AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Background

Although all infectious agents in humans are parasites, by convention, parasitic diseases are defined as those caused by protozoa or helminths. The old classification, in which a single phylum of protozoa encompassed all unicellular eukaryotic microorganisms, is no longer valid because of new ultrastructural and molecular taxonomic information.

For instance, Giardia lamblia has been shown to lack mitochondria and shown to contain ribosomal RNA sequences that resemble bacteria. These protozoa have been proposed to represent an evolutionary transition between prokaryotic and eukaryotic microorganisms. Both Giardia and Microsporidia (which also shares similarities with bacteria) have been reclassified as Archezoa, a term that reflects their evolutionary transitional nature. Clinicians can best classify unicellular eukaryotic microorganisms based on mode of transmission.

The classification of representative protozoa according to modes of transmission is as follows:

• Enteric transmission - Balantidium, Giardia, Entamoeba, Cryptosporidium, Toxoplasma, Cyclospora, Microsporidia
• Sexual transmission - Trichomonas
• Arthropod transmission - Babesia, Plasmodium, Leishmania, Trypanosoma
• Other modes of transmission - Naegleria, Acanthamoeba, Toxoplasma

Toxoplasma is the only pathogenic fecal-oral transmitted protozoa that has not been associated with gastroenteritis.

Among all intestinal protozoa, those listed in Table 1 have been confirmed to cause GI disease. Others, such as Trichomonas hominis (in infants) and Entamoeba polecki (associated with pigs), have rarely been associated with diarrheal disease and are not discussed in this article.

Table 1. Protozoa Associated with Intestinal Illness in Humans

Pathophysiology

Understanding the life cycle is essential to explain the pathophysiology of the diseases caused by these organisms. The life cycles of intestinal protozoa are very similar, with the exception of D fragilis, which lacks a cyst stage.

Mechanisms of diarrhea production by intestinal protozoa are related to direct cytotoxic effects, the ability to invade, and/or effects of the immune response on the intestinal epithelium. No evidence suggests that intestinal protozoa produce enterotoxins.

Entamoeba histolytica

Mature cysts are ingested via contaminated water or food. After excystation in the small intestine, trophozoites inhabit the large intestine and can either invade the tissue (pathogenic amebas) or are eliminated in the stools. Trophozoites do not survive outside the body. This parasite was named for its remarkable ability to lyse human tissues. A prerequisite to amebic invasion is the parasite's ability to colonize and penetrate colonic mucins overlying the intestinal epithelium. At least 22 amebic strains or zymodemes have been identified based on pulsed-field gel electrophoresis patterns of the 4 isoenzymes isolated from ameba. Nine zymodemes have been associated inconsistently with invasiveness.

In 1982, Sargeaunt postulated that instead of pathogenic and nonpathogenic zymodemes, 2 different amebas were present.¹ The concept of E histolytica as a pathogenic ameba and E dispar as a nonpathogenic ameba is currently accepted. Furthermore, both immunologic assays and amplification tests have been developed to distinguish these two species among symptomatic and asymptomatic patients. Upon invasion of the host, amebas are capable of killing immune effector cells by contact-dependent cytolysis, possibly by a calcium-dependent mechanism. They then disseminate to the liver or other tissues.

Giardia lamblia

After ingestion of mature cysts (infective dose varies from 10-100 cysts) via contaminated water or food, the trophozoite emerges in the small intestine, rapidly multiplies, and attaches to the small intestinal villi. Mature infective cysts pass in feces and complete the cycle. The pathogenesis of diarrhea in giardiasis is thought to be related to the following factors: (1) the number of organisms ingested, (2) specific strain ingested, (3) nonantibody protective factors in the GI tract, and (4) the immune response of the host.

Giardia trophozoites attach to the cell surface of villi by means of a disk on their posterior or ventral surface. Lectin, a protein on the trophozoite lining, recognizes specific receptors on the intestinal cell and may be partly responsible for the tight attachment between the parasite and the villi, which is followed by mucosal damage, mechanical obstruction (only caused in the presence of numerous organisms), and deconjugation of bile salts. Recent data has indicated that inflammatory mast cells may interfere with duodenal growth of G lamblia trophozoites.² Other inflammatory cells, as well as CD8+ T cells, contribute to villus-shortening and crypt hyperplasia.

Strains that infect humans are biologically diverse, as shown by differences in antigens, restriction endonuclease patterns, DNA fingerprinting, isoenzyme patterns, and pulsed-field gel electrophoresis patterns.

In giardiasis, secretory immunoglobulin A (IgA) is presumed to be important in host protection because invasion of the mucosa is not part of the pathogenic mechanism.

Spore-forming protozoa

Spore ingestion begins a life cycle that is similar in all 4 of the intestinal spore-forming protozoa (see Table 1). The ingested spores release sporozoites that invade enterocytes, primarily in the small intestine. The enterocyte infection progresses through 2 stages: merogenic and sporogonic.

The merogenic (or schizogonic) stage involves the maturation and development of meronts to reproduce and multiply in the infected cell or to infect other enterocytes. This asexual stage allows the infection to spread to many enterocytes, even if the host is not exposed repeatedly to the organism.

The sporogonic (ie, gametogonic, sexual) stage involves the maturation and development of sporozoites enclosed in cysts or spores. As the infected enterocytes die, cyst or spore shedding occurs. The spores are then excreted in the stool. The spore-forming protozoa are obligate intracellular pathogens. Infection by these protozoa has been associated with substantial alterations in intestinal structure and function, but the pathogenesis of the predominant symptom, diarrhea, is not completely understood.

Cryptosporidiosis is the best-studied spore-forming diarrhea, and its pathogenic mechanisms can also be related to other spore-forming protozoa. The hypothesized sequence of events is explained below.

