllobothriumspecies. Invasive tapeworm infections, including T solium (when infective eggs, rather than cysticerci are ingested) and Echinococcus species, will be discussed separately.

  1. Beef Tapeworm

Infection is most common in cattle breeding areas. Humans are the definitive host. Gravid segments of T saginata are passed in human feces to soil, where they are ingested by grazing animals, especially cattle. The eggs then hatch to release embryos that encyst in muscle as cysticerci. Humans are infected by eating raw or undercooked infected beef. Most individuals infected with T saginata are asymptomatic, but abdominal pain and other gastrointestinal symptoms may be present. Eosinophilia is common. The most common presenting finding is the passage of proglottids in the stool.

  1. Pork Tapeworm

T solium is transmitted to pigs that ingest human feces. Humans can be either the definitive host (after consuming undercooked pork, leading to tapeworm infection) or the intermediate host (after consuming food contaminated with human feces containing T solium eggs, leading to cysticercosis, which is discussed under invasive tapeworm infections). As with the beef tapeworm, infection with T solium adult worms is generally asymptomatic, but gastrointestinal symptoms may occur. Infection is generally recognized after passage of proglottids. Autoinfection with eggs can progress to cysticercosis.

  1. Fish Tapeworm

Infection with D latum follows ingestion of undercooked freshwater fish, most commonly in temperate regions. Eggs from human feces are taken up by crustaceans, these are eaten by fish, which are then infectious to humans. Infection with multiple worms over many years can occur. Infections are most commonly asymptomatic, but nonspecific gastrointestinal symptoms, including diarrhea, may occur. Diagnosis usually follows passage of proglottids. Prolonged heavy infection can lead to megaloblastic anemia and neuropathy from vitamin B12 deficiency, which is due to infection-induced dissociation of the vitamin from intrinsic factor and to utilization of the vitamin by worms.

  1. Dwarf Tapeworm

H nana is the only tapeworm that can be transmitted between humans. Infections are common in warm areas, especially with poor hygiene and institutionalized populations. Infection follows ingestion of food contaminated with human feces. Eggs hatch in the intestines, where oncospheres penetrate the mucosa, encyst as cysticercoid larvae, and then rupture after about 4 days to release adult worms. Autoinfection can lead to amplification of infection. Infection with H nana, the related rodent tapeworm H diminuta, or the dog tapeworm D caninum can also follow accidental ingestion of infected insects.H nana are dwarf in size relative to other tapeworms but can reach 5 cm in length. Heavy infection is common, especially in children, and can be accompanied by abdominal discomfort, anorexia, and diarrhea.

 Laboratory Findings

Diagnosis is usually made based on the identification of characteristic eggs or proglottids in stool. Egg release may be irregular, so examination of multiple specimens or concentration techniques may be needed.

 Treatment

The treatment of choice for noninvasive tapeworm infections is praziquantel. A single dose of praziquantel (5–10 mg/kg orally) is highly effective, except for H nana, for which the dosage is 25 mg/kg. Treatment of H nana is more difficult, as the drug is not effective against maturing cysts. Therefore, a repeat treatment after 1 week and screening after therapy to document cure are appropriate with heavy infections. Therapy can be accompanied by headache, malaise, dizziness, abdominal pain, and nausea.

The alternative therapy for these infections is niclosamide. A single dose of niclosamide (2 g chewed) is effective against D latum, Taenia, and D caninum infections. For H nana, therapy is continued daily for 1 week. Niclosamide may cause nausea, malaise, and abdominal pain.

Craig P et al. Intestinal cestodes. Curr Opin Infect Dis. 2007 Oct;20(5):524–32. [PMID: 17762788]

INVASIVE CESTODE INFECTIONS

  1. Cysticercosis

 ESSENTIALS OF DIAGNOSIS

 Exposure to T solium through fecal contamination of food.

 Seizures, headache, and other findings of a focal CNS lesion.

 Brain imaging shows cysts; positive serologic tests.

 General Considerations

Cysticercosis is due to tissue infection with cysts of T solium that develop after humans ingest food contaminated with eggs from human feces, thus acting as an intermediate host for the parasite. Prevalence is high where the parasite is endemic, in particular Mexico, Central and South America, the Philippines, and Southeast Asia. An estimated 20 million persons are infected with cysticerci yearly, leading to about 400,000 persons with neurologic symptoms and 50,000 deaths. Antibody prevalence rates up to 10% are recognized in some endemic areas, and the infection is one of the most important causes of seizures in the developing world and in immigrants to the United States from endemic countries. In Latin America, it is estimated that 0.5–1.5 million people suffer from epilepsy secondary to cysticercosis.

 Clinical Findings

  1. Symptoms and Signs

Neurocysticercosis can cause intracerebral, subarachnoid, and spinal cord lesions and intraventricular cysts. Single or multiple lesions may be present. Lesions may persist for years before symptoms develop, generally due to local inflammation or ventricular obstruction. Presenting symptoms include seizures, focal neurologic deficits, altered cognition, and psychiatric disease. Symptoms develop more quickly with intraventricular cysts, with findings of hydrocephalus and meningeal irritation, including severe headache, vomiting, papilledema, and visual loss. A particularly aggressive form of the disease, racemose cysticercosis, involves proliferation of cysts at the base of the brain, leading to alterations of consciousness and death. Spinal cord lesions can present with progressive focal findings.

Cysticercosis of other organ systems is usually clinically benign. Involvement of muscles can uncommonly cause discomfort and is identified by radiographs of muscle showing multiple calcified lesions. Subcutaneous involvement presents with multiple painless palpable skin lesions. Involvement of the eyes can present with ptosis due to extraocular muscle involvement or intraocular abnormalities.

  1. Laboratory Findings

CSF examination may show lymphocytic or eosinophilic pleocytosis, decreased glucose, and elevated protein. Serology plays an important role in diagnosis. ELISAs with sensitivity and specificity over 90% are available.

  1. Imaging

With neuroimaging by CT or MRI, multiple parenchymal cysts are most typically seen. Parenchymal calcification is also common. Ventricular cysts may be difficult to visualize, with MRI offering better sensitivity than CT.

 Treatment

The medical management of neurocysticercosis is controversial, as the benefits of cyst clearance must be weighed against potential harm of an inflammatory response to dying worms. Antihelminthic therapy hastens radiologic improvement in parenchymal cysticercosis, but some randomized trials have shown that corticosteroids alone are as effective as specific therapy plus corticosteroids for controlling seizures. Overall, most authorities recommend treatment of active lesions, in particular lesions with a high likelihood of progression, such as intraventricular cysts. At the other end of the spectrum, inactive calcified lesions probably do not benefit from therapy. When treatment is deemed appropriate, standard therapy consists of albendazole (10–15 mg/kg/d orally for 8 days) or praziquantel (50 mg/kg/d orally for 15–30 days). Albendazole is probably preferred, since it has shown better efficacy in some comparisons and since corticosteroids appear to lower circulating praziquantel levels but increase albendazole levels. Increasing the dosage of albendazole to 30 mg/kg/d orally may improve outcomes. Corticosteroids are usually administered concurrently, but dosing is not standardized. Patients should be observed for evidence of localized inflammatory responses. Anticonvulsant therapy is provided if needed, and shunting is performed if required for elevated intracranial pressure. Surgical removal of cysts may be helpful for some difficult cases of neurocysticercosis and for symptomatic non-neurologic disease.

