EPIDEMIOLOGY

Entamoeba histolytica was first linked causally to amebic colitis and liver abscess by Lösch in 1875, and it was named by Schaudinn in 1903 for its ability to destroy host tissues. In 1925, Emil Brumpt proposed the existence of a second, morphologically identical but nonpathogenic Entamoeba species, Entamoeba dispar, to explain why only a minority of people infected with what was then termed E. histolytica develop invasive disease. Although Brumpt’s hypothesis was not accepted during his lifetime, it is now clear that he was correct and E. histolytica (Schaudinn, 1903) was recently reclassified to include two morphologically indistinguishable species: E. histolytica, the cause of invasive amebiasis, and E. dispar, a nonpathogenic intestinal commensal parasite (see later section).¹

Entamoeba histolytica is a parasite of global distribution, but most of the morbidity and mortality from amebiasis occurs in Central and South America, Africa, and the Indian subcontinent.² Fortunately, the majority of the 500 million persons worldwide previously believed to be asymptomatic E. histolytica cyst passers are actually infected with E. dispar. The best current estimate is that E. histolytica causes 34 to 50 million symptomatic infections annually worldwide, resulting in 40,000 to 100,000 deaths each year.^3,4 In Dhaka, Bangladesh, where diarrheal diseases are the leading cause of childhood death, 80% of children studied prospectively were infected with E. histolytica at least once during four years of follow-up.⁵ Furthermore, E. histolytica–associated diarrhea in these children was associated with significantly low weight and height for age.⁶

E. histolytica has a simple, two-stage life cycle consisting of an infectious cyst and a motile trophozoite (Fig. 109-1). The cyst form measures 5 to 20 µm in diameter and contains four or fewer nuclei. The ameboid trophozoite, which is responsible for tissue invasion, measures 10 to 60 µm (Fig. 109-2) and contains a single nucleus with a central karyosome (Fig. 109-3). The cysts are relatively resistant to chlorination and desiccation, and they can survive in a moist environment for several weeks.

Figure 109-1. Life cycle of Entamoeba histolytica. PMNs, polymorphonuclear neutrophils.

(From Petri WA, Sing U, Ravdin JI. Enteric amebiasis. In: Guerrant RL, Walker DH, Weller PF, editors. Tropical Infectious Diseases: Principles, Pathogens, and Practice. Philadelphia: WB Saunders; 1999.)

Figure 109-2. Amebae that infect the human gastrointestinal tract. E., entamoeba.

(From Ravdin Jl, Guerrant RL. Current problems in the diagnosis and treatment of amebic infections. Curr Clin Trop Infect Dis 1986; 7:82.)

Figure 109-3. A, An Entamoeba histolytica trophozoite in a stool specimen. Note the nucleus with a prominent central karyosome. B, Giardia intestinalis cyst in stool. (Original magnification ×400.)

Infection occurs following ingestion of cysts in fecally contaminated food or water. Within the lumen of the small intestine, the quadrinucleate cyst undergoes nuclear then cytoplasmic division, giving rise to eight trophozoites.⁷ Only about 10% of infected persons develop invasive disease characterized by invasion of the colonic epithelium by trophozoites.¹ Trophozoites that gain access to the bloodstream can spread hematogenously to establish infection at distant sites (most commonly liver abscess, as discussed in Chapter 82). Why some persons develop invasive disease and others remain asymptomatic remains a mystery; parasite and host differences are likely to be important in this regard.

A molecular epidemiologic study that used the polymerase chain reaction (PCR) to amplify a polymorphic region of the E. histolytica genome and assign a genotype to different clinical isolates has demonstrated a correlation between different E. histolytica strains and the outcome of infection.⁸ The specific underlying genetic differences among ameba strains that are responsible for altered virulence, however, remains unknown. Furthermore, amebic liver abscess is primarily a disease of men, and studies suggest that susceptibility to both intestinal and hepatic amebiasis is linked to human leukocyte antigen (HLA) class II alleles.^9,10 For example, the HLA DQB1*0601 allele may be associated with protection from intestinal amebiasis.⁹ As is the case for genetic differences among E. histolytica strains, however, there is no evidence of a direct causal role for different HLA types; rather, these HLA types are likely to be in linkage disequilibrium with genes in the nearby vicinity that encode the causal factors.