After invasion of the enterocytes, the epithelial cells release cytokines. These cytokinins activate phagocytes and recruit new leukocytes, which, in turn, release soluble factors (resulting in intestinal secretion of chloride and water) and inhibit absorption. Enterocyte damage may be a direct consequence of parasite invasion, multiplication, and extrusion. Regardless of the specific mechanism, marked distortion of the villus architecture is accompanied by nutrient malabsorption and osmotic diarrhea. With the exception of the microsporidia S intestinalis, none of the spore-forming protozoa have the ability to invade beneath the mucosal layer of the intestine.

Dientamoeba fragilis

The exact mode of transmission of D fragilis has not been confirmed. This parasite is speculated to be transmitted when pinworm eggs containing D fragilis trophozoites are ingested and, by this mechanism, resist the acid pH in the stomach. It is not invasive and mostly inhabits the large intestine. The exact mechanisms of diarrhea are not known.

Balantidium coli

The cyst is the infectious stage and is acquired by ingestion of contaminated food or water. After excystation in the small intestine, the trophozoites colonize the terminal ileum and the large intestine. They can then invade tissues by mechanical action of ciliary movement and the secretion of hyaluronidase and probably other enzymes. Encystation occurs in the lumen of the colon or in freshly evacuated stools. As with E histolytica, invasiveness is the hallmark of the pathophysiology of balantidiasis.

Blastocystis hominis

Many experts believe that B hominis is pathogenic only when present in large numbers in the intestine (>5 organisms per 400X field) and when other infectious organisms are absent. Three distinct morphologic stages are recognized: vacuolar, granular, and ameboid. B hominis inhabits the large intestine and has no evident life cycle in humans. Cysticlike stages are rare and have been found in patients with acquired immunodeficiency syndrome (AIDS) and in vitro. The mechanisms of how this parasite causes illness have not been elucidated yet.

Frequency

United States

At least 325 water-associated outbreaks of parasitic protozoan disease have been reported.³ North America and Europe accounted for 93% of all reports, and nearly two thirds occurred in the United States. G lamblia and C parvum account for most outbreaks (40.6% and 50.8%, respectively), followed by E histolytica and C cayetanensis (1-3% each), and, less frequently, (£1%) by I belli, B hominis, and B coli.

• Amebiasis: E histolytica is not endemic in the United States, but travelers to high-risk areas where amebiasis is endemic may acquire the infection during their travel. Prevalence of amebiasis has increased in the southwestern United States as a result of emigration from Mexico.
• Giardiasis: Rate of prevalence varies from 3-13%. Giardiasis is one of several causes of traveler's diarrhea. Person-to-person transmission is associated with groups that exercise poor fecal-oral hygiene, such as children in childcare centers, male homosexuals, and institutionalized individuals. G lamblia is endemic in childcare centers and can be detected in approximately 20% of asymptomatic children. The attack rates of G lamblia during outbreaks in childcare centers range from 20-50%
• Spore-forming protozoa
• • The epidemiology of the intestinal spore-forming protozoa is not fully understood. Work in this area has been hampered by a lack of complete surveillance and widespread serologic surveys.
  • The generally quoted prevalence of cryptosporidia in stool specimens is 1-3%. C parvum is highly transmissible in the family setting, is one of many causes of traveler's diarrhea, and is associated with diarrhea outbreaks due to contaminated water supplies and in childcare centers, with attack rates that vary from 33-73%. New studies have provided more information regarding Cryptosporidium transmission.⁴ C hominis is spread only between humans; however, the major reservoir for C parvum is domestic livestock (predominantly cattle), and direct contact with infected cattle is a major transmission pathway along with indirect transmission through drinking water.
  • Isospora belli, which is less common than cryptosporidia, is endemic in many developing countries, with a lower prevalence in the United States. Even in the United States, sporadic outbreaks have occurred in mental institutions and childcare centers.
  • The epidemiology of human microsporidia is less understood. Widespread distribution of E bieneusi in Europe, North America, and South America led to the suggestion that this organism may be common in immunocompetent individuals but causes disease only in those with immunocompromise.
  • A report from Massachusetts showed that Cyclospora may cause community-acquired diarrhea in otherwise healthy persons.⁵ Fecal-oral transmission through infected water caused an epidemic of cyclosporidiosis in Chicago.⁶
  • All 4 spore-forming protozoa are frequent pathogens in individuals with human immunodeficiency virus (HIV) infection. Cryptosporidia are found in the stools of 10-20% of patients with AIDS-associated diarrhea. Microsporidia are associated more commonly with chronic diarrhea in patients with AIDS than are cryptosporidia, and prevalence ranges from 6-50%. The frequency with which cryptosporidia and microsporidia are identified in the stools of patients with AIDS is related to the CD4 count (identification is more frequent when the CD4 count is <100 cells/mL) and the presence of GI symptoms. Isospora are associated infrequently with AIDS-associated diarrhea in the United States and Europe (about 2%), and Cyclospora has been observed occasionally in patients with AIDS.
• D fragilis: The exact frequency of dientamoebiasis is not known.
• B coli: Sporadic infections have been reported in facilities for the handicapped, where poor conditions of personal hygiene prevail.
• B hominis: Surveillance data from clinical microbiology laboratories report prevalence rates in the range of 10-18%, but frequency of the disease is extremely low.