Brunetti E et al. Cestode infestations: hydatid disease and cysticercosis. Infect Dis Clin North Am. 2012 Jun;26(2):421–35. [PMID: 22632647]

Coyle CM et al. Neurocysticercosis: neglected but not forgotten. PLoS Negl Trop Dis. 2012;6(5):e1500. [PMID: 22666505]

Nash TE et al. Diagnosis and treatment of neurocysticercosis. Nat Rev Neurol. 2011 Sep 13;7(10):584–94. [PMID: 21912406]

  1. Echinococcosis

 ESSENTIALS OF DIAGNOSIS

 History of exposure to dogs or wild canines in an endemic area.

 Large cystic lesions, most commonly of the liver or lung.

 Positive serologic tests.

 General Considerations

Echinococcosis occurs when humans are intermediate hosts for canine tapeworms. Infection is acquired by ingesting food contaminated with canine feces containing parasite eggs. The principal species that infect humans are Echinococcus granulosus, which causes cystic hydatid disease, and Echinococcus multilocularis, which causes alveolar hydatid disease. E granulosus is transmitted by domestic dogs in areas with livestock (sheep, goats, camels, and horses) as intermediate hosts, including Africa, the Middle East, southern Europe, South America, Central Asia, Australia, New Zealand, and the southwestern United States. E multilocularis, which much less commonly causes human disease, is transmitted by wild canines, and endemic in northern forest areas of the northern hemisphere, including central Europe, Siberia, northern Japan, northwestern Canada, and western Alaska. An increase in the fox population in Europe has been associated with an increase in human cases. The disease range has also extended southward in Central Asia and China. Other species that cause limited disease in humans are endemic in South America and China.

After humans ingest parasite eggs, the eggs hatch in the intestines to form oncospheres, which penetrate the mucosa, enter the circulation, and encyst in specific organs as hydatid cysts. E granulosusforms cysts most commonly in the liver (65%) and lungs (25%), but the cysts may develop in any organ, including the brain, bones, skeletal muscles, kidneys, and spleen. Cysts are most commonly single. The cysts can persist and slowly grow for many years.

 Clinical Findings

  1. Symptoms and Signs

Infections are commonly asymptomatic and may be noted incidentally on imaging studies or present with symptoms caused by an enlarging or superinfected mass. Findings may include abdominal or chest pain, biliary obstruction, cholangitis, portal hypertension, cirrhosis, bronchial obstruction leading to segmental lung collapse, and abscesses. Cyst leakage or rupture may be accompanied by a severe allergic reaction, including fever and hypotension. Seeding of cysts after rupture may extend the infection to new areas.

E multilocularis generally causes a more aggressive disease than E granulosus, with initial infection of the liver, but then local and distant spread commonly suggesting a malignancy. Symptoms based on the areas of involvement gradually worsen over years, with the development of obstructive findings in the liver and elsewhere.

  1. Laboratory Findings

Serologic tests, including ELISA and immunoblot, offer sensitivity and specificity over 80% for E granulosus liver infections, but lower sensitivity for involvement of other organs. Serologic tests may also distinguish the two major echinococcal infections.

  1. Imaging

Diagnosis is usually based on imaging studies, including ultrasonography, CT, and MRI. In E granulosus infection, a large cyst containing daughter cysts is highly suggestive of the diagnosis. In E multilocularis infection, imaging shows an irregular mass, often with areas of calcification.

 Treatment

Treatment of cystic hydatid disease has traditionally involved cautious surgical resection of cysts, with care not to rupture cysts during removal. Injection of a cysticidal agent was used to limit spread in the case of rupture. Newer management algorithms include treatment with albendazole, often in conjunction with surgery. When used alone, as in cases where surgery is not possible, albendazole (10–15 mg/kg/d orally) has demonstrated efficacy, with courses of 3 months or longer duration, in some cases with alternating cycles of treatment and rest. Mebendazole (40–50 mg/kg/d orally) is an alternative drug, and praziquantel may also be effective. In some cases, medical therapy is begun, with surgery performed if disease persists after some months of therapy. Another approach, in particular with inoperable cysts, is percutaneous aspiration, injection, and reaspiration (PAIR). In this approach (which should not be used if cysts communicate with the biliary tract), patients receive antihelminthic therapy, and the cyst is partially aspirated. After diagnostic confirmation by examination for parasite protoscolices, a scolicidal agent (95% ethanol, hypertonic saline, or 0.5% cetrimide) is injected, and the cyst is reaspirated after about 15 minutes. PAIR includes a small risk of anaphylaxis, which has been reported in about 2% of procedures, but death due to anaphylaxis has been rare. Treatment of alveolar cyst disease is challenging, generally relying on wide surgical resection of lesions. Therapy with albendazole before or during surgery may be beneficial and may also provide improvement or even cure in inoperable cases.

Brunetti E et al. Cystic echinococcosis: chronic, complex, and still neglected. PLoS Negl Trop Dis. 2011 Jul;5(7):e1146. [PMID: 21814584]

McManus DP et al. Diagnosis, treatment, and management of echinococcosis. BMJ. 2012 Jun 11;344:e3866. [PMID: 22689886]

Nasseri-Moghaddam S et al. Percutaneous needle aspiration, injection, and re-aspiration with or without benzimidazole coverage for uncomplicated hepatic hydatid cysts. Cochrane Database Syst Rev. 2011 Jan 19;(1):CD003623. [PMID: 21249654]

INTESTINAL NEMATODE (ROUNDWORM) INFECTIONS

ASCARIASIS

 ESSENTIALS OF DIAGNOSIS

 Transient cough, urticaria, pulmonary infiltrates, eosinophilia.

 Nonspecific abdominal symptoms.

 Eggs in stool; adult worms occasionally passed.

 General Considerations

Ascaris lumbricoides is the most common of the intestinal helminths, infecting about a quarter of the world’s population, with estimates of over a billion infections, 12 million acute cases, and 10,000 or more deaths annually. Prevalence is high wherever there is poor hygiene and sanitation or where human feces are used as fertilizer. Heavy infections are most common in children.

Infection follows ingestion of eggs in contaminated food. Larvae hatch in the small intestine, penetrate into the bloodstream, migrate to the lungs, and then travel via airways back to the gastrointestinal tract, where they develop to adult worms, which can be up to 40 cm in length, and live for 1–2 years.

 Clinical Findings

Most persons with Ascaris infection are asymptomatic. In a small proportion of patients, symptoms develop during migration of worms through the lungs, with fever, nonproductive cough, chest pain, dyspnea, and eosinophilia, occasionally with eosinophilic pneumonia. Rarely, larvae lodge ectopically in the brain, kidney, eye, spinal cord, and other sites and may cause local symptoms.

Light intestinal infections usually produce no symptoms. With heavy infection, abdominal discomfort may be seen. Adult worms may also migrate and be coughed up, be vomited, or may emerge through the nose or anus. They may also migrate into the common bile duct, pancreatic duct, appendix, and other sites, which may lead to cholangitis, cholecystitis, pyogenic liver abscess, pancreatitis, obstructive jaundice, or appendicitis. With very heavy infestations, masses of worms may cause intestinal obstruction, volvulus, intussusception, or death. Although severe manifestations of infection are uncommon, the very high prevalence of ascariasis leads to large numbers of individuals, especially children, with important sequelae. Moderate to high worm loads in children are also associated with nutritional abnormalities due to decreased appetite and food intake, and also decreased absorption of nutrients.

The diagnosis of ascariasis is made after adult worms emerge from the mouth, nose, or anus, or by identifying characteristic eggs in the feces. Due to the very high egg burden, concentration techniques are generally not needed. Imaging studies demonstrate worms, with filling defects in contrast studies and at times evidence of intestinal or biliary obstruction. Eosinophilia is marked during worm migration but may be absent during intestinal infection.