PATHOGENESIS, PATHOLOGY, AND IMMUNOLOGY

Both amebic factors and the host’s inflammatory response contribute to tissue destruction during invasive amebiasis. Microscopy studies have defined a stepwise progression of disease.^11–13 After excystation within the lumen of the small intestine, trophozoites adhere to colonic mucins and epithelial cells, largely via an amebic galactose/N-acetyl-d-galactosamine inhibitable surface lectin.^14–16 Secreted cysteine proteinases then facilitate tissue invasion by degrading human colonic mucus and extracellular matrix proteins.^17–20 Further disruption of the colonic epithelium results directly from contact-dependent cytolysis of epithelial and immune cells and from an acute epithelial cell inflammatory response with recruitment of neutrophils and immune-mediated tissue damage.^14,21–25

The cecum and ascending colon are affected most commonly, although in severe disease the entire colon may be involved. On gross examination, pathology can range from mucosal thickening to multiple punctate ulcers with normal intervening tissue (Fig. 109-4) to frank necrosis. For unknown reasons, the downward invasion of amebic trophozoites often is halted at the level of the muscularis mucosa. Subsequent lateral spread of amebae undermines the overlying epithelium, resulting in the clean-based, flask-shaped ulcers that characterize amebic colitis.^26,27 Early in infection, an influx of neutrophils is typical, but in well-established ulcers, few inflammatory cells are seen.^13,26–28 Organisms may be seen ingesting red blood cells (erythrophagocytosis) (Fig. 109-5). At distant sites of infection (e.g., liver abscess), similar pathologic characteristics include central liquefaction of tissue surrounded by a minimal mononuclear cell infiltrate.^27–29

Figure 109-4. Colonoscopic findings in a patient with amebic colitis. Multiple punctate ulcers are visible.

Figure 109-5. Amebic colitis. This high-power view of a colon biopsy specimen shows multiple amebic trophozoites, many of which have ingested red blood cells (erythrophagocytosis). Nonpathogenic ameba do not exhibit erythrophagocytosis.

(From the photo collection of the late Harrison Juniper, MD.)

Because more than 90% of persons colonized with E. histolytica spontaneously clear the infection within a year, an effective immune response to amebiasis seems to develop.³⁰ Children with fecal anti-amebic lectin immunoglobulin (Ig)A have short-lived protection from subsequent intestinal infection.^5,31,32 The protective role of secretory IgA is not certain, however, and the contributions of humoral and cellular immunity to protection from amebiasis remain unknown. Nearly everyone with invasive amebiasis develops a systemic and a mucosal humoral immune response.^33–38 Antibodies alone are unable to clear established infection, however, because asymptomatic cyst passers remain infected for months after anti-amebic antibodies develop.^30,33 Passive immunization experiments in a severe combined immunodeficient (SCID) mouse model of liver abscess do suggest an important role for preexisting humoral immunity in protection from infection.³⁹ Reports that patients receiving glucocorticoids may be at increased risk for severe amebic colitis suggest that cellular immunity also plays an important role in control of E. histolytica infection^40,41; despite this concern, no increase in disease severity in patients with AIDS has been observed. In fact, in a mouse model of amebic colitis, disease was exacerbated by CD4⁺ T cells.⁴²

CLINICAL FEATURES

Infection with E. histolytica results in one of three outcomes. Approximately 90% of infected persons remain asymptomatic. The other 10% of infections result in invasive amebiasis characterized by dysentery (amebic colitis) or, in a minority of cases, extraintestinal disease (most commonly amebic liver abscess; see Chapter 82).^1,30

In the United States, immigrants from or travelers to endemic regions, male homosexuals, and institutionalized persons are at greatest risk for amebiasis. In addition, malnourished patients, infants, the elderly, pregnant women, and patients receiving glucocorticoids may be at increased risk for fulminant disease.^2,40,41 When one or more of these epidemiologic risk factors are present, amebic dysentery should be considered in the differential diagnosis of occult or grossly bloody diarrhea.

