Enteric parasites are important agents of disease throughout the world. Although the frequency and severity of parasitic diseases are most extreme in the developing world, changes in worldwide travel, immigration, commerce, and day care for young children and increasing numbers of immunocompromised patients have led to increased incidences of parasitic diseases in the developed world. Parasitic disease may mimic other gastrointestinal disorders, such as inflammatory bowel disease, hepatitis, sclerosing cholangitis, peptic ulcer disease, and celiac disease. Parasitic infection can also trigger overt manifestations of quiescent chronic intestinal disorders.
Epidemiology
A variety of epidemiologic factors predispose patients to parasitic infestation worldwide, but the single most important factor is socioeconomic status. It has been shown repeatedly, in both the developed and developing world, that children of lower socioeconomic status have higher parasite loads and a greater prevalence of multiple infestations. Travel to developing countries can expose an individual to parasites that may not cause symptoms until weeks, months, or years later. Immigrants from developing countries often harbor pathogens that are unfamiliar to physicians in their new homelands and may pass them on to their new neighbors. Less obvious sources of parasites include foodstuffs that are increasingly imported from all areas of the world. The United States has experienced outbreaks of intestinal cyclosporiasis from imported raspberries. Giardia , Cryptosporidium , and Cyclospora have been identified in packaged salad greens imported to Canada from the United States.
Protozoan infections endemic to the developed world, such as giardiasis, are transmitted with great efficiency in day-care centers, where fecal-oral contamination is common. Institutions for the developmentally disabled are also common reservoirs for Giardia , Entamoeba histolytica , and other protozoans. Pets and livestock are potential sources of Cryptosporidium , Giardia , and Toxocara species, canine hookworm, Balantidium coli , and other organisms.
Dietary habits can also be risk factors. Consumption of raw or undercooked fish can lead to Diphyllobothrium latum , Capillaria philippinensis , or Anisakis infection. Inadequate cooking of pork predisposes to Taenia solium and Trichinella infections. Raw or undercooked beef can harbor Taenia saginata . Furthermore, a variety of protozoan organisms can be transmitted via produce that has been exposed to human or animal waste. Unpasteurized apple juice has been reported as a cause of Cryptosporidium outbreaks.
Host Factors
Children, particularly toddlers, are more susceptible to these infestations, owing to their habits of mouthing environmental objects, their propensity to go barefoot, and their immunologic “naiveté.” Patients with compromised immune systems, whether due to congenital defects, infections such as human immunodeficiency virus (HIV), or medical ministrations (transplant and oncology patients), may have severe, protracted, or unusual manifestations of parasitic disease. Patients with hypogammaglobulinemia and immunoglobulin A (IgA) deficiency may have severe protozoan infections such as giardiasis. Patients with acquired immunodeficiency syndrome (AIDS) who are infected with Cryptosporidium organisms may have severe, prolonged diarrhea as well as unusual manifestations in the biliary tree and lungs, despite high levels of luminal IgA antibody directed against Cryptosporidium . Sexual practices, particularly those that involve anal penetration, are also associated with transmission of parasitic diseases.
Clinical Presentations
Enteric parasites most often produce gastrointestinal symptoms—abdominal pain, diarrhea, flatulence, and distension. In a children’s hospital laboratory survey of stool ova and parasites testing, it was found that stools sent from the gastroenterology clinic were most likely to be positive, as compared with stools submitted from other outpatient clinics, the emergency room, or inpatient settings. Heavy infestations of large worms such as Ascaris can lead to intestinal obstruction or, if they migrate into the biliary system, biliary obstruction with cholangitis or pancreatitis. Amoeba and Trichuris organisms can cause enterocolitis with tenesmus and mucoid, bloody stool.
Liver disease from enteric parasites can result from bile duct obstruction by organisms such as Ascaris worms or liver flukes or from portal hypertension caused by inflammatory reactions to ova, as in schistosomiasis. Some protozoans such as Cryptosporidium can infect biliary epithelium and produce syndromes such as cholangitis and cholecystitis. Other protozoans such as E. histolytica can cause hepatic parenchymal necrosis resulting in liver abscesses.
Systemic manifestations of parasitic infestation are also common. Intestinal luminal blood and protein loss can lead to anemia and edema. Fever is often the most prominent feature of amebic liver abscess. Malabsorption is common in giardiasis and cryptosporidiosis and can lead to wasting, fat soluble-vitamin deficiency, and failure to thrive. Onset of nephrotic syndrome has been associated with Giardia lamblia, Strongyloides stercoralis, and possibly hookworm species.
Diagnosis
Stool Examination
The mainstay of diagnosing enteric parasites is a skilled microscopist in the parasitology laboratory. Because the skills of the microscopists vary, clinicians are advised to select reference laboratories with care. Careful attention to the appropriate collection, preservation, and examination of samples is critical to successful diagnosis of enteric parasites. Furthermore, the observation of fecal leukocytes, eosinophils, and macrophages in preserved specimens may provide clues to parasitic gastrointestinal diseases.