International

• Amebiasis: An estimated 10% of the world's population is infected with E histolytica, the highest prevalence is in developing countries with the lowest levels of sanitation. This results in 50-100 million cases of colitis or liver abscesses per year and up to 100,000 deaths annually.
• Giardiasis: G lamblia is the most commonly isolated intestinal parasite throughout the world. Rates of 20-40% are reported in developing countries, especially in children.
• Spore-forming protozoa: All of these organisms may be common worldwide, and their frequency may be related to the adequacy of sanitation. In general, the infections are more common in developing countries. Prevalence of cryptosporidia in Asia and Africa ranges from 5-10%, but antibodies to cryptosporidia have been found in 32-58% of adults. Isospora and Cyclospora are endemic in many parts of Africa, Asia, and South America. The prevalence rates among patients with AIDS are higher in developing countries than in the United States, possibly because of the common use of prophylactic trimethoprim-sulfamethoxazole and/or underlying low prevalence in the United States.
• D fragilis: Data on the prevalence of this parasite are inadequate. Based on a few surveys, estimates among the general population in developed countries range from 2-4%. Much higher rates are observed among travelers and in institutions or crowded living groups in which hygiene is inadequate. Incidence of this parasite in a large series in Canada was 1-19% with a prevalence of 4%. A high frequency of concomitant infection with pinworms suggests that it is transmitted through the eggs of Enterobius vermicularis. D fragilis has infected 9% of children in childcare centers and 4% of childcare center providers. In a study performed in Belgium, D fragilis was associated with 6.3% of diarrhea cases among 448 patients.⁷
• B coli: Infections are rare in humans, and approximately 25% of symptomatic patients have a history of contact with swine. B coli is uncommon in temperate climates, and it is found in association with pigs throughout the tropics, especially in the Philippines.
• B hominis: This parasite is distributed throughout the world. Prevalence rates of 54% and 33% have been reported in Papua New Guinea and Nepal, respectively. In children, prevalence rates vary from 2% in Kuwait to 65% in Papua New Guinea. Studies performed in Africa have shown that B hominis could be a major cause of diarrhea in areas associated with deficient sanitation and low hygiene standards.⁸ Furthermore, in a study done in Turkey, children with B hominis had a lower growth status compared with children with negative stool sample findings for any parasite.⁹

Mortality/Morbidity

• Amebiasis: Estimates suggest that almost 500 million people in the world are carrying E histolytica. Roughly 50 million people develop invasive disease each year, and 50,000-100,000 people die of amebiasis each year, resulting in a mortality rate of 1 in 500-1000 diagnosed cases. This makes amebiasis the third most common cause of death due to parasites worldwide, behind malaria and schistosomiasis; however, among patients with illness severe enough to require hospitalization, the case-fatality ratio is higher. One small study in children reported a 9% mortality rate and a 27% morbidity rate. Liver abscesses and resultant complications account for approximately 40% of deaths from amebiasis, followed in frequency by invasive colitis and associated complications.
• Giardiasis
• • Giardiasis occurs worldwide and is the most common parasite identified in stool specimens in the United States.
  • Longitudinal prospective studies, in which stool specimens were collected either weekly or monthly for one year, showed that 33-37% of children who were observed became infected. In these studies, most infections were asymptomatic. During outbreaks of diarrhea in which G lamblia was implicated as the etiologic agent, attack rates ranged from 17-54%.
  • Although self-limited diarrheal disease is the most frequent symptomatic manifestation of Giardia infection, prolonged diarrhea with malnutrition and growth failure in infancy are occasional complications.
  • A study performed by the Centers for Disease Control and Prevention (CDC) in the United States showed that the rate of hospital admissions for giardiasis (2 per 100,000 population) rivaled those for shigellosis (2.4 per 100,000 population). Typically, giardiasis is not associated with mortality, even in patients with immunocompromise.
• Spore-forming protozoa: Based on studies done in the past, in which antibodies to cryptosporidia have been found in 32-58% of adults with much lower prevalences in stool specimens (1-10%), the presumption is that the morbidity rates associated with cryptosporidiosis in immunocompetent patients is low, although it is higher in outbreaks. Mortality is rare in this group of patients. The same can be said with other spore-forming protozoa, although their epidemiologies are less well known. All 4 intestinal spore-forming protozoa have much higher morbidity rates in patients with AIDS. In cases of cryptosporidiosis and microsporidiosis, presence of disease is intimately related to low CD4 counts and associated with higher mortality rates.
• Dientamoebiasis: The exact morbidity rate is not known but is presumably very low. Practically no mortality is associated with this parasitosis.
• Balantidiasis: Currently, precise information about exact morbidity and mortality rates of balantidiasis is lacking. A study performed in Amerindian populations of Amazonia found both a low prevalence of the disease and absence of symptoms or signs referable to this organism.¹⁰ The nutritional state and the immune status of the host have been mentioned as important factors in determining parasitic invasion through the intestinal wall. Fatal cases have been reported in malnourished and immunocompromised hosts.
• Blastocystosis: The exact morbidity rate is unknown, and whether this parasite is really a human pathogen is debatable. The isolation of this parasite with diarrhea in patients with renal transplants and other immunodeficiencies is correlated. Practically no mortality is associated with this parasitosis. Most individuals with AIDS and blastocystosis have spontaneous resolution of symptoms or successful identification of other infectious or noninfectious etiologies.

Race

Prevalence of intestinal protozoal disease is not associated with racial background. One study performed in Mexico demonstrated an increased frequency of HLA-DR3 and complotype SCO1 in mestizo children with amebic liver abscess.¹¹

Sex

A person's sex is neither a predisposing nor a protective factor for protozoal-associated diarrhea; however, amebic liver abscess is observed more frequently in men than in women (with male-to-female ratios of up to 10:1). The reason for this is unknown, although speculations regarding protective roles of estrogens versus invasiveness have been postulated.

