Endemic parasitic infections in the United States are more frequent than is commonly perceived. Intestinal parasitic infection with Cryptosporidium, Dientamoeba , and Giardia occurs most often in children in northern states during the summer months. Zoonotic Toxocara and Toxoplasma parasitic infections are more frequent in southern states, in African Americans, and in populations with lower socioeconomic status. Approximately 300, 000 people in the United States have Trypanosoma cruzi infection. Local, vector-borne transmission of T cruzi and Leishmania infections has been documented in southern states. Parasitic diseases endemic to the United States are not uncommon but are understudied.
Key points
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Infections with the intestinal parasites Cryptosporidium , Dientamoeba , and Giardia , each of which can lead to differing forms of diarrheal disease, are common in children in the United States, particularly in northern states in the summer months.
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Chronic infection with Trypanosoma cruzi , the cause of Chagas disease, is present in hundreds of thousands of people in the United States, mostly in southern states.
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Local, vector-borne transmission of T cruzi has been reported in Texas, California, Tennessee, and Louisiana.
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Local, vector-borne transmission of Leishmania species, leading to cutaneous leishmaniasis, has been reported in Texas.
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Toxocara and Toxoplasma infections are endemic zoonotic infections in the United States and both are more frequent in African American populations and in individuals with lower socioeconomic status.
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Parasitic diseases endemic to the United States are not uncommon but are understudied. Further study is required to determine the true prevalence and morbidity from these diseases in the United States.
Introduction and overview of childhood parasitic infections
Although parasitic infections are generally thought of as diseases of low- and middle-income countries, there is a rapidly expanding evidence base to indicate that these diseases also affect wealthy countries in North America, Europe, and Asia. Most of the parasitic diseases endemic to the United States fall into 2 major categories ( Box 1 ): (1) intestinal protozoan infections that disproportionately affect northern states during the summer months and are linked to recreational water use and (2) neglected tropical diseases (NTDs) and related neglected infections that disproportionately affect people living in severe poverty. The American South has the largest number of cases, with Texas possibly representing the single most affected state in the nation. Here the authors’ provide an overview of the major parasitic infections affecting children in the United States, with an emphasis on new insights and developments reported in the biomedical literature over the last 5 years.
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Intestinal parasitic infections
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Cryptosporidiosis
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Dientamoebiasis
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Giardiasis
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Parasitic neglected tropical diseases
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Chagas disease
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Cutaneous leishmaniasis
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Toxocariasis
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Toxoplasmosis
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Introduction and overview of childhood parasitic infections
Although parasitic infections are generally thought of as diseases of low- and middle-income countries, there is a rapidly expanding evidence base to indicate that these diseases also affect wealthy countries in North America, Europe, and Asia. Most of the parasitic diseases endemic to the United States fall into 2 major categories ( Box 1 ): (1) intestinal protozoan infections that disproportionately affect northern states during the summer months and are linked to recreational water use and (2) neglected tropical diseases (NTDs) and related neglected infections that disproportionately affect people living in severe poverty. The American South has the largest number of cases, with Texas possibly representing the single most affected state in the nation. Here the authors’ provide an overview of the major parasitic infections affecting children in the United States, with an emphasis on new insights and developments reported in the biomedical literature over the last 5 years.
- •
Intestinal parasitic infections
- ○
Cryptosporidiosis
- ○
Dientamoebiasis
- ○
Giardiasis
- ○
- •
Parasitic neglected tropical diseases
- ○
Chagas disease
- ○
Cutaneous leishmaniasis
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Toxocariasis
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Toxoplasmosis
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Intestinal parasitic infections
Cryptosporidiosis
Cryptosporidiosis is an intestinal infection caused by a 4- to 6-μm protozoal coccidia. There are several species of Cryptosporidium , but the two of particular interest in children are C hominis and C parvum. Each year, approximately 10 000 to 12 000 cases of cryptosporidiosis are reported, although the actual number of cases is probably much higher. Children aged 1 to 9 years are disproportionately affected, with the onset of infection peaking in the summer in association with communal swimming venues and recreational water use. Overall, northern states have the highest incidence. Cryptosporidiosis has been linked with large water-borne disease outbreaks in the United States, which have been linked to zoonotic transmission in summer camps in some cases. In addition to young children, immunosuppressed patients (human immunodeficiency virus [HIV]/AIDS and transplant) are particularly vulnerable to cryptosporidiosis.