Appropriate sample collection begins with ascertaining that no interfering substances are present in the stool that will invalidate the results. Common interfering substances include barium (from contrast radiography), bismuth preparations, antacids, and mineral oil. Antibiotics can also make detection of protozoans difficult. It is preferable to wait 2 weeks after the ingestion of any of these substances before obtaining a specimen. Clinicians evaluating gastrointestinal symptoms should obtain stool specimens before initiating gastrointestinal radiology studies and certain forms of empiric therapy. Water and urine contamination of stool lead to rapid lysis of trophozoites and should be avoided.
Although examination of a fresh stool specimen is useful for identification of motile trophozoites, it is rarely performed in laboratories in the United States. Most stools are collected in preservatives, which allows for convenience in both collection and examination. The commonly used preservatives, such as formalin and poly(vinyl) alcohol, are toxic if ingested.
The appropriate number and frequency of stool examinations are matters of some controversy. It is clear that repeated samples obtained on separate days enhance sensitivity by at least 20%, owing to variable shedding of eggs, cysts, and trophozoites. For patients with low clinical-epidemiologic risk factors in areas of low prevalence of parasitic infection, such as in the United States, one sample may be adequate, providing a sensitivity of about 70% and a negative predictive value greater than 90%. However, when there is a high index of suspicion for infection, at least three samples may be needed, particularly for E. histolytica, Strongyloides, and Dientamoeba fragilis .
Some enteric parasites, most notably Cryptosporidium and Cyclospora species, are not detected on routine ova and parasite examinations. These organisms require either acid-fast staining or special immunofluorescence techniques.
Immunoassay
Enzyme-linked immunosorbent assays (ELISAs) for antigen in stool samples are widely available for Giardia and Cryptosporidium species. These sensitive and specific assays can be useful adjuncts to standard stool examinations. Because several common organisms can cause the clinical picture of giardiasis, ELISA is not recommended as the sole means of evaluating patients, except in the context of a known outbreak. ELISA for Strongyloides has a sensitivity of up to 95% and specificity of 90%.
Macroscopic Examination
Ascaris lumbricoides worms can be passed intact in the stool or vomited, particularly during febrile illness. They are easily recognized because of their size (15 to 40 cm) and resemblance to earthworms. Cestodes, or more commonly, segments of cestodes, can also be passed per rectum. Species identification is possible by microscopic examination. Enterobius organisms venture nocturnally onto the perianal area to lay eggs. The small threadlike worms may be visualized, or the “Scotch tape” test may be employed to identify the eggs of this common parasite.
Serology
Serologic detection of antibodies to E. histolytica is possible in 85% of patients with dysentery and 95% of infected patients who have liver abscesses in nonendemic areas. Specific serology for Giardia and Strongyloides may be useful in some cases.
Eosinophilia
Eosinophils are granulocytes with cytoplasm that stains strongly with acid dyes such as eosin. They normally make up less than 5% of circulating granulocytes, or an absolute count of fewer than 500/mm 3 . Elevation of eosinophils in the peripheral blood is associated with allergy, connective tissue disease, infections, and malignancy. Only invasive parasitic infections are associated with a peripheral eosinophilia, and the degree of elevation is proportional to the degree of invasion. Protozoal infections rarely cause eosinophilia. Circulating eosinophils are a marker of much higher tissue aggregations of eosinophils, usually in the skin and epithelial tissues. Eosinophil production is stimulated by cytokines released by Th2 cells. The Th2 immune response is triggered by allergens and helminths and differs from the Th1 response involved in bacterial and viral infections. Eosinophilia is not a sensitive screening tool for parasitic infection. However, if eosinophilia is present, infection with Ascaris , hookworm, visceral or cutaneous larva migrans, Strongyloides, Trichinella, Trichuris, Cystisospora, Enterobius, C. philippinensis, or tapeworm must be considered.
Intestinal Fluid and Biopsy
Duodenal fluid may be useful in diagnosis of giardiasis or strongyloidiasis when stool specimens are negative. Fluid may be obtained by duodenal intubation or during endoscopy; it should be examined immediately. The Entero-Test is a gelatin capsule that contains a string that adsorbs duodenal fluid. It is swallowed and then retrieved by a string taped to the patient’s cheek. This technique may be difficult to perform in young children.
In selected patients, duodenal biopsy may reveal Giardia, Cryptosporidium, microsporidia, or Strongyloides organisms. Biopsy of the edges of colon ulcers may reveal trophozoites of E. histolytica . The sensitivity of intestinal biopsy for diagnosis of parasitic disease depends to a large degree on the interest and experience of the pathologist.