Age

• Amebiasis: Elderly patients and pregnant women have more severe symptoms with amebiasis. Dysenteric amebiasis in young infants, although relatively uncommon, is associated with high morbidity rates. Liver abscess is more common in adolescents and adults. Invasive disease is much less common in young children than in adults, possibly because ingestion of contaminated food with E histolytica in this age group is less frequent.
• Giardiasis: Infection is more common in children than in adults, except in epidemics, in which all age groups are equally affected. Infants younger than 12 months are less likely to be infected than older children.
• Spore-forming protozoa: Studies performed with cryptosporidia have shown a higher rate of oocyst excretion in children younger than 3 years. In Peru, cryptosporidium and Cyclospora infections occurred at the same time of year and primarily affected children aged 1-2 years. Attack rates in patients with AIDS are very high in both pediatric and adult populations.
• Dientamoebiasis: As mentioned before, this parasite has infected 9% of children in childcare centers and 4% of childcare center providers, which is probably related to fecal-oral transmission. Presumably, these protozoa infect children more frequently than adults, but this issue still needs to be examined. Exact estimates are difficult because of the high frequency of asymptomatic excretion.
• Balantidiasis: Pigs are the main source of infection for humans; therefore, this infection is expected to be more frequent in older children, adolescents, or adults than in young infants.
• Blastocystosis: No available data indicate that this disease has higher prevalence in any age group.

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

History

The spectrum of intestinal protozoal infections can range from asymptomatic to invasive disease (in the cases of E histolytica or B coli) to severe and/or chronic and protracted diarrhea (in the cases of giardiasis or in individuals who are severely immunosuppressed with spore-forming protozoal infections).

