Etiology and Pathogenesis

Intestinal parasites infect millions worldwide, particularly in developing countries with poor access to potable water and in patients with comorbidities. Intestinal parasites that are the most common in children in the United States include: G. lamblia, Entamoeba histolytica, and C. parvum. Table 99-1 reviews additional causes of intestinal parasitic infections (Figures 99-1 and 99-2).

Figure 99-1 Amebiasis.

Figure 99-2 Helminths and protozoa infesting the human intestine.

G. lamblia is a flagellated protozoon and the most common cause of parasitic enteritis in the United States. Outbreaks can occur from contaminated water supplies, including pools, because it is resistant to chlorination as well as person to person in daycare centers. The mode of transmission is often fecal–oral or direct person-to-person contact (Figure 99-3).

Figure 99-3 Giardiasis.

E. histolytica is a large intestinal amoeba occurring in 1% to 5% of people around the world and causes amebiasis. Cysts are ingested from contaminated water from which they enter and inhabit the colon lumen and may form shallow ulcers. Amebomas can form on the intestinal wall and present with obstruction. With penetration into intestinal wall, invasion of the bloodstream occasionally occurs, leading to amebic dysentery. By this mechanism, the parasite can pass to the biliary system in the liver and form amebic abscesses and can be transmitted to other tissues as well. Interestingly, when E. histolytica is disseminated to the liver or other tissues, peripheral eosinophilia is not seen on complete blood count.

Cryptosporidium spp. are a worldwide intracellular protozoon seen mostly in immunocompromised patients. The clinical presentation is commonly with diarrhea. Outbreaks occur in healthy individuals as well, especially because Cryptosporidium spp. are chlorine resistant and may be spread through infected water and swimming pools. Fecal–oral contamination can transmit the parasite to epithelial cells in the stomach and intestine.

Enterobius vermicularis (pinworm) is the most common helminth of industrialized nations, and causes pruritus ani. Cysts are often ingested by the host via hand contamination. The eggs hatch in the duodenum, and then adult females lay eggs on the perineum.

Clinical Presentation

Intestinal infection with parasites is often initially asymptomatic in a carrier state. Children with intestinal parasites can present with failure to thrive, diarrhea, abdominal pain, a protuberant abdomen, anemia, blood in the stool, and delayed development. A careful history with particular attention to travel and food and water intake is valuable. Additional details about sources and geography can be found in Table 99-1

Giardia spp. are often symptomatic in infants and young children with presentations including diarrhea to abdominal cramps with malabsorptive stool. Continued stool output can lead to protein loss and fat soluble vitamin deficiencies. Incubation in older children can occur 3 to 40 days after cyst ingestion until diarrhea. The symptoms and presentation of Entamoeba infection can also involve asymptomatic carriage. The symptoms include abdominal cramping, discomfort, anorexia, weight loss, and diarrhea with blood and mucus. Extraintestinal manifestations particularly hepatic abscesses can be seen. Cryptosporidium spp. have a variety of presentations depending on the host’s immune system. Whereas immunocompetent hosts usually present with watery, self-limited diarrhea, immunocompromised hosts can present with intractable diarrhea, fever, anorexia, and vomiting. Enterobius vermicularis infections classically present with perianal pruritus.

Differential Diagnosis

The differential diagnosis for intestinal parasite infections is broad and includes noninfectious malabsorption and infectious diarrhea caused by viruses or bacteria. Anemia and failure to thrive seen in chronic infection with some parasites can also be misdiagnosed as other etiologies of iron-deficiency anemia and other systemic reasons for failure to thrive. Therefore, chronic infection should be considered in the differential of failure to thrive.

Evaluation and Management

Laboratory evaluation for parasitic infection can start with sending stool for ova and parasites (O+P). Several parasites are not found on standard testing such as Cryptosporidium, Cyclospora, and Microspora spp.; if these pathogens are suspected, the microbiology laboratory should be notified. Rapid immunoassays for Giardia spp., Cryptosporidium spp., and amebiasis can be sent and are more sensitive than O+P. Pinworms can be diagnosed by tape test to the anus. Mucosal biopsy can aid in diagnosis of Giardia spp. and Entamoeba histolyticum. Serology can be used for helminthic infections.