Benefits of Parasites
Interest is growing in a hypothesized link between lack of exposure to helminthic infection and the development of allergy. Several studies have shown that children with chronic parasitic infections have reduced skin reactivity to common environmental allergens such as the house dust mite, as compared to noninfected children with otherwise similar exposures. There seems to be benefit both from current parasite infection and from repetitive infection in infancy. Inflammation triggers CD4+ T-cell production of either a Th1- or Th2-predominant response. Th1 cytokines stimulated by bacterial and viral infections are the cytokines that mediate a normal inflammatory response. Th2 cytokines are stimulated by parasites and allergens and cause an allergic response, but in the case of parasitic infections, the response is modified and IgE degranulation is inhibited. Recurrent exposure to parasites in infancy is thought to downregulate the Th2 response and lessen the likelihood of induction of allergy. Current parasite infection also downregulates the inflammatory response, possibly to allow the parasite to mature and reproduce. The role of the anti-inflammatory cytokines such as interleukin 10 (IL-10) is important, because repetitive parasitic and other infections upregulate IL-10 and ensure a normal termination of inflammation.
As with allergy, the incidence of inflammatory bowel disease is said to be inversely related to the prevalence of parasitic infection. Immune tolerance and autoimmunity, mediated by Th3/Tr1 cells, also depends on the balance of anti-inflammatory cytokines IL-10 and transforming growth factor β (TGF-β) with pro-inflammatory cytokines from the Th1 pathway. Parasitic infections downregulate Th1 responses that are implicated in the mucosal inflammation seen in inflammatory bowel disease. After promising experiments on mice, humans with inflammatory bowel disease have been dosed with Trichuris suis (pig whipworm) and Necator americanus . The preliminary results suggest efficacy.
Pathogenic Organisms
Protozoa
Giardia Intestinalis
Giardiasis is the most common pathogenic intestinal protozoan infection in the world. It has been estimated that some 2% to 5% of the population of the industrialized world and up to 30% of those in the developing world are infected at any time. It is increasingly recognized in day-care center outbreaks and in food- and waterborne outbreaks in industrialized countries. The majority of these infections are asymptomatic. Prevalence of infection increases through infancy and early childhood, not decreasing until early adolescence. A major pediatric health concern is that this protozoan may be contributing to failure of growth and cognitive development in the developing world. However, Giardia was recognized as a major pathogen only in the 1970s and was listed as a parasitic pathogen by the World Health Organization (WHO) in 1981. Giardia was also the first-described human protozoan agent of intestinal disease. In 1861, von Leeuwenhoek observed Giardia in his own diarrheal stool and described them as “animalcules.” Giardia is an ancient organism and was recently demonstrated in the stools of prehistoric Peruvian human populations. It is a primitive eukaryocyte and relies on anaerobic metabolism because it lacks mitochondria. These organisms share many properties with bacteria and hence are susceptible to antibiotics.
G. intestinalis exists in two forms: the encysted, environmentally stable form that is responsible for transmission and the small intestine-dwelling trophozoite, which is the motile form observed by von Leeuwenhoek. The process of excystation is thought to be pH dependent and follows the transition of the cyst from acid stomach to alkaline duodenum, causing the characteristic heavy infestation in the proximal small bowel. In the small intestine, the trophozoites adhere to enterocytes by a ventral disk, causing local effacement of the microvilli. Giardia is a waterborne pathogen that can be transmitted via the fecal-oral route. The study of Giardia species has been hampered by multiple naming systems. The Giardia that are pathogenic to mammals are known as Giardia lamblia and also as G. intestinalis and G. duodenalis . Several different assemblage types identified within G. intestinalis have relevance for host specificity, but evidence is lacking for effect on clinical disease severity. A variety of domestic mammals including dogs and cats; wild mammals such as beavers, raccoons, and rodents; and domestic livestock such as cattle and sheep can harbor the organism. The role of animals in the transmission of Giardia to humans remains controversial, partly because of emerging data about the relevance of assemblage types within the G. lamblia species that may determine host specificity.
The pathophysiology of giardiasis is unclear, but several pathogenic mechanisms have been proposed: disruption of the intestinal epithelial brush border, mucosal invasion, and elaboration of an enterotoxin. Pathologic changes in the small intestine are quite variable. Although most symptomatic patients have normal or nearly normal villi, 5% to 10% or more have subtotal villus atrophy. Host defenses are B-cell dependent, with secretory IgA antibodies playing an important role. Patients with hypogammaglobulinemia, such as associated with common variable immunodeficiency, X-linked agammaglobulinemia (XLA), or nephrotic syndrome are particularly prone to prolonged infection with histopathologic changes on small bowel biopsy. Although T cells also appear to play a role in the intestinal elimination of the organism, patients with marked T-cell deficiencies including those with AIDS do not seem to be at increased risk of severe or persistent giardiasis. Invasive disease may rarely occur with spread to the gallbladder and urinary system. Most symptomatic patients develop disaccharidase deficiency, particularly lactose intolerance, both clinically and as measured by the hydrogen breath test.
The 1- to 3-week incubation period may be followed by a phase of acute illness, but more than half of infected children will be asymptomatic. Symptoms of diarrhea, flatulence, malabsorption with weight loss, constipation, and abdominal pain can be intermittent or continuous. Stools may be watery, malabsorptive, or formed, but are not bloody and do not contain leukocytes. Urticaria may occur and may be prolonged.