 Treatment

All infections should ideally be treated. Treatments of choice are albendazole (single 400 mg oral dose), mebendazole (single 500 mg oral dose or 100 mg twice daily for 3 days), or pyrantel pamoate (single 11 mg/kg oral dose, maximum 1 g). These drugs are all well tolerated but may cause mild gastrointestinal toxicity. They are considered safe for children above 1 year of age and in pregnancy, although use in the first trimester is best avoided. In endemic areas, reinfection after treatment is common. Intestinal obstruction usually responds to conservative management and antihelminthic therapy. Surgery may be required for appendicitis and other gastrointestinal complications.

TRICHURIASIS

Trichuris trichiura, the whipworm, infects about a billion persons throughout the world, particularly in humid tropical and subtropical environments. Infection is heaviest and most frequent in children. Infections are acquired by ingestion of eggs. The larvae hatch in the small intestine and mature in the large bowel to adult worms of about 4 cm in length. The worms do not migrate through tissues.

Most infected persons are asymptomatic. Heavy infections may be accompanied by abdominal cramps, tenesmus, diarrhea, distention, nausea, and vomiting. The Trichuris dysentery syndrome may develop, particularly in malnourished young children, with findings resembling inflammatory bowel disease including bloody diarrhea and rectal prolapse. Chronic infections in children can lead to iron deficiency anemia, growth retardation, and clubbing of the fingers.

Trichuriasis is diagnosed by identification of characteristic eggs and sometimes adult worms in stools. Concentration techniques are not needed. Eosinophilia is common. Treatment is with albendazole (400 mg/d orally) or mebendazole (200 mg/d orally), for 1–3 days for light infections or 3–7 days for heavy infections, but cure rates are lower than for ascariasis or hookworm infection. The addition of ivermectin (200 mcg/kg orally daily for 1–2 days) to these drugs improves outcomes.

HOOKWORM DISEASE

 ESSENTIALS OF DIAGNOSIS

 Transient pruritic skin rash and pulmonary symptoms.

 Anorexia, diarrhea, abdominal discomfort.

 Iron deficiency anemia.

 Characteristic eggs and occult blood in the stool.

 General Considerations

Infection with the hookworms Ancylostoma duodenale and Necator americanus is very common, especially in most tropical and subtropical regions. Both worms are broadly distributed. Prevalence is estimated at about 1 billion, causing approximately 65,000 deaths each year. When eggs are deposited on warm moist soil they hatch, releasing larvae that remain infective for up to a week. With contact, the larvae penetrate skin and migrate in the bloodstream to the pulmonary capillaries. In the lungs, the larvae penetrate 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, where they mature to adult worms. Ancylostoma infection can also be acquired by ingestion of the larvae in food or water. Hookworms attach to the intestinal mucosa and suck blood. Blood loss is proportionate to the worm burden.

 Clinical Findings

  1. Symptoms and Signs

Most infected persons are asymptomatic. A pruritic maculopapular rash (ground itch) may occur at the site of larval penetration, usually in previously sensitized persons. Pulmonary symptoms may be seen during larval migration through the lungs, with dry cough, wheezing, and low-grade fever, but these symptoms are less common than with ascariasis. About 1 month after infection, as maturing worms attach to the small intestinal mucosa, gastrointestinal symptoms may develop, with epigastric pain, anorexia, and diarrhea, especially in previously unexposed individuals. Persons chronically infected with large worm burdens may have abdominal pain, anorexia, diarrhea, and findings of marked iron-deficiency anemia and protein malnutrition. Anemia can lead to pallor, weakness, dyspnea, and heart failure, and protein loss can lead to hypoalbuminemia, edema, and ascites. These findings may be accompanied by impairment in growth and cognitive development in children. Infection with the dog hookwormAncylostoma caninum can uncommonly lead to abdominal pain, diarrhea, and eosinophilia, with intestinal ulcerations and regional lymphadenitis.

  1. Laboratory Findings

Diagnosis is based on the demonstration of characteristic eggs in feces; concentration techniques are usually not needed. Microcytic anemia, occult blood in the stool, and hypoalbuminemia are common. Eosinophilia is common, especially during worm migration.

 Treatment

Treatment is with albendazole (single 400 mg oral dose) or mebendazole (100 mg orally twice daily for 3 days). These drugs are teratogenic, but experience suggests that they are safe in children over 1 year of age and during the second and third trimesters of pregnancy. Occasional adverse effects are diarrhea and abdominal pain. Pyrantel pamoate and levamisole are also effective. Anemia should be managed with iron replacement and, for severe symptomatic anemia, blood transfusion. Mass treatment of children with single doses of albendazole or mebendazole at regular intervals limits worm burdens and the extent of disease and is advocated by the WHO.

STRONGYLOIDIASIS

 ESSENTIALS OF DIAGNOSIS

 Transient pruritic skin rash and pulmonary symptoms.

 Anorexia, diarrhea, abdominal discomfort.

 Hyperinfection syndrome in the immunocom-promised.

 Larvae detected in stool.

 With hyperinfection, larvae detected in sputum or other fluids.

 Eosinophilia.

 General Considerations

Strongyloidiasis is caused by infection with Strongyloides stercoralis. Although much less prevalent than ascariasis, trichuriasis, or hookworm infections, strongyloidiasis is nonetheless a significant problem, infecting tens of millions of individuals in tropical and subtropical regions. Infection is also endemic in some temperate regions of North America, Europe, Japan, and Australia. Of particular importance is the predilection of the parasite to cause severe infections in immunocompromised individuals due to its ability to replicate in humans. A related parasite, Strongyloides fuelleborni, infects humans in parts of Africa and New Guinea.

Among nematodes, S stercoralis is uniquely capable of maintaining its full 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, ascend the bronchial tree, and are then swallowed and carried to the duodenum and upper jejunum, where maturation to the adult stage takes place. Females live embedded in the mucosa for up to 5 years, releasing eggs that hatch in the intestines as free rhabditiform larvae that pass to the ground via the feces. In moist soil, these larvae metamorphose into infective filariform larvae. Autoinfection can occur in humans, when some rhabditiform larvae develop into filariform larvae that penetrate the intestinal mucosa or perianal skin, and enter the circulation. The most dangerous manifestation of S stercoralis infection is the hyperinfection syndrome, with dissemination of large numbers of filariform larvae to the lungs and other tissues in immunocompromised individuals. Mortality with this syndrome approaches 100% without treatment and has been about 25% with treatment. The hyperinfection syndrome is seen in patients receiving corticosteroids and other immunosuppressive medications; patients with hematologic malignancies, malnutrition, or alcoholism; or persons with AIDS. The risk seems greatest for those receiving corticosteroids.

 Clinical Findings

  1. Symptoms and Signs

As with other intestinal nematodes, most infected persons are asymptomatic. An acute syndrome can be seen at the time of infection, with a pruritic, erythematous, maculopapular rash, usually of the feet. These symptoms may be followed by pulmonary symptoms (including dry cough, dyspnea, and wheezing) and eosinophilia after a number of days, followed by gastrointestinal symptoms after some weeks, as with hookworm infections. Chronic infection may be accompanied by epigastric pain, nausea, diarrhea, and anemia. Maculopapular or urticarial rashes of the buttocks, perineum, and thighs, due to migrating larvae, may be seen. Large worm burdens can lead to malabsorption or intestinal obstruction. Eosinophilia is common but may fluctuate.