The intestinal parasitic infections described here (cryptosporidiosis, dientamoebiasis, and giardiasis) are all transmitted via the fecal-oral route, either through contaminated water or food. They also share a similar life cycle that begins with the ingestion of oocysts found in contaminated water or food or by autoinfection. Once the Cryptosporidium oocysts are excreted, they are highly contagious. The oocysts are also able to persist in the environment for a prolonged time, possibly up to 6 months. The low infectious dose and prolonged infective capability of Cryptosporidium help explain why it is easily transmitted. Other factors influencing transmission are a prolonged incubation period and the lack of protective immunity in the host.
The clinical presentation of cryptosporidiosis is large-volume watery diarrhea associated with nausea, vomiting, abdominal cramping, and anorexia. The diarrhea usually lasts between 5 and 10 days and is often self-limiting. In immunosuppressed patients, the diarrhea can last longer and results in malnutrition caused by poor absorption of nutrients and dehydration. Cryptosporidiosis can also present with extraintestinal manifestations, particularly in patients with HIV/AIDS and transplant patients, which can lead to pancreatitis, biliary strictures, hepatitis, and pneumonia.
Cryptosporidiosis can be diagnosed by oocyst visualization, antigen detection, or molecular testing. To visualize the oocyst, the stool is stained with trichrome or modified acid-fast stains or with a direct immunofluorescence stain ( Fig. 1 ). Although the specificity of direct visualization of the oocyst is around 100%, the sensitivity can range from 37% to 97%. In comparison, the antigen detection method gives a specificity and sensitivity of 90% and is the most widely use method today for the diagnosis of cryptosporidiosis. The antigen detection is a simple point-of-care testing method that is both economical and reliable. Cryptosporidiosis antigen detection can be paired with the detection of antigens from other intestinal protozoan infections, such as giardiasis and amebiasis, for diagnosis in the field.
The drug used to treat cryptosporidiosis is nitazoxanide, a thiazole derivative. Nitazoxanide has been has been approved by the Food and Drug Administration (FDA) since 2004 for use in children more than 1 year of age. See Table 1 for pediatric dosing guidelines. Nitazoxanide is a well-tolerated drug with few adverse side effects. In the immunosuppressed host, the reestablishment of the immune system is critical, either by treating the HIV infection or by lowering the immunosuppressive medications, in addition to nitazoxanide therapy.
| Drug | Nitazoxanide | ||
|---|---|---|---|
| Age of patient | 1–3 y | 4–11 y | Older than 11 y |
| Dose | 100 mg per dose | 200 mg per dose | 500 mg per dose |
| Frequency of doses | Twice daily | Twice daily | Twice daily |
| Duration of therapy | 3 d | 3 d | 3 d |
Dientamoebiasis
Since the first report by Jepps and Dobell in 1918, dientamoebiasis has been involved in controversies ranging from the proper classification of the organism to the clinical significance of the syndrome. Dientamoeba fragilis is an intestinal protozoan of the trichomonadida family. It can be found worldwide and is estimated to have a prevalence as high as 42% in some regions. As opposed to other intestinal protozoans that are linked with poverty, dientamoebiasis is more prevalent in developed countries. Examples of prevalence rates in developed countries include 11.7% in the United States, 11.5% in Canada, and up to 16.9% in the United Kingdom. The mode of transmission is thought to be fecal-oral; however, no cyst stage has been described for this pathogen. There is some evidence that Dientamoeba may use the vector Enterobious vermicularis (pinworm) during transmission, although it is difficult to distinguish if the pinworm is a vector or simply a bystander. Making this distinction more difficult to elucidate is that patients with dientamoebiasis often have polyparasitism with other intestinal protozoa, such as Blastocystosis hominis, Giardia lamblia, Entamoeba histolytica , and Cryptosporidium spp.
Clinically, patients with dientamoebiasis present with abdominal pain, bloating, diarrhea, and loose stools, which lasts 3 to 7 days. After this acute stage, patients can progress to the chronic stage, which can last from 1 month up to 2 years and may lead to irritable bowel syndrome (IBS). The diagnosis of dientamoebiasis is challenging. Fresh or fixed stool, when examined under the light microscope, will show a rounded, amoeboidlike structure measuring 5 to 15 um (see Fig. 1 ). The use of real-time polymerase chain reaction (PCR) that targets ribosomal RNA gives a sensitivity of 93.5% and specificity of 100%.