Laboratory findings are generally nonspecific. Fat may be found in the stool. Rarely, serum albumin level is decreased and fecal α 1 -antitrypsin is increased. Eosinophilia does not occur. Radiologic findings are generally nonspecific. Giardiasis localized to the terminal ileum may radiologically mimic Crohn’s disease. Ophthalmoscopy may demonstrate salt-and-pepper retinal degeneration in preschool children, but progressive retinal disease does not occur.
Diagnosis is based on demonstration of Giardia trophozoites, cysts, or antigen in stool, duodenal fluid, or intestinal biopsy specimens ( Figure 39-1 ). Microscopic examination of a single stool specimen is approximately 70% sensitive for detection. Sensitivity increases to approximately 85% with three samples. Examination of duodenal fluid has been reported to be 40% to 90% sensitive. Antigen detection assays by direct fluorescence antibody (DFA) or enzyme immunoassay (EIA) on stool offers 89% to 100% sensitivity and 99.3% to 100% specificity on a single specimen, but do not identify other protozoans that can cause similar symptoms.
Prevention of infection is a major public health concern. An inoculum of only 10 to 100 cysts can cause infection in humans. Giardia is more resistant than bacteria and the cyst can survive 3 months in water at 4° C. Waterborne infections account for 60% of cases in the United States. Standard iodine water purification tablets will not reliably kill Giardia in infected water, and Giardia are relatively resistant to chlorination and ozonolysis. Swimming pools, and even tap water, are common sources of infection. Filtration of water and ultraviolet light treatment are most effective at eradicating Giardia from the water supply. Foodborne infection outbreaks are usually secondary to infected or excreting food handlers, but viable Giardia have been found on fruits and vegetables such as lettuce and strawberries. Outbreaks in day-care centers are also common. Thorough handwashing is essential to disease prevention. Antigenic variation in the Giardia surface antigens has slowed development of a vaccine for humans, but a veterinary vaccine for cats and dogs is commercially available. Breast-feeding is protective for preventing infection and symptomatic infection.
Treatment options for giardiasis include metronidazole (and its derivatives), nitazoxanide, paromomycin, quinacrine, and furazolidone ( Table 39-1 ). Immunocompromised patients may require prolonged therapy to clear the organism. Some apparent clinical treatment failures are caused by lactose intolerance, which can persist for weeks after successful treatment. There is no clear role for the use of probiotics in the treatment or prevention of Giardia infection. No treatment is recommended for asymptomatic children carrying cysts. However, treatment may be considered in outbreak control and in patients with cystic fibrosis, celiac disease, or hypogammaglobinemia.
| Disease | Drug | Dosage | Comments |
|---|---|---|---|
| Amebiasis (E. histolytica) | |||
| Asymptomatic and luminal clearance | Iodoquinol or | 30-40 mg/kg per day in 3 doses × 20 days (max. 2 g/day) | Asymptomatic cyst passers in nonendemic areas should be treated. |
| Paromomycin or | 25-35 mg/kg per day in 3 doses × 7 days (max. 1.5 g/day) | ||
| Diloxanide furoate | 20 mg/kg per day in 3 doses × 10 days (max. 1.5 g/day) | Not commercially available in United States. | |
| Colitis, liver abscess Treatment should be followed by luminal clearance (e.g., with iodoquinol or paromomycin) | Metronidazole or | 35-50 mg/kg per day in 3 doses × 7-10 days (max. 2.25 g/day) | Oral metronidazole is very well absorbed. |
| Tinidazole or | 50 mg/kg per day in 1 dose × 3 days (max. 2 g/day) | May be less effective but better tolerated. Follow with luminal clearance as above. | |
| Ornidazole | 25 mg/kg per day × 5-10 days | Not available in the United States. Alternates include dehydroemetine or combination therapy with chloroquine phosphate. | |
| Ancylostoma caninum (dog hookworm, eosinophilic enterocolitis) | Albendazole or | 400 mg once (may repeat in 3 weeks) | Serologic/clinical diagnosis; no ova or parasites are found in stool. |
| Pyrantel pamoate or | 11 mg/kg per day × 3 days (max. 1 g/day) | ||
| Mebendazole or endoscopic removal | 100 mg bid × 3 days | Mebendazole not currently available in the United States. | |
| Anisakiasis (fish worm) | Surgical or endoscopic removal | For symptoms of obstruction, use nasogastric infusion of piperazine citrate 75 mg/kg per day (max. 3.5 g) to induce paralysis of worms. | |
| Ascariasis | Albendazole or | 400 mg once | |
| mebendazole or pyrantel pamoate or ivermectin | 100 mg bid × 3 days or 500 mg once 11 mg/kg once (max. 1 g) 150-200 µg/kg once | ||
| Balantidium coli | Tetracycline or | 40 mg/kg per day in 4 doses × 10 days (max. 2 g/day) | Contraindicated in pregnant women and children younger than 8 years old. Paromomycin is an alternative for pregnant women. |