With hyperinfection large numbers of larvae can migrate to many tissues, including the lungs, CNS, kidneys, and liver. Gastrointestinal symptoms can include abdominal pain, nausea, vomiting, diarrhea, and more severe findings related to intestinal obstruction, perforation, or hemorrhage. Bacterial sepsis, probably secondary to intestinal ulcerations, is a common presenting finding. Pulmonary findings include pneumonitis, cough, hemoptysis, and respiratory failure. Sputum may contain adult worms, larvae, and eggs. CNS disease includes meningitis and brain abscesses; the CSF may contain larvae. Various presentations can progress to shock and death.

  1. Laboratory Findings

The diagnosis of strongyloidiasis can be difficult, as eggs are seldom found in feces. Diagnosis is usually based on the identification of rhabditiform larvae in the stool or duodenal contents. These larvae must be distinguished from hookworm larvae, which may hatch after stool collection. Repeated examinations of stool or examination of duodenal fluid may be required for diagnosis because the sensitivity of individual tests is only about 30%. Hyperinfection is diagnosed by the identification of large numbers of larvae in stool, sputum, or other body fluids. An ELISA from the CDC offers about 90% sensitivity and specificity, but cross-reactions with other helminths may occur. Eosinophilia and mild anemia are common, but eosinophilia may be absent with hyperinfection. Hyperinfection may include extensive pulmonary infiltrates, hypoproteinemia, and abnormal liver function studies.

  1. Screening

It is important to be aware of the possibility of strongyloidiasis in persons with even a distant history of residence in an endemic area, since the infection can be latent for decades. Screening of at-risk individuals for infection is appropriate before institution of immunosuppressive therapy. Screening can consist of serologic tests, with stool examinations in those with positive serologic tests, but consideration of presumptive treatment even if the stool evaluations are negative (see below).

 Treatment

Full eradication of S stercoralis is more important than with other intestinal helminths due to the ability of the parasite to replicate in humans. The treatment of choice for routine infection is ivermectin (200 mcg orally daily for 1–2 days). This treatment has replaced thiabendazole (25 mg/kg orally twice daily for 3 days), which is relatively poorly tolerated, and albendazole (400 mg orally twice daily for 3 days), which is less effective. For hyperinfection, ivermectin should be administered daily until the clinical syndrome has resolved and larvae have not been identified for at least 2 weeks. Follow-up examinations for larvae in stool or sputum are necessary, with repeat dosing if the infection persists. With continued immunosuppression, eradication may be difficult, and regular repeated doses of antihelminthic therapy (eg, monthly ivermectin) may be required.

ENTEROBIASIS

 ESSENTIALS OF DIAGNOSIS

 Nocturnal perianal pruritus.

 Identification of eggs or adult worms on perianal skin or in stool.

 General Considerations

Enterobius vermicularis, the pinworm, is a common cause of intestinal infections worldwide, with maximal prevalence in school-age children. Enterobiasis is transmitted person-to-person via ingestion of eggs after contact with the hands or perianal region of an infected individual, food or fomites that have been contaminated by an infected individual, or infected bedding or clothing. Auto-infection also occurs. Eggs hatch in the duodenum and larvae migrate to the cecum. Females mature in about a month, and remain viable for about another month. During this time they migrate through the anus to deposit large numbers of eggs on the perianal skin. Due to the relatively short lifespan of these helminths, continuous reinfection, as in institutional settings, is required, for long-standing infection.

 Clinical Findings

  1. Symptoms and Signs

Most individuals with pinworm infection are asymptomatiC. The most common symptom is perianal pruritus, particularly at night, due to the presence of the female worms or deposited eggs. Insomnia, restlessness, and enuresis are common in children. Perianal scratching may result in excoriation and impetigo. Many mild gastrointestinal symptoms have also been attributed to enterobiasis, but associations are not proven. Serious sequelae are uncommon. Rarely, worm migration results in inflammation or granulomatous reactions of the gastrointestinal or genitourinary tracts. Colonic ulceration and eosinophilic colitis have been reported.

  1. Laboratory Findings

Pinworm eggs are usually not found in stool. Diagnosis is made by finding adult worms or eggs on the perianal skin. A common test is to apply clear cellophane tape to the perianal skin, ideally in the early morning, followed by microscopic examination for eggs. The sensitivity of the tape test is reported to be about 50% for a single test and 90% for three tests. Nocturnal examination of the perianal area or gross examination of stools may reveal adult worms, which are about 1 cm in length. Eosinophilia is rare.

 Treatment

Treatment is with single oral doses of albendazole (400 mg), mebendazole (100 mg) or pyrantel pamoate (11 mg/kg, to a maximum of 1 g). The dose is repeated in 2 weeks due to frequent reinfection. Other infected family members should be treated concurrently, and treatment of all close contacts may be appropriate when rates of reinfection are high in family, school, or institutional settings. Standard handwashing and hygiene practices are helpful in limiting spread. Perianal scratching should be discouraged. Washing of clothes and bedding should kill pinworm eggs.

Greaves D et al. Strongyloides stercoralis infection. BMJ. 2013 Jul 30;347:f4610. [PMID: 23900531]

Jia TW et al. Soil-transmitted helminth reinfection after drug treatment: a systematic review and meta-analysis. PLoS Negl Trop Dis. 2012;6(5):e1621. [PMID: 22590656]

Knopp S et al. Nematode infections: soil-transmitted helminths and trichinella. Infect Dis Clin North Am. 2012 Jun;26(2):341–58. [PMID: 22632643]

Mejia R et al. Screening, prevention, and treatment for hyperinfection syndrome and disseminated infections caused by Strongyloides stercoralis. Curr Opin Infect Dis. 2012 Aug;25(4):458–63. [PMID: 22691685]

Steinmann P et al. Efficacy of single-dose and triple-dose albendazole and mebendazole against soil-transmitted helminths and Taenia spp.: a randomized controlled trial. PLoS One. 2011;6(9):e25003. [PMID: 21980373]

Vercruysse J et al. Assessment of the anthelmintic efficacy of albendazole in school children in seven countries where soil-transmitted helminths are endemic. PLoS Negl Trop Dis. 2011 Mar 29;5(3):e948. [PMID: 21468309]

INVASIVE NEMATODE (ROUNDWORM) INFECTIONS

DRACUNCULIASIS

 ESSENTIALS OF DIAGNOSIS

 Tender cutaneous ulcer and worm protruding from the skin of an individual who has ingested untreated water in rural Africa.

 General Considerations

Dracunculiasis is caused by the nematode Dracunculus medinensis, or Guinea worm. It causes chronic cutaneous ulcers with protruding worms in rural Africa. It occurs only in humans and is a major cause of disability, although recent control efforts have been remarkably successful, with decreased annual incidence from about 3.5 million cases in the late 1980s to 542 reported cases in 2012. Dracunculiasis has been eradicated from Asia, but remains endemic in a four countries in Africa, with > 90% of cases in South Sudan and 10 or fewer cases reported in 2012 from Mali, Chad, and Ethiopia. The disease occurs almost exclusively in isolated rural areas.

Infection occurs after swallowing water containing the infected intermediate host, the crustacean Cyclops (known as copepods or water fleas). In the stomach, larvae escape from the copepods and migrate through the intestinal mucosa to the retroperitoneum, where mating occurs. Females then migrate to subcutaneous tissue, usually of the legs, over about a year. A subcutaneous ulcer then forms. Upon contact with water, the parasite discharges large numbers of larvae, which are ingested by copepods. Adult worms, which can be up to a meter in length, are gradually extruded. Worm death and disintegration in tissue may provoke a severe inflammatory reaction.