• Amebiasis
• • Noninvasive intestinal infection: Noninvasive amebiasis most frequently produces no symptoms. Nevertheless, some patients may have some ill-defined GI tract symptoms. These symptoms include alternating periods of mild diarrhea and constipation with or without mild abdominal pain; however, for the most part, patients tolerate the infection.
  • Intestinal amebiasis or amebic colitis: Patients typically have 1-3 weeks of diarrhea to grossly bloody dysenteric stools with abdominal pain. Constitutional symptoms are often mild, and fever is present only in about 10-20% of cases; however, weight loss is common. Some patients manifest chronic nondysenteric diarrhea, combined with months or even years of abdominal pain associated with varying amounts of flatulence, mucus in stools, and weight loss.
  • Acute fulminant or necrotizing colitis: This presentation occurs in only 0.5% of intestinal amebiasis cases and has been associated with patients inappropriately treated with corticosteroids. The patient develops sudden constipation following an acute and severe episode of dysenteric diarrhea that is followed by signs of shock.
  • Ameboma: This is a mass of granulation tissue in the cecum or ascending colon, and it usually occurs in fewer than 1% of patients with intestinal amebiasis. Concurrent amebic dysentery is present in two thirds of patients. Patients usually report a tender, palpable, lower-left quadrant abdominal mass.
  • Liver abscess: This occurs in 10% or fewer patients with invasive E histolytica infections. Patients usually have a history of more than 1-2 weeks of fever, abdominal pain, poor appetite, and, less commonly, cough and pleuritic chest pain. Liver abscess is associated with diarrhea only in 20% of cases. Jaundice occurs only in severe cases.
• Giardiasis
• • Following excystation and colonization, a spectrum of clinical manifestations can occur. Symptomatic infections are noted more frequently in children than in adults.
  • Asymptomatic excretion: The asymptomatic carrier rate of G lamblia in the United States is estimated to be 3-7% but is as high as 20% in southern regions and possibly even higher in children attending childcare centers. In endemic giardiasis, most infections produce no symptoms.
  • Acute infectious diarrhea: Infections resulting from waterborne outbreaks and infections in travelers and among children in childcare centers are associated more often with significant illness. Most patients have symptoms within 10 days of exposure, and more than 90% of patients have symptoms within 3 weeks. The usual symptoms are short-lasting acute diarrhea (with or without low-grade fever), nausea, abdominal distension, greasy stools, and anorexia. Acute giardiasis may spontaneously resolve. Parasites disappear from the stools within 4-6 weeks in both experimental and naturally acquired infections; however, giardiasis can sometimes occur as intermittent diarrheal episodes and/or evolve to chronic diarrhea, anorexia, bloating, and weight loss.
  • Chronic diarrhea: Chronic giardiasis is usually associated with intermittent, loose, foul-smelling stools that resemble those of malabsorption states. Abdominal distension, sulfurous belching, flatulence, epigastric pain, substernal burning, nausea, anorexia, and failure to thrive may occur. Although severe forms of chronic giardiasis may occur in otherwise healthy individuals, they are common in patients with hypoglobulinemia, particularly IgA deficiency in association with lymphoid hyperplasia of the bowel. Chronic giardiasis may contribute to protein-energy malnutrition in children. Protein-losing enteropathy has also been described. Intestinal disaccharidase deficiency associated with giardiasis can be manifested by carbohydrate intolerance, especially lactose. Evidence suggests that giardiasis may be associated with chronic urticaria, gallbladder disease, and treatment failures because of malabsorption of antibiotics during episodes of otitis media.
• Spore-forming protozoa
• • Asymptomatic infections: Asymptomatic infection is part of the clinical spectrum of disease produced by these parasites. Asymptomatic infections with cryptosporidia occur in normal and immunodeficient hosts. Some data suggest that asymptomatic carriage of microsporidia in patients with AIDS may precede wasting and diarrheal illness. In one study, only 11-18% of immunocompetent Peruvian children with acute cyclosporal infections had diarrhea.¹² The reported frequency of asymptomatic infection is controversial, especially with microsporidia, Isospora, and Cyclospora. The link between infection and clinically apparent disease is strong; however, the frequency that asymptomatic infection is identified depends on the sensitivity of the assay used to detect the parasite.
  • Acute infectious diarrhea in immunocompetent hosts: Acute diarrhea in immunocompetent hosts has been shown to be a predominant clinical manifestation of infection with these parasites, except for microsporidia (only one case of microsporidial diarrhea has been reported in a normal host).
  • • In a study developed in Austria, the correlation between detection of microsporidia in stool and GI symptoms was transient, suggesting that microsporidia infection may cause clinical symptoms during the early stages of infection that resolve even though the microsporidia persist.¹³ Many studies report acute diarrhea in infants and children living in underdeveloped countries, medical personnel, travelers, and persons in institutions.
    • In March 1993, the municipal water supply in Milwaukee became contaminated with cryptosporidia, and an estimated 403,000 residents developed diarrhea.¹⁴ In normal hosts, infections by cryptosporidia, Cyclospora, and Isospora are characterized by 3-25 days of diarrhea, malaise, abdominal pain with or without nausea, vomiting, and fever. However, studies performed in the United Kingdom have shown that cryptosporidiosis can cause recurrence of gastrointestinal symptoms in as many as 40% of immunocompetent patients (more with C hominis than with C parvum), and all episodes have been self limited.¹⁵ Giving specific treatment to immunocompetent patients with cryptosporidiosis is still not well supported.
  • Disease in immunodeficient hosts
  • • All spore-forming protozoa have a predisposition for more frequent and prolonged infections in patients who are immunodeficient. Most reported cases are in patients with AIDS, but reports document severe cryptosporidia infections in patients with renal transplantation and persons with IgA deficiency. Isosporiasis has been reported in persons with cancer.
    • The symptoms range from asymptomatic infection to severe life-threatening diarrhea, dehydration and chronic malabsorption leading to lethargy, failure to thrive, and malnutrition.
    • The clinical features of 128 patients with AIDS-related cryptosporidiosis showed the following 4 patterns of disease: transient (29%), chronic (60%), fulminant (8%), and asymptomatic (4%).¹⁶
    • As mentioned above, more severe cases of cryptosporidiosis and microsporidiosis are observed in patients with AIDS who have very low CD4 counts (<50-100/mL). A similar spectrum of disease severity is seen in AIDS-related intestinal infection with Cyclospora and Isospora.
    • HIV-wasting syndrome is a well-established clinical syndrome in patients with AIDS characterized by chronic diarrhea, chronic weakness, and/or documented fever. The physiopathogenesis of this syndrome is multifactorial, from hypermetabolism, decreased oral intake, and cytokine dysregulation, to the coparticipation of various pathogens in which spore-forming protozoa are included.
    • The advent of highly active antiretroviral therapy (HAART) has decreased the frequency and severity of cryptosporidiosis in HIV infected individuals. Recovery of CD4 with HAART has resulted in resolution of chronic diarrhea in many patients.
  • Extraintestinal disease: The primary location of all intestinal spore-forming protozoal infections is the small intestine, predominately the distal small bowel. Colonic infection is common with microsporidiosis. Infection in the biliary tract has been reported with cryptosporidium, Isospora, and microsporidia leading to right upper quadrant abdominal pain, occasionally with jaundice and fever. Invasion by S intestinalis beneath the epithelial surface and dissemination to the liver, respiratory tract, or the kidney has been reported. The other intestinal microsporidia E bieneusi has also been isolated from the lungs in individuals with AIDS.
• Dientamoebiasis
• • Symptoms commonly associated with D fragilis infection include abdominal pain, diarrhea, anorexia, nausea, vomiting, and flatulence. Bloody stools are not observed. In a study in Belgium of 448 patients with diarrhea, D fragilis was found in 6.3%, and G lamblia was found in 7.1%.⁷ Both parasites caused diarrhea and abdominal pain, but D fragilis was less frequently associated with nausea, vomiting, and weight loss.
  • Less common symptoms include fever, weight loss, and fatigue.
  • Diarrhea usually lasts 1-2 weeks, whereas abdominal pain can persist for 1-2 months. Because of its very high association with pinworms, some patients can also manifest anal pruritus, lower urinary tract infection (particularly young girls), or both.
• Balantidiasis
• • Most infections with B coli are asymptomatic; however, some patients experience an acute or chronic illness.
  • When acutely affected, the patient has diarrhea with stools containing abundant mucus and blood. Patients may also have concurrent nausea, vomiting, tenesmus, and intestinal colic, resembling an amebic colitis.
  • In most patients, recovery occurs without treatment; however, in some patients, especially those who are malnourished or immunodeficient, the course can be fulminant and fatal. Usually, the course is long term with episodes of intermittent diarrhea and constipation, with or without abdominal pain, anorexia, weight loss, and weakness.
  • Patients may present with an appendicitislike illness, and, in some patients, amebomalike presentations occur.
  • Extraintestinal infection is rare.
• Blastocystosis
• • Many experts believe that B hominis is pathogenic only when present in large numbers, but some studies have shown that the quantity of the parasite is not predictive of the presence (or severity) of the disease.
  • The association of this protozoa with traveler's diarrhea and disease in the normal host is controversial. A study developed in Egypt found high concentrations of B hominis in symptomatic patients compared with asymptomatic patients, suggesting that blastocystosis may be an uncommon cause of gastroenteritis and travelers diarrhea; however, convincing information suggests that B hominis causes diarrhea in immunosuppressed patients, such as patients with renal transplants and AIDS.¹⁷
  • The most common symptoms associated with infection include abdominal discomfort, diarrhea, flatulence, and sometimes fever and bloating. A study done in Turkey showed an association between lower anthropometric indexes and B hominis infection.⁹