The choice of drug in the treatment of dientamoebiasis is controversial because many therapeutic agents have been used successfully, including metronidazole, iodoquinol, erythromycin, paromomycin, and secnidazole. The most commonly used treatment option is metronidazole, which has cure rates of up to 80%. One study of 21 patients with a 2-month history of IBS who were found to have dientamoebiasis and were treated with iodoquinol and doxycycline found complete elimination of the Dientamoeba and 67% improvement in IBS symptoms. Secnidazole, a nitroimidazole used to treat other intestinal protozoans, was recently shown to have good amebicidal properties when compared with other treatment options. Advantages of secnidazole are that a single dose (30 mg/kg) can eliminate Dientamoeba with few adverse side effects.
Giardiasis
Giardia lamblia was one of the first protozoans to be seen in 1681 by Van Leewenhoek when examining stool under a microscope. G lamblia is a flagellated protozoan with a global distribution. It is one of the causes of traveler’s diarrhea and of diarrheal outbreaks from contaminated water. It is also considered a zoonotic disease, first known as beaver fever . There are approximately 19 000 cases of giardiasis reported annually; as with cryptosporidiosis, infection is most common in children aged 1 to 9 years and occurs most frequently in the summer months in northern states. Giardiasis and dientamoebiasis are also found commonly among internationally adopted children living in the United States. Infection occurs via the fecal-oral route when contaminated food and water containing Giardia cysts is ingested. As mentioned previously, the life cycle is similar to that of cryptosporidiosis. Giardia predominantly infects cells of the duodenum and upper jejunum.
Clinically, giardiasis presents as a mild to severe diarrheal disease, which can progress to a chronic form involving IBS. The incubation period of giardiasis is 9 to 15 days, after which patients develop anorexia, abdominal cramping, bloating, and explosive foul-smelling diarrhea. This acute stage can be self-limiting. However, up to 50% of patients do not clear the Giardia and chronic disease can result. During the chronic stage, patients experience weight loss, anorexia, malabsorption, and intermittent bouts of diarrhea, which can last for years. In the pediatric population, this can lead to failure to thrive, stunned growth, lower IQ, and urticaria. Rarely the chronic stage can include arthritis, cholecystitis, and pancreatitis. Giardiasis is diagnosed by direct observation of the stool (low diagnostic yield, see Fig. 1 ), serology using antigen detection kits (sensitivity and specificity >90%), and real-time PCR.
Giardiasis is treated with nitroimidazole compounds, including metronidazole, tinidazole, secnidazole, and ornidazole. See Table 2 for dosing guidelines. Metronidazole is very effective, with a cure rate of close to 95%. Tinidazole is also very efficacious with few side effects and has the advantage of only requiring a single dose. Nitazoxanide is an excellent alternative. It is FDA approved for the treatment of Giardia in children who are 1 year of age or older and has very few side effects. If patients do not respond to any of these medications, quinacrine is another highly efficacious option; however, this drug is associated with more adverse side effects.
| Drug | Metronidazole | Tinidazole | Quinacrine | Nitazoxanide | ||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Age | Younger than 11 y | Older than 11 y | Older than 11 y | Younger than 11 y | Older than 11 y | Younger than 11 y | Older than 11 y | 1–3 y | 4–11 y | ≥12 y |
| Dose | 5 mg/kg | 250 mg | 2 g | 30 mg/kg | 2 g | 2 mg/kg | 100 mg | 100 mg per dose | 200 mg per dose | 500 mg per dose |
| Frequency of doses | 3 times daily | 3 times daily | Once daily | Once | Once | 3 times daily | 3 times daily | Twice daily | Twice daily | Twice daily |
| Duration of therapy | 10 d | 10 d | 3 d | Single dose | Single dose | 7 d | 7 d | 3 d | 3 d | 3 d |
Parasitic NTDs
Chagas Disease
Chagas disease is a chronic systemic infection caused by the parasite Trypanosoma cruzi . The disease is most commonly transmitted through defecation by T cruzi –infected triatomine insects after a blood meal. Chagas disease has long been known to be an important parasitic infection in Latin America, with 8 million people or more currently infected. However, there is increasing attention to the presence of the disease in the United States. An estimated 300 000 cases of Chagas disease occur in the United States, although there are very few programs of active surveillance for this disease and some estimates indicate that almost as many T cruzi infected individuals may live in Texas alone. It is assumed that most of the Chagas disease cases in the United States result from immigration; however, new evidence documents at least 23 cases of autochthonous, vector-borne transmission within the United States, and the disease is widespread among dogs living in Texas. The triatomine vector can be found across the southern half of the country, with the largest species diversity in Texas, Arizona, and New Mexico. Of increasing concern in the United States is maternal transmission of Chagas disease. Recently, the first case report of congenital Chagas disease in the United States confirmed by the Centers for Disease Control and Prevention (CDC) was published. Reports suggest that vertical transmission occurs in 1% to 10% of pregnancies in infected women, which could indicate that there are as many as 638 cases of congenital Chagas annually in the United States.