 Clinical Findings

Patients are usually asymptomatic until the time of worm extrusion. At that time a painful papule develops, with erythema, pruritus, and burning, usually on the lower leg. Multiple lesions may be present. At this time, some patients may also develop a short-lived systemic reaction, which may include fever, urticaria, nausea, vomiting, diarrhea, and dyspnea. The skin lesion vesiculates over a few days, followed by ulceration. The ulcer is tender, often with a visible worm. The worm is then extruded or absorbed over a few weeks, followed by ulcer healing. Secondary infections, including infectious arthritis and tetanus, are common. The disease causes significant disability; lesions commonly prevent walking for a month or more.

Diagnosis follows identification of a typical skin ulcer with a protruding worm. When the worm is not visible, larvae may be identified on smears or seen after immersion in cold water. Eosinophilia is usually present.

 Treatment

No drug cures the infection, but metronidazole and mebendazole are sometimes used to limit inflammation and facilitate worm removal. Wet compresses may relieve discomfort. Occlusive dressings improve hygiene and limit shedding of infectious larvae. Worms are typically removed by sequentially rolling them out over a small stick. When available, simple surgical procedures can be used to remove worms. Corticosteroid ointments may hasten healing. Topical antibiotics may limit bacterial superinfection.

 Prevention

Dracunculiasis has proven to be easier to control than most parasitic infections. The disease is prevented by avoidance of contaminated drinking water. This can be accomplished by boiling, chlorination, or filtration through finely woven cloth. A WHO dracunculiasis eradication program, initiated in 1986, has been highly successful.

Centers for Disease Control and Prevention (CDC). Progress toward global eradication of dracunculiasis, January 2012–June 2013. MMWR Morb Mortal Wkly Rep. 2013 Oct 25;62(42):829–33. [PMID: 24153313]

TRICHINOSIS

 ESSENTIALS OF DIAGNOSIS

 Ingestion of inadequately cooked pork or game.

 Transient intestinal symptoms followed by fever, myalgias, and periorbital edema.

 Eosinophilia and elevated serum muscle enzymes.

 General Considerations

Trichinosis (or trichinellosis) is caused worldwide by Trichinella spiralis and related Trichinella species. The disease is spread by ingestion of undercooked meat, most commonly pork in areas where pigs feed on garbage. When infected raw meat is ingested, Trichinella larvae are freed from cyst walls by gastric acid and pass into the small intestine. The larvae then invade intestinal epithelial cells, develop into adults, and the adults release infective larvae. These parasites travel to skeletal muscle via the bloodstream. They invade muscle cells, enlarge, and form cysts. These larvae may be viable for years. Pigs and other animals become infected by eating infected uncooked food scraps or other animals, such as rats.

The worldwide incidence of trichinosis has decreased, but human infections continue to occur sporadically or in outbreaks, with estimates of ~10,000 cases annually. In addition to undercooked pork, infections have been transmitted by ingestion of game and other animals, including bear and walrus in North America and wild boar and horse in Europe. In the United States, about 20 infections are reported annually, mostly from ingesting wild game.

 Clinical Findings

  1. Symptoms and Signs

Most infections are asymptomatic. In symptomatic cases, gastrointestinal symptoms, including diarrhea, vomiting, and abdominal pain, develop within the week after ingestion of contaminated meat. These symptoms usually last for less than a week but can occasionally persist for much longer. During the following week, symptoms and signs related to migrating larvae are seen. These findings include, most notably, fever, myalgias, periorbital edema, and eosinophilia. Additional findings may include headache, cough, dyspnea, hoarseness, dysphagia, macular or petechial rash, and subconjunctival and retinal hemorrhages. Systemic symptoms usually peak within 2–3 weeks, and commonly persist for about 2 months. In severe cases, generally with large parasite burdens, muscle involvement can be pronounced, with severe muscle pain, edema, and weakness, especially in the head and neck. Muscle pain may persist for months. Uncommon severe findings include myocarditis, pneumonitis, and meningoencephalitis, sometimes leading to death.

  1. Laboratory Findings

The clinical diagnosis is supported by findings of elevated serum muscle enzymes (creatine kinase, lactate dehydrogenase, aspartate aminotransferase). A commercial ELISA assay is available in the United States. Serologic tests become positive 2 or more weeks after infection, but cross-reactivity can be seen with other parasites. Rising antibody titers are highly suggestive of the diagnosis. Muscle biopsy can usually be avoided, but if the diagnosis is uncertain, biopsy of a tender, swollen muscle may identify Trichinella larvae. For maximal yield, biopsy material should be examined histologically, and a portion enzymatically digested to release larvae, but evaluation before 3 weeks after infection may not show muscle larvae. Serum and muscle biopsy analysis are available from the CDC.

 Treatment

No effective specific therapy for full-blown trichinosis has been identified. However, if infection is suspected early in the course of illness, treatment with mebendazole (2.5 mg/kg orally twice daily) or albendazole (5–7.5 mg/kg orally twice daily) will kill intestinal worms and may limit progression to tissue invasion. Supportive therapy for systemic disease consists of analgesics, antipyretics, bed rest and, in severe illness, corticosteroids. Infection is prevented by cooking to a temperature of at least 71°C for at least 1 minute. Irradiation of meat is also effective in eliminating Trichinella larvae, but freezing is not reliable.

Gottstein B et al. Epidemiology, diagnosis, treatment, and control of trichinellosis. Clin Microbiol Rev. 2009 Jan;22(1):127–45. [PMID: 19136437]

ANGIOSTRONGYLIASIS

Nematodes of rats of the genus Angiostrongylus cause two distinct syndromes in humans. Angiostrongylus cantonensis, the rat lungworm, causes eosinophilic meningoencephalitis, primarily in Southeast Asia and some Pacific islands. Angiostrongylus costaricensis causes gastrointestinal inflammation. In both diseases, human infection follows ingestion of larvae within slugs or snails (and also crabs or prawns for A cantonensis) or on material contaminated by these organisms. Since the parasites are not in their natural hosts, they cannot complete their life cycles, but they can cause disease after migrating to the brain or gastrointestinal tract.

 Clinical Findings

  1. A cantonensisInfection

The disease is caused primarily by worm larvae migrating through the CNS and an inflammatory response to dying worms. After an incubation period of 1 day to 2 weeks, presenting symptoms and signs include headache, stiff neck, nausea, vomiting, cranial nerve abnormalities, and paresthesias. Most cases resolve spontaneously after 2–8 weeks, but serious sequelae and death have been reported. The diagnosis is strongly suggested by the finding of eosinophilic CSF pleocytosis (over 10% eosinophils) in a patient with a history of travel to an endemic area. Peripheral eosinophilia may not be present. A cantonensis larvae have rarely been recovered from the CSF and the eyes.

  1. A costaricensis Infection

Parasites penetrate ileocecal vasculature and develop into adults, which lay eggs, but do not complete their life cycle. Disease is due to an inflammatory response to dying worms in the intestinal tract, with an eosinophilic granulomatous response, at times including vasculitis and ischemic necrosis. Common findings are abdominal pain, vomiting, and fever. Pain is most commonly localized to the right lower quadrant, and a mass may be appreciated, all mimicking appendicitis. Symptoms may recur over months. Uncommon findings are intestinal perforation or obstruction, or disease due to migration of worms to other sites. Many cases are managed surgically, usually for suspected appendicitis. Biopsy of inflamed intestinal tissue may show worms localized to mesenteric arteries and eosinophilic granulomas.