| Iodoquinol or | 30-40 mg/kg per day in 3 doses × 20 days (max. 2 g/day) | ||
| Metronidazole | 35-50 mg/kg per day in 3 doses × 5 days (max. 2.25 g/day) | ||
| Blastocystis hominis | Metronidazole or | 35-50 mg/kg per day in 3 doses × 5-10 days (max. 2.25 g/day) | |
| Iodoquinol | 40 mg/kg per day in 3 doses × 20 days (max. 2 g/day) | Alternatives: trimethoprim-sulfamethoxazole and nitazoxanide. | |
| Capillaria philippinensis | Mebendazole or | 200 mg bid × 20 days | Noncompliance with prolonged course leads to frequent relapse. |
| Albendazole or | 400 mg daily × 10 days | ||
| Thiabendazole | 25 mg/kg per day in 2 doses × 30 days | ||
| Cryptosporidiosis | Nitazoxanide or | 100 mg bid × 3 days (children 1-3 years old), 200 mg bid × 3 days (children 4-11 years old), 500 mg bid × 3 days (≥12 years old) | Improved immune function is best prognosis. |
| Azithromycin dihydrate alone or with paromomycin (minimally effective) | 25 mg/kg per day bid × 14 days 30 mg/kg per day in 3 doses (max. 4 g/day) | ||
| Cyclospora | Trimethoprim-sulfamethoxazole (TMP-SMZ) | TMP 10 mg/kg per day, SMZ 50 mg/kg per day bid × 7-10 days (max. 1 DS tablet bid) | HIV-infected patients may need higher dose and longer treatment. Ciprofloxacin is an alternative for sulfa-allergic patients. |
| Dientamoeba fragilis | Iodoquinol or | 30-40 mg/kg per day in 3 doses × 20 days (max. 2 g/day) | Contraindicated in pregnant women and children younger than 8 years old. |
| Tetracycline or | 40 mg/kg per day in 4 doses × 10 days (max. 2 g/day) | Take tetracycline 1 hour before or 2 hours after antacids, calcium supplements, and laxatives containing magnesium. Take tetracycline 2 hours before or 3 hours after iron preparations and vitamin products that contain iron. | |
| Metronidazole or | 35-50 mg/kg per day in 3 doses × 10 days (max. 2.25 g/day) | ||
| Paromomycin | 25-35 mg/kg per day in 3 doses × 7 days | ||
| Enterobius vermicularis (pinworm) | Pyrantel pamoate or | 11 mg/kg (max. 1 g) once; repeat in 2 weeks | Treatment of household contacts is often advised. |
| Mebendazole or | 100 mg once; repeat in 2 weeks | ||
| Albendazole | 400 mg × once; repeat in 2 weeks | ||
| Giardiasis | Metronidazole or | 15 mg/kg per day in 3 doses × 5-7 days (max. 750 mg/dose) | |
| Tinidazole or ornidazole or nitroimidazole | 50 mg/kg once (max. 2 g) | ||
| Furazolidone or | 6 mg/kg per day in 4 doses × 7-10 days (max. 400 mg/day) | For resistant Giardia . | |
| Albendazole or | 400 mg once × 5 days | ||
| Nitazoxanide or | 100 mg bid × 3 days (children 1-3 years old), 200 mg bid × 3 days (children 4-11 years old), 500 mg bid × 3 days (≥12 years old) | With metronidazole for resistant strains. | |
| Paromomycin or | 25-35 mg/kg per day in 3 doses × 5-10 days (max. 1.5 g/day) | Least efficacious, but recommended for pregnant women. | |
| Quinacrine | 6 mg/kg tid × 5 days (max. 300 mg/day) | Colors skin yellow. | |
| Hookworm (Ancylostoma duodenale, Necator americanus) | Albendazole or | 400 mg once | |
| Pyrantel pamoate or | 11 mg/kg per day × 3 days (max. 1 g) | ||
| Mebendazole | 100 mg bid × 3 days or 500 mg once | ||
| Cystisospora belli | TMP-SMZ | TMP 10 mg/kg per day, SMZ 50 mg/kg per day bid × 10 days (max. 1 DS tab bid) | Pyrimethamine and ciprofloxacin are alternates for sulfa allergic patients. |
| Microsporidiosis (intestinal) (Enterocytozoon bieneusi, Encephalitozoon [Septata] intestinalis) | Fumagillin or | 60 mg/d × 14 days (adult dose) | E. intestinalis is more responsive to treatment. |
| Albendazole | 400 mg bid × 21 days (adult dose) | Alternatives include metronidazole, atovaquone, and nitazoxanide. | |
| Schistosomiasis | |||
| S. japonicum | Praziquantel | 60 mg/kg in 3 doses × 1 day | Treatment does not reverse established portal hypertension. As praziquantel does not kill developing worms, if treatment is given within 1 to 2 months of exposure, it should be repeated 1 to 2 months later. |
| S. mansoni | Praziquantel or | 40 mg/kg in 2 doses × 1 day | |
| Oxamniquine | 20 mg/kg in 2 doses × 1 day | Contraindicated in pregnancy. | |
| S. haematobium | Praziquantel | 40 mg/kg in 2 doses × 1 day | |
| S. mekongi | Praziquantel | 60 mg/kg in 3 doses × 1 day | |
| Strongyloidiasis (Strongyloides stercoralis) | Ivermectin or | 200 µg/kg per day × 2 days | Discontinuation of steroids is important in fulminant, disseminated disease. |
| Thiabendazole or | 50 mg/kg per day in 2 doses × 2 days (max. 3 g/day) | ||
| Albendazole | 400 mg bid × 7 days | ||
| Tapeworm (adult worm) (D. latum, T. solium, T. saginata, D. canium) | Praziquantel or | 5-10 mg/kg once | |
| Niclosamide | 50 mg/kg once | ||
| Tapeworm (Hymenolepis nana) | Praziquantel or | 25 mg/kg once | |
| Nitazoxanide | 200 mg bid × 3 days (children 4-11 years old), 100 mg bid × 3 days (children 1-3 years old) | ||
| Trichuris trichiura (whipworm) | Mebendazole or | 100 mg bid × 3 days or 500 mg once | |
| Albendazole or | 400 mg × 3 days | ||