Physical

• Amebic or balantidic colitis
• • Most patients have nonlocalized abdominal tenderness, and one third of patients have fever (usually low-grade fever).
  • Signs of dehydration are rare with these pathogens, although they can be present in young infants.
  • An ameboma can be palpated on the lower right abdominal quadrant, and it is usually tender and mobile.
  • Patients with acute or fulminant colitis present with severe abdominal pain, distension, and rebound tenderness, with or without fever.
  • The patient may also present with signs of shock.
  • In patients with amebic liver abscess, tender hepatomegaly is present in almost 100% of cases, and fever is present in 80-90% of cases, with or without hypoventilation of the lower right lung. Peritoneal signs and jaundice are unusual but, when present, are signs of severe disease.
• Giardiasis
• • In children younger than 5 years, acute giardiasis can be complicated by signs of dehydration that may lead to hospitalization. However, these events are not as prominent as with other enteropathogens, such as rotavirus or enterotoxigenic bacteria.
  • Signs of chronic giardiasis are more subtle. The patient may show some degree of protein-energy malnutrition, with a distended abdomen but no other pathognomonic signs.
• Spore-forming protozoa
• • In immunocompetent patients, clinical findings are no different than the findings associated with giardiasis.
  • Signs of dehydration are unusual but can occur.
  • In immunodeficient hosts, especially patients with AIDS, diarrhea has been associated with accompanying signs of protein-energy malnutrition and even signs of hypokalemia with or without hyponatremia.
  • Some patients with acute exacerbations can also manifest acute dehydration with or without metabolic acidosis.
• Dientamoebiasis and blastocystosis
• • Clinical findings of dientamoebiasis and blastocystosis are no different than those found with acute giardiasis, although signs of dehydration are less frequent.
  • Some immunosuppressed patients with blastocystosis may present with signs of malnutrition, but these observations can be more attributable to their underlying disease than to the parasitosis itself.

Causes

• For all intestinal protozoa, fecal-oral transmission is the primary route of transmission.
• Water and/or food contamination contributes to most, if not all, individual cases and outbreaks.
• Immunologic factors, such as IgA and T-cell responses, are important for giardiasis and spore-forming protozoa.
• Malnutrition is an important risk factor for susceptibility to all protozoa.
• Swine are, by far, the most important reservoir for balantidiasis.
• Dientamoebiasis is frequently associated with pinworm co-infection.

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Other Problems to be Considered

Gastroenteritis, Viral

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• For all protozoa-related gastroenteritis, direct observation of the parasite from stools is the confirmatory diagnostic method. Morphologic characteristics and laboratory techniques for observation of the protozoa are listed in Table 2.
• Table 2. Laboratory Procedures for Identification of Intestinal Protozoa

  Organism	Size (mm)	Stain Used	Other Tests
  E histolytica	Trophozoite: 10-60 Cyst: 10-20	Wet mount,* trichrome, periodic Schiff	Enzyme-linked immunosorbent assay (ELISA)
  G lamblia	Trophozoite: 9-21 Cyst: 7-12	Wet mount,* trichrome, hematoxylin, Lugol	ELISA*
  C parvum	2-5	Modified acid-fast,* auramine-rhodamine, Sheafer method	ELISA*
  I belli	30x12	Wet mount,* modified acid-fast*	None
  C cayetanensis	8-10	Modified acid-fast,* wet mount	Electron microscopy
  Microsporidia	1-2	Modified trichrome*	Electron microscopy, fluorescence methods, small intestine biopsy
  D fragilis	7-12	Iron hematoxylin,* trichrome*	None
  B. coli	50-200	Wet mount,* concentration techniques	None
  B hominis	5-30	Trichrome,* iron hematoxylin*	None

  *Preferred screening test in clinical settings.
• Amebiasis
• • Amebic colitis
  • • The diagnosis of amebic infection requires examination of stools passed on 3 separate occasions. These tests include a wet preparation (must be performed within 30 min of collection) to identify motile trophozoites and a formalin-ethyl acetate concentration step to identify amebic cysts and trophozoites.
    • E histolytica is indistinguishable from the noninvasive and more prevalent E dispar, with the exception that E histolytica trophozoites may contain ingested RBCs. An ELISA test for E histolytica antigen in stools can also be used and will soon be commercially available. E histolytica can be cultured for research and susceptibility purposes (especially for emetine susceptibility) but does not contribute to diagnostic purposes.
    • As mentioned before, techniques using both ELISA and polymerase chain reaction (PCR) have been tested to distinguish between E histolytica from E dispar (nonpathogenic); however, these tests have been used only for epidemiological purposes.
  • Amebic liver abscess: For amebic liver abscess and extraintestinal illness, serologic tests are the diagnostic hallmark. An indirect hemagglutination assay titer higher than 128 or ELISA titer higher than 40 U have more than 99% and more than 95% specificity, respectively. Abscess aspiration is no longer considered useful as a diagnostic tool because it is an invasive procedure. Usually, trophozoites are attached to the abscess wall and cannot be observed in the abscess fluid, and serologic tests are extremely sensitive and specific.
• Giardiasis
• • Use of polyclonal antisera or monoclonal antibodies against Giardia-specific antigens is improving diagnostic testing. ELISA has been used for G lamblia antigen in stool, with sensitivities of 92-98% and specificities of 87-100%. This is currently the laboratory procedure most commonly used in clinical settings.
  • No single method appears to detect every infection with G lamblia. In general, specimens should be examined within 1 hour after being collected or should be preserved in polyvinyl alcohol or 10% formalin. The following tests are generally available:
  • • Fecal examination (for both trophozoites and cysts) - Direct, wet preparation in saline with/without iodine; trichrome stained slides; formalin-ethyl-acetate concentration method; ELISA
    • When giardiasis is suspected and 5 stool specimens are negative, duodenal or upper jejunum aspiration should be performed. This can be accomplished by duodenal drainage by intubation, mucus collected by the Entero-test capsule (a weighted length of nylon yarn is introduced into the duodenum in a gelatin capsule), or by endoscopy.
  • Appropriately conducted direct examination of stools establishes the diagnosis in up to 70-85% of cases after 2 examinations.
  • The main reason for failure to identify G lamblia is the use of medications such as antibiotics, antacids, and other medications that can distort protozoal morphology. Radiographic examinations with contrast material may also distort morphology. Intermittent excretion of the parasite, improper specimen collection, and inadequate training of the observer also contribute to the difficulty in identifying the organism.
• Spore-forming protozoa
• • Specific diagnosis of these parasites depends on stool examination. Table 2 shows the stains recommended for adequate visualization of spores or oocysts in stool samples.
  • The modified acid-fast stain can be routinely used to visualize the oocysts of cryptosporidium, Cyclospora, and Isospora in stool or duodenal aspirate.
  • Differentiating these 3 organisms requires expertise. The sensitivity of the acid-fast stain is low, with approximately 30% sensitivity for cryptosporidiosis after 1 sample, but the diagnostic yield increases by examining multiple specimens. Enhanced sensitivity can be obtained by concentrating oocysts with various techniques, such as the Sheafer method or, for cryptosporidium, by using the monoclonal antibody-based immunofluorescent stain.
  • An ELISA test for cryptosporidium also is available.
  • The first step in diagnosing intestinal microsporidia is to examine the stool specimen using the modified trichrome stain. The spores are usually very small and can be misinterpreted as fecal debris. An available nonspecific fluorescence method may enhance speed and sensitivity.
  • Small intestine biopsy with visualization by electron microscopy is the only method that differentiates between E bieneusi and S intestinalis. For microsporidiosis, a PCR technique has been successfully used to identify a spore-shedding pattern of E bieneusi in asymptomatic children; however, this test is not available for clinical use.
• Dientamoebiasis
• • Examination of the stools by properly trained personnel is essential.
  • Permanent stained slides from freshly passed feces or from specimens preserved in polyvinyl alcohol are essential for the diagnosis because this parasite does not have a cystic phase.
  • Examination of 3 specimens has a diagnostic yield of 70-85%, but the diagnostic yield increases to 90-100% after 10 specimen collections.
• Balantidiasis
• • B coli is shed irregularly, and repeated examinations of stools are necessary for identification.
  • As in amebiasis, a wet preparation using saline can be useful for the identification of trophozoites if the examination is performed immediately after stool sample collection.
  • Concentration techniques are useful for identification, but the parasite does not stain well on permanently stained smears.
• Blastocystosis: This organism remains intact after concentration of stool for examination by wet mount or by using trichrome or iron hematoxylin permanent-stained smears.