 Treatment

Antihelminthic therapy may be harmful for A cantonensis infection, since responses to dying worms may worsen with therapy. If antihelminthic treatment is to be used, albendazole is probably the best choice. Corticosteroids have been used in severe cases, and these are probably appropriate if antihelminthics are provided. It is not known if antihelminthic therapy is helpful for A costaricensis infection.

Ramirez-Avila L et al. Eosinophilic meningitis due to Angiostrongylus and Gnathostoma species. Clin Infect Dis. 2009 Feb 1;48(3):322–7. [PMID: 19123863]

Wang QP et al. Human angiostrongyliasis. Lancet Infect Dis. 2008 Oct;8(10):621–30. [PMID: 18922484]

TOXOCARIASIS

 General Considerations

The dog roundworm Toxocara canis, the cat roundworm Toxocara cati, and less commonly other helminths may cause visceral larva migrans. T canis is highly prevalent in dogs. Humans are infected after ingestion of eggs in material contaminated by dog or other feces. Infection is spread principally by puppies and lactating females, and the eggs must be on the ground for several weeks before they are infectious. After ingestion by humans, larvae migrate to various tissues but cannot complete their life cycle.

 Clinical Findings

Visceral larva migrans is seen principally in young children. Most infections are asymptomatic. The most commonly involved organs are the liver and lungs. Presentations include cough, fever, wheezing, hepatomegaly, splenomegaly, lymphadenopathy, pulmonary infiltrates, and eosinophilia. Involvement of the CNS can occur rarely, leading to eosinophilic meningitis and other abnormalities. Ocular larva migrans is a distinct syndrome, usually in children older than is typical for visceral larva migrans. Children present with visual deficits, pain, and a retinal mass, which can be confused with retinoblastoma.Baylisascaris procyonis, a roundworm of raccoons, can rarely cause visceral larva migrans in humans, typically with similar, but more severe manifestations than T canis.

The diagnosis of visceral larva migrans is suggested by the finding of eosinophilia in a child with hepatomegaly or other signs of the disease, especially with a history of exposure to puppies. The diagnosis is confirmed by the identification of larvae in a biopsy of infected tissue, usually performed when other diseases are suspected. Serologic tests may be helpful; an available ELISA was estimated to have 78% sensitivity and 92% specificity. Most patients recover without specific therapy, although symptoms may persist for months.

 Treatment

Treatment with antihelminthics or corticosteroids may be considered in severe cases. No drugs have been proven to be effective, but albendazole (400 mg orally twice daily for 5 days), mebendazole, thiabendazole, diethylcarbamazine, and ivermectin have been used, and albendazole has been recommended as the treatment of choice.

CUTANEOUS LARVA MIGRANS (Creeping Eruption)

Cutaneous larva migrans is caused principally by larvae of the dog and cat hookworms, Ancylostoma braziliense and A caninum. Other animal hookworms, gnathostomiasis, and strongyloidiasis may also cause this syndrome. Infections are common in warm areas, including the southeastern United States. They are most common in children. The disease is caused by the migration of worms through skin; the non-human parasites cannot complete their life cycles, so only cause cutaneous disease.

 Clinical Findings

Intensely pruritic erythematous papules develop, usually on the feet or hands, followed within a few days by serpiginous tracks marking the course of the parasite, which may travel several millimeters per day (Figure 35–8). Several tracks may be present. The process may continue for weeks, with lesions becoming vesiculated, encrusted, or secondarily infected. Systemic symptoms or eosinophilia are uncommon.

 Figure 35–8. Cutaneous larva migrans on the foot. (Reproduced, with permission, from Richard P. Usatine, MD.)

The diagnosis is based on the characteristic appearance of the lesions. Biopsy is usually not indicated.

 Treatment

Without treatment, the larvae eventually die and are absorbed. Mild cases do not require treatment. Thiabendazole (10% aqueous suspension) can be applied topically three times daily for 5 or more days. Systemic therapy with albendazole (400 mg orally once or twice daily for 3–5 days) or ivermectin (200 mcg/kg orally single dose) is highly effective.

Heukelbach J et al. Epidemiological and clinical characteristics of hookworm-related cutaneous larva migrans. Lancet Infect Dis. 2008 May;8(5):302–9. [PMID: 18471775]

ANISAKIASIS

Anisakiasis is caused by infection with larvae of parasites of saltwater fish and squid. Multiple species of the family Anisakidae may occasionally infect humans. Definitive hosts for these parasites are marine mammals. Eggs are passed in the feces and ingested by crustaceans, which are then eaten by fish and squid. When ingested by humans in undercooked seafood, larvae penetrate the stomach or intestinal wall but cannot complete their life cycle. The disease is most common in Japan.

 Clinical Findings

Clinical manifestations of anisakiasis follow burrowing of worms into the stomach or intestinal wall, leading to localized ulceration, edema, and eosinophilic granuloma formation. Symptoms usually occur within 2 days of parasite ingestion and include severe epigastric or abdominal pain, nausea, and vomiting. Intestinal involvement can mimic appendicitis. Allergic symptoms, including urticaria, angioedema, and anaphylaxis, have also been attributed to acute infection. Acute symptoms generally resolve within 2 weeks, but chronic symptoms may also be seen, suggesting inflammatory bowel disease, diverticulitis, or carcinoma. Rarely, worms may migrate to other sites or be coughed up. Eosinophilia is usually not seen.

The diagnosis is suggested in those with acute abdominal symptoms after ingestion of raw fish. Radiographic studies may identify stomach or intestinal lesions, and endoscopy may allow visualization and removal of the worm. When surgery is performed due to consideration of other diagnoses, eosinophilic inflammatory lesions and the invading worms are found.

 Treatment

Specific therapy is not indicated, but endoscopic worm removal hastens recovery. The parasites are killed by cooking or deep freezing fish.

Hochberg NS et al. Anisakidosis: perils of the deep. Clin Infect Dis. 2010 Oct 1;51(7):806–12. [PMID: 20804423]

FILARIASIS

LYMPHATIC FILARIASIS

 ESSENTIALS OF DIAGNOSIS

 Episodic attacks of lymphangitis, lymphadenitis, and fever.

 Chronic progressive swelling of extremities and genitals; hydrocele; chyluria; lymphedema.

 Microfilariae in blood, chyluria, or hydrocele fluid; positive serologic tests.

 General Considerations

Lymphatic filariasis is caused by three filarial nematodes: Wuchereria bancrofti, Brugia malayi, and Brugia timori, and is among the most important parasitic diseases of man. Approximately 120 million people are infected with these organisms in tropical and subtropical countries, about a third of these suffer clinical consequences of the infections, and many are seriously disfigured. W bancrofti causes about 90% of episodes of lymphatic filariasis. It is transmitted by Culex, Aedes, and Anopheles mosquitoes and is widely distributed in the tropics and subtropics, including sub-Saharan Africa, Southeast Asia, the western Pacific, India, South America, and the Caribbean. B malayi is transmitted by Mansonia and Anopheles mosquitoes and is endemic in parts of China, India, Southeast Asia, and the Pacifi C.B timori is found only in islands of southeastern Indonesia. Mansonella are filarial worms transmitted by midges and other insects in Africa and South America.

Humans are infected by the bites of infected mosquitoes. Larvae then move to the lymphatics and lymph nodes, where they mature over months to thread-like adult worms, and then can persist for many years. The adult worms produce large numbers of microfilariae, which are released into the circulation, and infective to mosquitoes, particularly at night (except for the South Pacific, where microfilaremia peaks during daylight hours).