| Ivermectin | 200 µg/kg per day × 3 days |
Entamoeba Histolytica
Although a variety of amebae species inhabits the human intestine, only E. histolytica is clearly pathogenic. Although they appear identical on light microscopy, newer biochemical, immunologic, and DNA analyses distinguish between pathogenic and nonpathogenic strains. The strains Entamoeba dispar and Entamoeba moshkovskii are generally considered nonpathogenic. Even within an endemic area there are genetically distinct strains of E. histolytica that are capable of invading the mucosa and causing disease, and different strains appear to cause intestinal versus hepatic disease. Virulence factors are related to a number of proteins produced by the parasite, including a lectin that mediates adherence to epithelial cells, a peptide that lyses cells by creating a pore, and matrix-digesting proteases. Indeed, the name histolytica refers to the ability to break down extracellular matrix proteins and cause necrosis of host cells.
The life cycle of these unicellular eukaryocytes is similar to that of Giardia . Ingested cysts are stimulated by gastric acid to excystate in the small intestine. The resulting trophozoites colonize the large intestine, where they multiply in the mucin layer. The trophozoites then invade either the mucosa or encystate, depending on local conditions and the nature of the particular strain. The interaction of the genetic capabilities of the strain and host factors such as the bacterial flora of the gut determine virulence. Invading trophozoites destroy epithelial target cells by releasing substances such as hemolysins, which disrupt cell membranes by creating an amoebapore. A variety of excreted cysteine proteases disrupt the extracellular matrix. Injury to epithelial cells triggers release of cytokines leading to chemotaxis of leukocytes, which also contributes to the local inflammatory response. Eventually, ulceration of the mucosa occurs and invading amebae may enter the portal circulation and eventually the liver. In vitro, the trophozoites have a powerful ability to kill T lymphocytes, neutrophils, and macrophages. Virulence may also be related to the trophozoites’ ability to cause apoptosis in these inflammatory cells and then phagocytose them, thus limiting further inflammatory response. Unlike intestinal lesions, hepatic abscesses contain few inflammatory cells, consisting almost entirely of necrotic liver cells. In patients treated with large doses of steroids, amebae may spread to a variety of organs, including the lungs, brain, and eyes. For unknown reasons, such systemic dissemination is not common in AIDS patients, who are often infected with Entamoeba species.
E. histolytica causes an estimated 34 to 50 million symptomatic infections worldwide every year. Risk factors for development of amebiasis include poverty, crowding, poor hygiene, travel in endemic areas, and male homosexual promiscuity. Host genotype also affects risk of symptomatic infection, with certain uuman leukocyte antigen (HLA) types appearing to be protective. There are an estimated 100,000 deaths per year due to amebiasis. Risk factors for severe disease include young age (particularly infants), malnutrition, and corticosteroid use.
Although physicians in the United States may think of amebic disease as exotic, amebiasis is the third most common parasitic infection in the United States, after giardiasis and cryptosporidiosis. In addition, amebiasis is the second most common cause of diarrhea in travelers returning to the United States. Asymptomatic infections commonly last more than a year, and latency periods as long as several years are possible. Clinicians need to take a detailed and distant travel history and maintain a high index of suspicion for late development of liver abscesses.
Symptoms of intestinal amebiasis vary with the location and extent of the infection. E. histolytica may invade any portion of the colon, although the cecum and ascending colon are most commonly affected. Patients often complain of abdominal pain, anorexia, malaise, and intermittent diarrhea. Patients with rectosigmoid involvement have tenesmus and more frequent diarrhea. Patients with extensive involvement have symptoms similar to those of ulcerative colitis, with frequent mucoid bloody stools. In nonfulminant cases, fever is uncommon, but with fulminant colitis or hepatic abscess, fever can be prominent. Toxic megacolon or perforation can occur and are leading causes of mortality in untreated patients. In some cases, a localized granulomatous reaction to E. histolytica known as an ameboma occurs. Amebomas are difficult to distinguish from colon carcinoma. Amebic dysentery may mimic inflammatory bowel disease, leading to institution of high-dose steroid therapy, which can be lethal in persons with amebiasis. Painful cutaneous ulcers may complicate colitis. Salpingitis and lymphadenitis due to E. histolytica have also been reported.