In addition to rehydration and supportive care, antimicrobial recommendations for each intestinal parasite covered in this chapter can be found in Table 99-1.

Etiology and Pathogenesis

The pathogenesis of individual parasites differs by the type of parasite and the mode of transmission. Protozoa are free-living, single-celled eukaryotic organisms. Systemic protozoan infections in humans include T. gondii, Plasmodium spp., Babesia spp., Naegleria fowleri, and Acanthamoeba spp. A systemic parasite particularly important in pediatrics because of congenital infection is T. gondii. T. gondii is the third leading cause of death from foodborne illness in the United States. It is estimated that about 22% of the U.S. population has been infected with Toxoplasma spp. from undercooked meat or contaminated food or utensils in contact with the parasite, zoonotic transmission often from Toxoplasma oocytes shed in cat litter or soil, or newly infected mothers transmitting the organisms to unborn children. Toxocara is also a roundworm infection transferred to humans from domestic animals, with estimates of almost 14% of the United States population estimated to be infected.

Leishmania and Trypanosoma are bloodborne flagellates that are transmitted by the bite of blood-sucking insects. Leishmania spp. are spread by the sandfly. African trypanosomes, the cause of African sleeping sickness, are spread by the tsetse fly, and American trypanosomes, the cause Chagas’ disease, are spread by reduviid bugs.

Systemic helminth infections, including Strongyloides stercoralis, Trichinella spiralis, Ascaris lumbricoides, Toxocara canis, and Trichuris trichiura, are spread via fecal contamination with worms penetrating into the toes of barefoot humans or through ingestion of cysts (Figure 99-4). Discussion of individual parasites is included in Table 99-2.

Figure 99-4 Parasitic diseases: ascariasis.

An additional common human ectoparasite includes Pediculus humanus capitis or head lice, which can be spread by close contact. Adult lice can live up to 30 days on a person’s scalp by feeding on blood.

Clinical Presentation

The clinical presentations of many extraintestinal parasites are in Table 99-2. Particular parasites are known for infection within the United States both from zoonotic spread and from international travel. The clinical presentation and burden of disease of Toxoplasma and Toxocara spp. are discussed. The use of clinical testing can aid in the differential diagnosis of parasitic infection. Malaria is covered in a subsequent section in this chapter.

Toxoplasma spp. are estimated to cause 1.5 million new infections each year, with 400 to 4000 cases of congenital toxoplasmosis yearly in the United States. Primary infection during pregnancy can pass Toxoplasma spp. directly to the fetus transplacentally. Potential complications include miscarriage, stillborn birth, or congenital infection. An infant with congenital toxoplasmosis may be asymptomatic at birth but then develop with age vision loss, seizure activity, and developmental delay with intracranial calcifications on imaging. Treatment can be undertaken in the mother as discussed below and in Table 99-2. In addition, more than 1 million people have eye involvement with toxoplasmosis either from congenital or postnatal infection. An inflammatory lesion of the retina caused by direct infection of Toxoplasma spp. can lead to retinal scarring. This infection clinically can present with photophobia, blurred vision, and pain and may over time cause loss of vision, leading to blindness. Toxoplasma spp. are known for more severe infection in immunocompromised hosts either through reactivation of latent infection or new primary infection. In particular, Toxoplasma spp. Have a tropism for cardiac tissue and the brain, so they are of particular concern in heart transplant recipients. Clinical symptoms from toxoplasmosis usually occur 2 to 24 weeks after transplantation often from reactivation of cysts within a graft. Prophylaxis may be achieved with pyrimethamine or trimethoprim–sulfamethoxazole.