 Clinical Findings

  1. Symptoms and Signs

Many infections remain asymptomatic despite circulating microfilariae. Clinical consequences of filarial infection are principally due to inflammatory responses to developing, mature, and dying worms. The initial manifestation of infection is often acute lymphangitis, with fever, painful lymph nodes, edema, and inflammation spreading peripherally from involved lymph nodes (in contrast to bacterial lymphangitis, which spreads centrally). Lymphangitis and lymphadenitis of the upper and lower extremities is common (Figure 35–9); genital involvement, including epididymitis and orchitis, with scrotal pain and tenderness, occurs principally only with W bancrofti infection. Acute attacks of lymphangitis last for a few days to a week and may recur a few times per year. Filarial fevers may also occur without lymphatic inflammation.

 Figure 35–9. Elephantiasis of legs due to filariasis. (Public Health Image Library, CDC.)

The most common chronic manifestation of lymphatic filariasis is swelling of the extremities or genitals due to chronic lymphatic inflammation and obstruction. Extremities become increasingly swollen, with a progression over time from pitting edema, to nonpitting edema, to sclerotic changes of the skin that are referred to as elephantiasis. Genital involvement, particularly with W bancrofti, occurs more commonly in men, progressing from painful epididymitis to hydroceles that are usually painless but can become very large, with inguinal lymphadenopathy, thickening of the spermatic cord, scrotal lymphedema, thickening and fissuring of the scrotal skin, and occasionally chyluria. Lymphedema of the female genitalia and breasts may also occur.

Tropical pulmonary eosinophilia is a distinct syndrome principally affecting young adult males with either W bancrofti or B malayi infection but typically without microfilaremia. This syndrome is characterized by asthma-like symptoms, with cough, wheezing, dyspnea, and low-grade fevers, usually at night. Without treatment, tropical pulmonary eosinophilia can progress to interstitial fibrosis and chronic restrictive lung disease. Mansonella can inhabit serous cavities, the retroperitoneum, the eye, or the skin, and cause abnormalities related to inflammation at these sites.

  1. Laboratory Findings

The diagnosis of lymphatic filariasis is strongly suggested by characteristic findings of lymphangitis or lymphatic obstruction in persons with risk factors for the disease. The diagnosis is confirmed by finding microfilariae, usually in blood, but microfilariae may be absent, especially early in the disease progression (first 2–3 years) or with chronic obstructive disease. To increase yields, blood samples are obtained at about midnight in most areas, but during daylight hours in the South Pacifi C. Smears are evaluated by wet mount to identify motile parasites and by Giemsa staining; these examinations can be delayed until the following morning, with storage of samples at room temperature. Of note, the periodicity of microfilaremia is variable, and daytime samples may yield positive results. Microfilariae may also be identified in hydrocele fluid or chylous urine. Eosinophilia is usually absent, except during acute inflammatory syndromes. Serologic tests may be helpful but cannot distinguish past and active infections. Rapid antigen tests with sensitivity and specificity over 90% are available. These can be considered the diagnostic tests of choice and are increasingly used to guide control programs. Adult worms may also be found in lymph node biopsy specimens (although biopsy is not usually clinically indicated) or by ultrasound of a scrotal hydrocele or lymphedematous breast. When microfilaremia is lacking, especially if sophisticated techniques are not available, diagnoses may need to be made on clinical grounds alone.

 Treatment & Control

  1. Drug Treatment

Diethylcarbamazine is the drug of choice, but it cannot cure infections due to its limited action against adult worms. Asymptomatic infection and acute lymphangitis are treated with this drug (2 mg/kg orally three times daily) for 10–14 days, leading to a marked decrease in microfilaremia. Therapy may be accompanied by allergic symptoms, including fever, headache, malaise, hypotension, and bronchospasm, probably due to release of antigens from dying worms. For this reason, treatment courses may begin with a lower dosage, with escalation over the first 4 days of treatment. Single annual doses of diethylcarbamazine (6 mg/kg orally), alone or with ivermectin (400 mcg/kg orally) or albendazole (400 mg orally) may be as effective as longer courses of diethylcarbamazine. When onchocerciasis or loiasis is suspected, it may be appropriate to withhold diethylcarbamazine to avoid severe reactions to dying microfilariae; rather, ivermectin plus albendazole may be given, although these drugs are less active than diethylcarbamazine against adult worms. Appropriate management of advanced obstructive disease is uncertain. Drainage of hydroceles provides symptomatic relief, although they will recur. Therapy with diethylcarbamazine cannot reverse chronic lymphatic changes but is typically provided to lower worm burdens. An interesting approach under study is to treat with doxycycline (100–200 mg/d orally for 4–6 weeks), which kills obligate intracellular Wolbachia bacteria, leading to death of adult filarial worms. Doxycycline was also effective at controlling Mansonella perstansinfection, which does not respond well to standard antifilarial drugs. Secondary bacterial infections must be treated. Surgical correction may be helpful in some cases.

  1. Disease Control

Avoidance of mosquitoes is a key measure; preventive measures include the use of screens, bed nets (ideally treated with insecticide), and insect repellents. Community-based treatment with single annual doses of effective drugs offers a highly effective means of control. The current WHO strategy for control includes mass treatment of at risk communities with single annual doses of diethylcarbamazine plus albendazole or, for areas with onchocerciasis, albendazole plus ivermectin; in some circumstances, more frequent dosing offers improved control.

Hoerauf A et al. Filariasis in Africa—treatment challenges and prospects. Clin Microbiol Infect. 2011 Jul;17(7):977–85. [PMID: 21722251]

Taylor MJ et al. Lymphatic filariasis and onchocerciasis. Lancet. 2010 Oct 2;376(9747):1175–85. [PMID: 20739055]

Tisch DJ et al. Reduction in acute filariasis morbidity during a mass drug administration trial to eliminate lymphatic filariasis in Papua New Guinea. PLoS Negl Trop Dis. 2011 Jul;5(7):e1241. [PMID: 21765964]

ONCHOCERCIASIS

 ESSENTIALS OF DIAGNOSIS

 Severe pruritus; skin excoriations, thickening, and depigmentation; and subcutaneous nodules.

 Conjunctivitis progressing to blindness.

 Microfilariae in skin snips and on slit-lamp examination; adult worms in subcutaneous nodules.

 General Considerations

Onchocerciasis, or river blindness is caused by Onchocerca volvulus. An estimated 37 million persons are infected, of whom 3–4 million have skin disease, 500,000 have severe visual impairment, and 300,000 are blinded. Over 99% of infections are in sub-Saharan Africa, especially the West African savanna, with about half of cases in Nigeria and Congo. In some hyperendemic African villages, close to 100% of individuals are infected, and 10% or more of the population is blind. The disease is also prevalent in the southwestern Arabian peninsula and Latin America, including southern Mexico, Guatemala, Venezuela, Colombia, Ecuador, and northwestern Brazil. Onchocerciasis is transmitted by simulium flies (blackflies). These insects breed in fast-flowing streams and bite during the day.

After the bite of an infected blackfly, larvae are deposited in the skin, where adults develop over 6–12 months. Adult worms live in subcutaneous connective tissue or muscle nodules for a decade or more. Microfilariae are released from the nodules and migrate through subcutaneous and ocular tissues. Disease is due to responses to worms and to intracellular Wolbachia bacteria.