Amebic liver abscess is manifested by right upper quadrant pain, leukocytosis, fever, and hepatomegaly. Liver abscess usually occurs in the absence of current or recent overt intestinal disease. Results of liver function tests, including bilirubin and transaminases, are often normal. Ultrasonography shows one or more cystic masses in the hepatic parenchyma. Complications of abscesses include rupture, with possible pericardial or pleural spread. Cases of postinfectious glomerulonephritis have been reported following amebic liver abscess.
Diagnosis of colonic amebiasis is best made by microscopic examination of fresh stool. Three to six samples should be adequate to identify 90% of cases. Biopsies taken from the edge of colon ulcers may also be useful in identifying trophozoites, particularly with periodic acid–Schiff (PAS) stain ( Figure 39-2 ). Indications for biopsy include negative stool exams and negative serum antibodies, chronic syndrome, or mass lesions noted in a highly suspicious setting for amebiasis. Stool EIA panels are available to detect E. histolytica and E. dispar antigens with excellent sensitivity and specificity with the ability to distinguish between the two . Molecular analysis utilizing polymerase chain reaction (PCR)–based assays is also able to discriminate between the pathogenic E. histolytica and the nonpathogenic E. dispar, but this can be done only in reference diagnosis laboratories, PCR and EIA studies cannot be performed on fixed stool; the stool must be fresh or frozen.
Most patients with amebic liver abscess have neither overt intestinal symptoms nor detectable cysts or trophozoites in their stool. Suspected liver abscesses may require aspiration to exclude bacterial causes, particularly in nonendemic areas or if a patient fails to respond to standard therapy. Amebic liver abscesses contain acellular, proteinaceous debris consisting predominantly of necrotic hepatocytes and trophozoites seen on microscopy of the aspirate in less than 20% of cases. Although EIA or PCR testing of aspirated fluid may have increased sensitivity and aid in diagnosis, serologic studies are particularly useful for suspected amebic liver abscess in individuals from nonendemic regions.
Serologic EIA detects the IgG specific for E. histolytica in 95% of patients with extraintestinal amebiasis, 70% of patients with luminal infection, and 10% of asymptomatic cyst passers. Unfortunately, standard serology is difficult to interpret in endemic areas. If the EIA is negative during the acute presentation, a repeat serology testing is recommended in 1 week. If the second serology remains negative, other etiologies should be considered. EIA serology usually reverts to negative 6 to 12 months after infection is cleared, which can be useful in monitoring the response to treatment.
Treatment of amebiasis is highly effective. The importance of correct diagnosis must again be emphasized, as only about 10% of people with stools testing positive for Entamoeba by microscopy will have the pathogenic histolytica strain. The drug of choice for invasive colon or liver disease is metronidazole (or the related drugs, tinidazole and ornidazole). The recommended dosage (30 to 50 mg/kg/day three times daily to a maximum of 750 mg/dose) is three times that employed for giardiasis. The drug is absorbed extremely well from the gut, and oral therapy is usually effective. Indications for drainage of liver abscesses include diagnosis, imminent rupture (cavity greater than 10 cm in adults), or failure to respond to 72 hours of metronidazole. Recommendations for all symptomatic patients as well as asymptomatic cyst passers in developed countries include treatment with a luminal agent such as iodoquinol or paromomycin to prevent disease spread (see Table 39-1 ). Organisms that are resistant to metronidazole can be treated with nitazoxanide or tizoxanide.
Outbreaks of infection can be prevented by attention to water supplies, good handwashing, and general hygiene. As with Giardia, a very low inoculum is needed, perhaps only a single cyst. Humans and non-human primates are thought to be the only reservoirs of E. histolytica, but insect vectors such as cockroaches may contribute to spread. Because immunity to E. histolytica is related to mucosal IgA, oral vaccines are under development.
Dientamoeba Fragilis
D. fragilis is a binucleate flagellate related to Trichomonas, which inhabits the large intestine. It has worldwide distribution; infection is found most often in children, day-care center attendees, and persons with poor hygiene. It is associated with traveler’s diarrhea. Seroprevalence studies suggest that 90% of children have experienced infection by age 5 years. Most infections are asymptomatic. There is an association with pinworm infestation: patients with D. fragilis are 8 to 20 times more likely than uninfected persons to have pinworms. Experimental ingestion of pinworm ova has led to D. fragilis infection. D. fragilis DNA has been identified inside the pinwork eggs. Coinfection with Blastocystis species has also been described. Dientamoeba has only recently been shown to have a cyst form. The organism is unstable in water; gastric juice and the fragilis name refer to this fragile nature noted by early researchers. The transmission is person-to-person rather than through contaminated foods or water. Prevention is therefore achieved by good handwashing.