Toxocara infections are most common in those younger than age 20 years, with most infections being asymptomatic. The two major clinical presentations of toxocariasis are visceral larva migrans (VLM) and ocular larva migrans (OLM). VLM involves larval invasion into liver, heart, lungs, brain, or muscle and may cause fever, wheezing, weight loss, and hepatosplenomegaly associated with eosinophilia. Pneumonitis with eosinophilia (Loeffler’s syndrome) may occur with VLM. Ocular involvement has very different presentations but often does not have peripheral eosinophilia.

Although the clinical range of parasitic infections is quite broad and overlaps with other infectious diseases, certain clinical and laboratory presentations are associated with particular parasitic infections. Some of these distinctive features are captured in Table 99-2. With the clinical presentation of pneumonia and peripheral eosinophilia, Ascaris spp., hookworms, Strongyloides spp., and Toxocara spp. should be considered. Isolated eosinophilia can be seen in Strongyloides, hookworm, Schistosomia, and Toxocara infections. Toxocara infections are often associated with hepatosplenomegaly.

Differential Diagnosis

The differential diagnosis for systemic parasites is quite broad. Parasitic infection needs to be considered in returning travelers and those with fever without localizing symptoms. With fever with eosinophilia in returned travelers, schistosomiasis, toxocariasis, hookworm, filariasis, and trichinosis should be entertained. Malaria and leptospirosis needs to be considered in the differential of undifferentiated fever and fever with hemorrhage that also includes meningococcemia and viral hemorrhagic fevers. Fever and splenomegaly include evaluation for malaria, schistosomiasis, toxoplasmosis, trypanosomiasis, leishmaniasis, babesiosis as well as nonparasitic causes, including typhoid, tularemia, rickettsial disease, cytomegalovirus, Epstein-Barr virus, and HIV.

Evaluation and Management

The history and physical examination are keys to the evaluation of patients with bloodborne or other systemic parasitic infection. As discussed above in the differential diagnosis section, fever and the presence of localizing symptoms as well as travel history aid in evaluating for parasitic disease. Exposure to animals, water sources, food history, and direct travel should be elucidated.

The diagnosis of extraintestinal parasites is often made through evaluation for peripheral eosinophilia, direct microscopy of the parasite, and serology testing for antibodies against the parasite of concern. Diagnosis of Toxoplasma spp. is made by serologic testing for immunoglobulin against Toxoplasma spp. or by direct microscopic identification of the parasite. The diagnosis of Toxocara infection is presumptive based on clinical presentation, history, and antibodies to Toxocara spp.

Treatment of extraintestinal parasitic infections is further described in Table 99-2. Head lice are often treated with pyrethrins or permethrin lotions that are over the counter.

Etiology and Pathogenesis

Malaria is caused by protozoa of the genus Plasmodium with four species using humans as the intermediary host. These species include P. falciparum, Plasmodium malariae, Plasmodium ovale, and Plasmodium vivax. The infectious cycle of Plasmodium species can be seen in the attached image. In short, Plasmodium spp. is transmitted by arthropod vector, the Anopheles mosquito, which is active during nighttime hours. The female Anopheles mosquito spreads sporozoites into the human host which then go on to infect liver cells and continue to mature. They then undergo multiplication in the erythrocyte cells, with blood stage parasites causing clinical manifestations of malaria. P. vivax and P. ovale may stay as liver stage parasites for months and then reactivate (Figure 99-5).

Figure 99-5 Malaria clinical course and diagnosis.

Distribution of Plasmodium spp. depends on the correct environment that allows for parasite multiplication in the mosquito. P. falciparum is the predominant organism in sub-Saharan Africa, Hispaniola, and New Guinea (50% of cases in United States). P. vivax is the next most common and is seen in South Asia, Eastern Europe, Northern Asia, and South America, accounting for 25% of cases in the United States. P. ovale is often seen in Western Africa. P. malariae is distributed worldwide. Typical incubation periods are 9 to 18 days for P. falciparum, P. vivax, and P. ovale with longer incubation for P. malariae.