 Clinical Findings

  1. Symptoms and Signs

After an incubation period of up to 1–3 years, the disease typically produces an erythematous, papular, pruritic rash, which may progress to chronic skin thickening and depigmentation. Itching may be severe and unresponsive to medications, such that more disability-adjusted life years are lost to onchocercal skin problems than to blindness. Numerous firm, nontender, movable subcutaneous nodules of about 0.5–3 cm, which contain adult worms, may be present. Due to differences in vector habits, these nodules are more commonly on the lower body in Africa but on the head and upper body in Latin America. Inguinal and femoral lymphadenopathy is common, at times resulting in a “hanging groin,” with lymph nodes hanging within a sling of atrophic skin. Patients may also have systemic symptoms, with weight loss and musculoskeletal pain.

The most serious manifestations of onchocerciasis involve the eyes. Microfilariae migrating through the eyes elicit host responses that lead to pathology. Findings include punctate keratitis and corneal opacities, progressing to sclerosing keratitis and blindness. Iridocyclitis, glaucoma, choroiditis, and optic atrophy may also lead to vision loss. The likelihood of blindness after infection varies greatly based on geography, with the risk greatest in savanna regions of West Africa.

  1. Diagnostic Testing

The diagnosis is made by identifying microfilariae in skin snips, by visualizing microfilariae in the cornea or anterior chamber by slit-lamp examination, by identification of adult worms in a biopsy or aspirate of a nodule or, uncommonly, by identification of microfilariae in urine. Skin snips from the iliac crest (Africa) or scapula (Americas) are allowed to stand in saline for 2–4 hours or longer, and then examined microscopically for microfilariae. Deep punch biopsies are not needed, and if suspicion persists after a skin snip is negative, the procedure should be repeated. Ultrasound may identify characteristic findings suggestive of adult worms in skin nodules. When the diagnosis remains difficult, the Mazzotti test can be used; exacerbation of skin rash and pruritus after a 50-mg dose of diethylcarbamazine is highly suggestive of the diagnosis. This test should only be used after other tests are negative, since treatment can elicit severe skin and eye reactions in heavily infected individuals. A related and safer test using topical diethylcarbamazine is also available. Eosinophilia is a common, but inconsistent finding. Antigen and antibody detection tests are under study.

 Treatment & Control

The treatment of choice is ivermectin, which has replaced diethylcarbamazine due to a much lower risk of severe reactions to therapy. Ivermectin kills microfilariae, but not adult worms, so disease control requires repeat administrations. Treatment is with a single oral dose of 150 mcg/mL, but schedules for re-treatment have not been standardized. One regimen is to treat every 3 months for 1 year, followed by treatment every 6–12 months for the suspected lifespan of adult worms (about 15 years). Treatment results in marked reduction in numbers of microfilariae in the skin and eyes, although its impact on the progression of visual loss remains uncertain. Toxicities of ivermectin are generally mild; fever, pruritus, urticaria, myalgias, edema, hypotension, and tender lymphadenopathy may be seen, presumably due to reactions to dying worms. Ivermectin should be used with caution in patients also at risk for loiasis, since it can elicit severe reactions including encephalopathy. As with other filarial infections, doxycycline acts against O volvulus by killing intracellular Wolbachia bacteria. A course of 100 mg/d for 6 weeks kills the bacteria and prevents parasite embryogenesis for at least 18 months. Doxycycline shows promise as a first-line agent to treat onchocerciasis because of its improved activity against adult worms compared to other agents and limited toxicity due to the slow action of the drug.

Protection against onchocerciasis includes avoidance of biting flies. Major efforts are underway to control insect vectors in Africa. In addition, mass distribution of ivermectin for intermittent administration at the community level is ongoing, and the prevalence of severe skin and eye disease is decreasing.

Knopp S et al. Nematode infections: filariases. Infect Dis Clin North Am. 2012 Jun;26(2):359–81. [PMID: 22632644]

LOIASIS

 ESSENTIALS OF DIAGNOSIS

 Subcutaneous swellings; adult worms migrating across the eye.

 Encephalitis, which may be brought on by treatment.

 Microfilariae in the blood.

 General Considerations

Loiasis is a chronic filarial disease caused by infection with Loa loa. The infection occurs in humans and monkeys in rainforest areas of West and central Africa. An estimated 3–13 million persons are infected. The disease is transmitted by chrysops flies, which bite during the day. Over 6–12 months after infection, larvae develop into adult worms, which migrate through subcutaneous tissues, including the subconjunctiva (leading to the term “eye worm”). Adults can live for up to 17 years.

 Clinical Findings

  1. Symptoms and Signs

Many infected persons are asymptomatic, although they may have high levels of microfilaremia and eosinophilia. Transient subcutaneous swellings (Calabar swellings) develop in symptomatic persons. The swellings are nonerythematous, up to 20 cm in diameter, and may be preceded by local pain or pruritus. They usually resolve after 2–4 days but occasionally persist for several weeks. Calabar swellings are commonly seen around joints and may recur at the same or different sites. Visitors from nonendemic areas are more likely to have allergic-type reactions, including pruritus, urticaria, and angioedema. Adult worms may be seen to migrate across the eye, with either no symptoms or conjunctivitis, with pain and edema. The most serious complication of loiasis is encephalitis, which is most common in those with high level microfilaremia and microfilariae in the CSF. Symptoms may range from headache and insomnia to coma and death. Encephalitis may be brought on by treatment with diethylcarbamazine or ivermectin. Other complications of loiasis include kidney disease, with hematuria and proteinuria; endomyocardial fibrosis; and peripheral neuropathy.

  1. Laboratory Findings

The diagnosis is established by identifying microfilariae in blood. Blood is evaluated as for lymphatic filariasis, but for loiasis blood should be obtained during the day. The failure to find microfilariae does not rule out the diagnosis. Identification of a migrating eye worm is also diagnostic. Serologic tests may be helpful in persons from nonendemic areas who may be acutely ill without detectable microfilaremia, but such tests have limited utility for residents of endemic areas because most of them will have positive test results. PCR methods are available to rule out loiasis before administration of ivermectin for the control of other filarial infections.

 Treatment

The treatment of choice is diethylcarbamazine, which eliminates microfilariae and has some activity against adult worms. Treatment is with 8–10 mg/kg/d orally for 21 days; repeat courses may be needed. Mild side effects are common, including fever, pruritus, arthralgias, nausea, diarrhea, and Calabar swellings. These symptoms may be lessened by antihistamines or corticosteroids. Patients with large worm burdens are at greater risk for serious complications of therapy, including kidney injury, shock, encephalitis, coma, and death. Treatment with ivermectin, which is highly active against microfilariae, but not adult worms, entails a higher risk of severe reactions. To attempt to avoid these sequelae, pretreatment with corticosteroids and antihistamines, and escalating dosage of diethylcarbamazine have been used, but this strategy does not prevent encephalitis. The circulating parasite load that indicates particular risk for severe complications with therapy has been estimated at 2500/mL. Strategies to treat patients with high parasite loads include (1) no treatment; (2) apheresis, if available, to remove microfilariae prior to therapy with diethylcarbamazine; or (3) therapy with albendazole, which appears to be well tolerated due to its slow antiparasitic effects, prior to therapy with diethylcarbamazine or ivermectin. Doxycycline is not effective for loiasis.

Fink DL et al. Rapid molecular assays for specific detection and quantitation of Loa loa microfilaremia. PLoS Negl Trop Dis. 2011 Aug;5(8):e1299. [PMID: 21912716]

Padgett JJ et al. Loiasis: African eye worm. Trans R Soc Trop Med Hyg. 2008 Oct;102(10):983–9. [PMID: 18466939]