Symptoms of D. fragilis infestation include diarrhea (predominantly during the first or second week), abdominal pain, flatulence, and weight loss. Occasionally, mild colitis has been described that mimics allergic colitis. But D. fragilis is not known to cause invasive disease, even in the immunocompromised. Diagnosis is made by stool examination. The stool must be placed in preservative immediately to fix the trophozoite, because there is no easily identifiable cyst form of Dientamoeba . Those diagnosed should undergo evaluation for concurrent Enterobius infestation. Treatment is usually metronidazole, although iodoquinol, paromomycin, and secnidazole have also been effective.
Blastocystis Species
Blastocystis species are stramenopile protists, a group that includes brown algae and diatoms. Humans can be infected with Blastocystis hominis as well as a number of zoonotic subtypes from mammals such as pigs, rodents, primates, or birds such as chickens. Blastocystis species are common inhabitants of the human cecum and colon worldwide, with widely variable reports of prevalence from 1% to 3% in some developed countries such as Japan and Singapore, and as high as 33% to 60% in some developing countries such as Egypt, Cuba, and Indonesia. Its pathogenic role has been controversial, because some early studies demonstrated similar prevalence of infection in symptomatic and asymptomatic persons, whereas others supported a link to clinical infection with acute or chronic symptoms of diarrhea, bloating, flatulence, abdominal pain, and fatigue. A link to allergic skin disease has also been reported. There is no evidence of invasive disease. It has been hypothesized that the conflicting evidence of pathogenicity may be due to the genetic diversity of Blastocystis species and a lack of distinction between pathogenic and nonpathogenic subtypes in studies. Furthermore, as with other enteric parasites, such as Giardia, a substantial number of those infected may be asymptomatic. Several studies have shown improvement in clinical symptoms with treatment and eradication of the organism. Infection may be significant and cause chronic diarrhea in people with AIDS or other immunocompromising conditions. A possible link between B. hominis and irritable bowel syndrome has been proposed. Diagnosis can be made by stool examination, which allows for assessment of the organism burden, but culture is more sensitive. Molecular PCR-based studies are used in a research setting. Treatment is recommended in symptomatic patients if a complete workup does not identify an alternate etiology. Metronidazole is typically used for treatment; trimethoprim-sulfamethoxazole, nitazoxanide, and iodoquinol are alternatives. One small study suggested that treatment with Saccharomyces boulardii may be effective in eradicating the organism and improving clinical symptoms.
Balantidium Coli
B. coli are very large (50 to 200 µm) ciliate protozoa that may invade the colonic mucosa to induce abdominal pain, diarrhea, and frank dysentery. Fulminant colitis has also been reported. Distribution is worldwide, although most infections occur in the tropics in association with poor hygiene and contact with livestock. Swine are a major reservoir of B. coli , and farmers and slaughterhouse workers are at increased risk. Immunocompromised patients are at risk of severe or even fatal infection. Diagnosis is made by finding the characteristic large trophozoites in fresh stool. Tetracycline, metronidazole, and iodoquinol are used to treat this infection.
Cryptosporidium
Cryptosporidium organisms were described early in this century as a veterinary pathogen, but it was not until 1976 that human disease was recognized. These small protozoans are classified in the order Eucoccidiida, along with Plasmodium (malaria), Cystisospora, and Toxoplasma gondii . Cryptosporidium infect a wide variety of mammals and may complete their complex life cycle, which involves both asexual and sexual multiplication in the intestinal epithelia of one host. They are intracellular but do not enter the cytoplasm of host cells. The final product of the life cycle is the oocyst, which measures 4 to 6 µm in diameter and contains four infectious sporozoites.
With the advent of improved diagnostic testing and increased physician awareness, a great deal has been learned about the epidemiology of Cryptosporidium infection. Cryptosporidium parvum is prevalent among livestock such as cattle, pigs, and sheep and domestic pets such as kittens and puppies. C. parvum has also be found in wildlife such as rodents, geese, flies, and shellfish. The contamination of wildlife leads to continual reinfecting of water sources. Genotype analysis has shown that, as with Giardia and Entamoeba , there are numerous different subgroups. Although C. parvum and Cryptosporidium hominis are the most prevalent species causing disease in humans, infections caused by Cryptosporidium felis, Cryptosporidium meleagridis, Cryptosporidium canis, and Cryptosporidium muris have also been reported. The discovery of infection with these genotypes adds weight to the theory that human-to-human as well as zoonotic spread occurs.
Cryptosporidium is a relatively common cause of human diarrhea, accounting for up to 20% of cases in the developing world and up to 9% in the developed world. Infection may contribute to malnutrition and failure of linear growth in endemic areas. Measurement of C. parvum IgG and IgA antibodies suggests that the majority of children, even in the developed world, have been exposed to the organism, although rates vary depending on water supply. This protozoan is transmitted primarily via the fecal-oral route, although the respiratory route has also been reported. Aside from contact with animals, other known risk factors include day-care center attendance, drinking untreated and recreational waters, employment in hospitals, and immunosuppression. Prior infection offers some protection against reinfection.
Parasite replication occurs mainly in the apical border of jejunal, ileal, and colonic enterocytes ( Figure 39-3 ). Pathologic examination shows variable villus atrophy with crypt hyperplasia, usually with a mild mixed inflammatory infiltrate.