Imaging Studies

• In general, imaging studies do not contribute to the etiologic diagnosis of intestinal protozoal infections, but these studies may be helpful in some situations.
• • Amebic colitis: In cases of necrotizing colitis, plain abdominal radiography can reveal air-fluid levels in the intestine, radiologic signs of mucosal edema, and/or evidence of perforation.
  • Ameboma: It typically appears as single or multiple apple core lesions on barium enema findings.
  • Amebic liver abscess: Chest radiography reveals an elevation of the right hemidiaphragm, with or without atelectasis and pleural effusion, in 70-80% of cases. In complicated cases, patients may have lung infiltrates, pericardial effusions, or both. Ultrasonography, CT scanning, or MRI are equally sensitive in revealing liver abscesses, but ultrasonography is the imaging study of choice because of a much lower cost. Amebic liver abscesses disappeared on ultrasonographic findings in one to two thirds of cases following 6 months of therapy.
• For the other intestinal protozoa, imaging studies are not usually necessary for diagnosis. For some parasites, such as G lamblia, contrast-based studies are contraindicated because of potential morphologic disruption for microscopic analysis.
• In cases of severe balantidiasis, plain abdominal radiography can be useful to rule out the possibility of other causes of acute and severe abdominal pain. In some cases of giardiasis, edema and segmentation of the small intestine can be observed.

Other Tests

• For some parasites, axenic cultures can be obtained for research purposes. They are not needed for diagnosis.
• Serologic tests are used only for epidemiological surveys, with the exception of invasive amebiasis.
• For most spore-forming protozoals, molecular assays, such as reverse transcriptase (RT)-PCR, have not shown a significant superiority when compared with staining methods as standard diagnostic tools.

Procedures

• Endoscopic evaluation is useful in patients with chronic and/or severe giardiasis and spore-forming parasitosis.
• Macroscopic inspection and histologic evaluation are necessary for diagnosis.
• Colonoscopy is useful for the diagnosis of chronic colitis due to either E histolytica or B coli. It is also helpful for the diagnosis of an ameboma. The colonic mucosa usually appears hemorrhagic, with discrete shallow-based ulcers that have raised edges.
• Endoscopic studies are also useful to differentiate these diseases from other pathologic conditions, such as pseudomembranous colitis, Crohn disease, and many others.

Histologic Findings

Histologic evaluation is not indicated routinely. Usually, biopsy specimens are collected only when the parasite has not been observed by routine laboratory techniques or when the presence of other pathologic conditions needs to be ruled out.

• Amebiasis: Biopsy specimens from the margin of colonic ulcerations are the most rewarding. Special stains, such as periodic acid-Schiff, are used to visualize E histolytica in the biopsy specimen.
• Giardiasis
• • Duodenal biopsy represents the optimal method for diagnosing giardiasis and should be considered in patients with characteristic clinical symptoms, negative stool and duodenal specimens, and one of the following: abnormal radiographic findings (eg, edema and segmentation of the small intestine), abnormal lactose tolerance test, absent secretory IgA, hypogammaglobulinemia, or achlorhydria.
  • When a small-bowel biopsy is obtained, a touch preparation stained with Giemsa should be performed in addition to routine histology. The pathology can be assessed to detect spruelike lesions that may occur with G lamblia or with other conditions, such as gluten-sensitive enteropathy. Searching for trophozoites is necessary, mainly because they may be difficult to recognize. Commonly, a disruption of the brush border of the epithelium is observed in association with giardiasis.
• Spore-forming protozoa
• • Both cryptosporidia and Isospora are easily observed in intestinal biopsy specimens with routine light microscopy, but many patients whose stools test positive for these organisms may have duodenal biopsy specimens that test negative.
  • Cyclospora have not been observed with light microscopy in duodenal biopsy specimens, but, in one study, electron microscopy showed the organisms. Small-bowel biopsy may be more sensitive than stool examination for the diagnosis of intestinal microsporidiosis. Hematoxylin and eosin stains are adequate in most cases, but other stains, such as Warthin-Starry, Giemsa, toluidine blue, and Gram, can be used.
  • The histologic spectra of spore-forming protozoal infection can vary from normal to villus shortening or flattening, crypt hyperplasia, and increased number of leukocytes in the lamina propria and epithelium. Invasion and ulceration do not occur, with the exception of the microsporidia S intestinalis. Microsporidia typing is done by the morphologic appearance on electronic microscopy of biopsy specimens.
• Other protozoa: Indications for intestinal biopsy or pathognomonic pathologic lesions are not described for dientamoebiasis and blastocystosis. In balantidiasis with chronic colitis, colonoscopy with biopsy can reveal similar histologic findings as in amebiasis, and identification of the parasite is diagnostic.