P. falciparum causes the most severe disease and is associated with the greatest risk of death. The pathogenesis of severe malaria caused by P. falciparum is associated with its ability to cause budding on the surface of the erythrocytes. The erythrocyte malformation reduces malleability causing stasis and thrombosis in the visceral capillary beds (i.e., the kidney, liver and brain).

Clinical Presentation

Uncomplicated malaria often presents with nonspecific symptoms, particularly fever, chills, headache, weakness, vomiting, diarrhea, and myalgias. The clinical examination may often reveal splenomegaly. Severe malaria, often caused by P. falciparum, may involve the following symptoms as described by Griffith et al.: coma, respiratory distress, acidosis, seizures, pulmonary edema, circulatory shock, acute respiratory distress syndrome, jaundice, bleeding, anemia, acute renal failure, hemoglobinuria, parasitemia greater than 5%, and disseminated intravascular coagulation. Cerebral malaria may lead to signs of increased intracranial pressure, and vascular collapse and shock may occur with hypothermia and adrenal insufficiency. P. vivax and P ovale are known to cause splenomegaly with some reported causes of splenic rupture. P. malariae has been associated with nephrotic syndrome caused by immune complex deposition in the kidney.

Differential Diagnosis

As with other extraintestinal parasites, the differential diagnosis for malaria is broad, including viral and bacterial causes of undifferentiated fever. However, malaria must be considered in all febrile returned travelers from endemic areas.

Evaluation and Treatment

The evaluation for malaria should be undertaken with any suspicion for infection. A comprehensive discussion and flow chart for evaluation were undertaken by Griffith et al. In summary, Giemsa-stained thin and thick blood smears should be reviewed microscopically for evaluation of presence of Plasmodium spp. within 12 hours of presentation of a patient with suspected malaria. Parasite density in erythrocytes on thin smear will need to be calculated as an indicator of severity of disease. Molecular diagnosis can help identify different species, which may aid in tailoring treatment. If malaria is still clinically suspected despite initially negative thin or thick smears, these should be repeated every 12 to 24 hours for a 72-hour period. The complete blood cell count can also be helpful in looking for thrombocytopenia and hemolysis. If the presentation includes clinical shock or severe infection, the prothrombin time, partial thromboplastin time, and fibrinogen can be helpful.

After infection is identified, treatment should begin immediately. Therapy should be guided by the species of Plasmodium, the clinical status of patient, and drug susceptibility of the region where the infection occurred. The clinical status of the patient is important as uncomplicated malaria can be treated with oral antimalarials, but complicated infection has to be more tailored to parenteral therapy. Exchange transfusion may be considered with parasitemia of 10% or evidence of complications, including cerebral malaria. Treatment in areas of chloroquine resistance includes atovaquone and proguanil. Treatment of P. falciparum infection in nonchloroquine-resistant areas includes quinine sulfate plus doxycycline, tetracycline, or clindamycin. P. vivax (chloroquine resistant) treatment includes quinine sulfate plus doxycycline. Infection with all other Plasmodium spp. may be treated with chloroquine, with parenteral treatment with quinidine. For up-to-date recommendations and dosing, please refer to the Centers for Disease Control and Prevention’s website (www.cdc.gov).

Malaria is a reportable disease, and local health departments should be notified with any infections.

Traveler Prophylaxis

Travelers to endemic areas are at high risk for acquiring malaria and should take chemoprophylaxis beginning 1 week before travel to endemic region for mefloquine and 1 to 2 days for doxycycline and atovaquone-proguanil. Preventionof chloroquine-resistant malaria includes treatment with atovaquone/proguanil, doxycycline, or mefloquine. Atovaquone/proguanil is not approved for children who weigh less than 11 kg. Mefloquine can be considered for children, despite FDA approval only for children who weigh more than 5 kg and older than 6 months of age, and needs to be taken for 4 weeks after travel is over.

Future Directions

Understanding of transmission of parasitic disease and public and physician awareness in a world with increased international travel are important for further prevention and treatment. Prevention of malaria including prophylaxis and netting to prevent inoculation with Plasmodium spp. are current efforts to decrease infections. There are many efforts at preventive malaria vaccines underway.