Chagas infection first presents as an acute illness that can either be asymptomatic or a self-limiting febrile illness. After a decrease in parasitemia, patients enter the indeterminate chronic stage. Between 60% and 70% of patients in the indeterminate stage will never experience symptoms. The remaining 30% to 40% of patients will develop chagasic cardiomyopathy or digestive symptoms, including megaesophagus or megacolon, often 10 to 30 years after the initial infection. Congenital Chagas disease frequently has no specific symptoms, making recognition of the infection challenging for physicians. Many infants are asymptomatic, and the remaining 10% to 40% of infants present with features including low birth weight, low Apgar scores, respiratory distress, cardiac failure, anasarca, hepatosplenomegaly, and meningoencephalitis. Severe congenital Chagas infection is associated with high neonatal mortality rates.
Diagnosis of acute Chagas disease relies on detection of T cruzi trypomastigotes in blood by microscopic analysis. Once parasitemia is low during the chronic infection phase, antibody-based tests are used for diagnosis, including enzyme-linked immunosorbent assay (ELISA), indirect immunofluorescence, or indirect haemagglutination. Positive results from 2 of these tests are recommended for the diagnosis of Chagas disease in the chronic phase. Although PCR is a more sensitive test, poor standardization and variable results across laboratories exclude it as a routine method of diagnosis. PCR can be used to monitor treatment failure but should not be used to confirm treatment success because PCR cannot exclude the possibility of low levels of parasite in the tissue. In neonates with suspected congenital Chagas disease, Giemsa-stained blood smears or buffy coat should be examined by light microscopy for trypomastigotes. PCR should be used with caution and confirmed with a second specimen because low levels of T cruzi DNA can sometimes be found in uninfected neonates of women with Chagas disease. Neonates with negative results should be retested at 4 to 6 weeks because parasitemia typically increases during the first month of life. Antibody-based tests can be used after 9 to 12 months, when maternal antibodies have waned.
There are 2 pharmacologic options for the treatment of Chagas disease. Neither of these drugs are FDA approved but may be obtained free of charge from the CDC under investigational protocols. For questions regarding treatment or to obtain the medications contact the CDC Parasitic Diseases Public Inquiries (1-404-718-4745; e-mail chagas@cdc.gov ). For after-hours emergencies contact the CDC Emergency Operations Center (770-488-7100) and ask for the on-call parasitic diseases physician. Benznidazole is the drug with the best safety profile and the highest efficacy rates and is recommended as the first-line therapy. Alternatively, nifurtimox can be given. See Table 3 for dosing guidelines. All infected children less than 18 years of age should be treated. Congenital Chagas disease should be treated promptly once a confirmatory diagnosis is obtained. Cure rates are more than 90% when therapy is initiated within the first few weeks of life, and fewer adverse reactions occur than in the adult population if therapy occurs within the first year of life. Recently, the nonprofit product development partnership Drugs for Neglected Diseases initiative registered a new pediatric formulation of benzimidazole in Brazil. The formulation is comprised of a 12.5-mg tablet that is adapted for children less than 2 years of age (20 kg body weight), with the treatment comprised of 1, 2, or 3 tablets depending on weight (5–10 mg/kg/d). Currently, the safety of benzimidazole and nifurtimox is unknown during pregnancy, so recommendations regarding the treatment of pregnant women suggest delaying therapy until after delivery and breastfeeding have concluded. Targeted screening of pregnant women based on risk factors (history of living or having receiving a blood transfusion in a disease-endemic area) is recommended to identify pregnancies that could result in congenital Chagas disease as well as to prevent future possible congenital Chagas cases.
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