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical Care

• The most important aspect of providing care for children with diarrhea caused by intestinal protozoa includes standard pediatric assessments.
• Evaluate the child for signs of dehydration, including tachycardia, delayed capillary refill, decreased tears, decreased activity, decreased urine output, and altered mental status.
• Hypovolemic shock rarely occurs with these infections but must be recognized.
• The child must be evaluated for the adequacy of the nutritional status. This is particularly important in cases of chronic diarrhea and possible immunodeficiency.
• Weight must be measured and compared on the growth curve. Appropriate interventions occur following this immediate assessment.
• Oral rehydration therapy (ORT) is the preferred approach for children with mild-to-moderate dehydration. Intravenous rehydration should rarely be necessary. Current recommendations for pediatric rehydration are outlined best in The Management of Acute Diarrhea in Children: Oral Rehydration, Maintenance, and Nutritional Therapy.¹⁸
• Following immediate fluid resuscitation for dehydration, the clinician must address potential nutritional issues and provide adequate nutrition to the child with acute or chronic diarrhea.
• Protozoal GI infections in immunocompetent patients are usually mild-to-moderate self-limited diseases, and special precautions are not needed.
• The hallmark for treatment of these diseases is specific antiprotozoal therapy.
• Patients with severe amebic or balantidic colitis should not receive oral nutrition and should be monitored for potential surgical complications.
• Consider parenteral nutrition in some patients.
• Patients with amebic liver abscess should be treated in the hospital until potential complications have been ruled out.

Surgical Care

Only 2 well-recognized conditions in which surgical therapy is necessary for intestinal protozoal diseases are known: necrotizing colitis, caused by E histolytica or B coli, and complicated amebic liver abscess.

• Indications for surgery in fulminant amebic colitis include the following:
• • Failure to respond to antiamebic drugs following perforation and localized abscess formation
  • Persistence of abdominal distension and tenderness despite effective antiamebic therapy
  • Toxic megacolon
• Partial colectomy with colostomy is recommended over primary anastomosis for localized colonic disease because an anastomosis may be incompetent because of the friable condition of the affected intestinal wall.
• For extensive disease, better surgical results have been obtained with total colectomy with exteriorization of the proximal and distal ends.
• Indications for needle aspiration in amebic liver abscess include the following:
• • Rupture to pleura, pericardium, or both
  • Left lobe abscesses and proximity to the pericardium
  • As a diagnostic procedure when a pyogenic abscess is highly suspected
  • When surgical drainage is indicated because of imminent rupture of the abscess to the peritoneal cavity or presence of necrotizing colitis
  • When, in some cases, perianal fistulization of intestinal amebic foci is present and necessitates surgical drainage

Consultations

• The primary care physician can manage the vast majority of cases of gastroenteritis associated with protozoal infections. These infections rarely result in complications requiring hospitalization.
• In patients with chronic diarrhea or amebic liver abscess, consultation with a gastroenterologist along with an infectious-disease specialist may be useful.
• Surgeons should be consulted when the patient is suspected to have necrotizing colitis, complicated amebic liver abscess, or both.
• Nutritional support may also be beneficial in severe cases.

Diet

• In immunocompetent patients, effective antiprotozoal therapy results in full recovery.
• Some patients with severe giardiasis may experience disaccharidase deficiency and may require lactose-free diets, but this is a temporary condition that usually does not last more than 2 weeks.
• Patients with AIDS and severe spore-forming protozoal infections (chronic diarrhea with wasting syndrome) require hypercaloric diets. This is indicated for the protozoal illness in addition to the wasting syndrome associated with the underlying disease.
• For amebic liver abscess, some experts recommend a low-fat diet during antiamebic treatment, but no clinical trials have examined the effects of this diet on the patient's outcome.

Activity

The only limitations for physical activity are in patients with amebic liver abscess who may require hospitalization and patients who require surgery for necrotizing colitis.

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

The drugs of choice for each protozoon are listed in Table 3 and are followed by specific considerations for each drug.

Table 3. Specific Therapy for Intestinal Protozoal Infections

Drug Category: Antiprotozoal agents

Protozoal infections occur throughout the world and are a major cause of morbidity and mortality in some regions. Immunocompromised patients are especially at risk. Primary immune deficiency is rare, whereas secondary deficiency is more common. Immunosuppressive therapy, cancer and its treatment, HIV infection, and splenectomy can all increase vulnerability to infection. Infectious risk is proportional to neutropenia duration and severity. Protozoal infections are typically more severe in immunocompromised patients than in immunocompetent patients. In the case of cryptosporidiosis, nitazoxanide has been shown to be effective in immunocompetent and probably in immunocompromised patients, and the role of HAART has significantly reduced the incidence of all spore-forming protozoal infections.