The major diagnostic challenge for the clinician seeing a patient with amebic colitis is to distinguish the illness from other causes of bloody diarrhea. The differential diagnosis includes the causes of bacterial dysentery, such as Shigella, Salmonella, and Campylobacter species and enteroinvasive or enterohemorrhagic Escherichia coli, and noninfectious diseases, including inflammatory bowel disease, and ischemic colitis.^2,43 In contrast to bacterial dysentery, which typically begins abruptly, amebic colitis begins gradually over one to several weeks (Table 109-1). Although more than 90% of patients with amebic colitis present with diarrhea, abdominal pain can occur without diarrhea; abdominal pain, tenesmus, and fever are highly variable. Weight loss is common because of the chronicity of the illness. Microscopic blood is present in the stool of most patients with amebic dysentery.^2,43,44

Table 109-1 Comparison of Amebic Colitis and Invasive Bacterial Dysentery

* See Chapter 107.

Adapted from Huston CD, Petri WA. Amebiasis. In: Rakel RE, Bope ET, editors. Conn’s Current Therapy, 2001. Philadelphia: WB Saunders; 2001. pp 50-4.

The most feared complication of amebic dysentery, acute necrotizing colitis with toxic megacolon, occurs in 0.5% of cases. This complication manifests as an acute dilatation of the colon, and 40% of patients die from sepsis unless it is promptly recognized and treated surgically.^45,46 Unusual complications include the formation of enterocutaneous, rectovaginal, and enterovesicular fistulas and ameboma. Ameboma, due to intraluminal granulation tissue, can cause bowel obstruction and mimic carcinoma of the colon.^2,43

Although a history of dysentery early in the illness is common, dysentery has resolved in most patients by the time of presentation.^47–49 Extraintestinal sites of infection are involved and typically result either from direct extension of liver abscesses (e.g., amebic pericarditis or lung abscess) or from hematogenous spread of disease (e.g., brain abscess).^2,50

DIAGNOSIS

Because amebiasis patients erroneously treated for inflammatory bowel disease with glucocorticoids can develop fulminant colitis, accurate initial diagnosis is critical.^40,41 The gold standard for diagnosis of amebic colitis remains colonoscopy with biopsy, and colonoscopy should be performed whenever infectious causes of bloody diarrhea are strong considerations in the differential diagnosis of ulcerative colitis. Because the cecum and ascending colon are affected most often, colonoscopy is preferred to sigmoidoscopy. Classically, multiple punctate ulcers measuring 2 to 10 mm are seen with essentially normal intervening tissue (see Fig. 109-4); however, the colonic epithelium might simply appear indurated with no visible ulcerations; appear like ulcerative colitis with a myriad of ulcerations and granular, friable mucosa; or, in severe cases where the ulcers have coalesced, the epithelium may appear necrotic. Histologic examination of a biopsy specimen taken from the edge of an ulcer reveals amebic trophozoites and a variable inflammatory infiltrate (see Fig. 109-5).²⁷ Identification of amebae can be aided by periodic acid–Schiff staining of biopsy tissue, which stains trophozoites magenta.

Stool examination for ova and parasites, the traditional method for diagnosing amebiasis, should not be relied upon. Although the presence of amebic trophozoites with ingested erythrocytes strongly correlates with E. histolytica infection, these rarely are present,⁵¹ and in the absence of hematophagous trophozoites, microscopy cannot distinguish E. histolytica from E. dispar. Difficulty in distinguishing other nonpathogenic amebae (see later) and white blood cells from E. histolytica also limits the specificity of stool microscopy.⁵² The sensitivity of microscopy for identification of amebae is at best 60% and it may be reduced by delays in processing of stool samples.^52,53 The primary utility of stool microscopy for ova and parasites in a patient with diarrhea, therefore, is to evaluate the stool for other parasitic causes of diarrhea.

Noninvasive methods to accurately differentiate E. histolytica from E. dispar include stool culture with isoenzyme analysis, serum amebic-antibody titers, PCR, and an enzyme-linked immunosorbent assay (ELISA) that detects the amebic lectin antigen in stool samples.^54–64 Of these, only serum amebic-antibody titers and the stool ELISA are widely available for clinical use.

Because serum anti-amebic antibodies do not develop in patients infected with E. dispar, serologic tests for amebiasis accurately distinguish E. histolytica and E. dispar infection. From 75% to 85% of patients with acute amebic colitis have detectable anti-amebic antibodies on presentation, and convalescent titers develop in more than 90% of patients.^34,35,65 For amebic liver abscess, 70% to 80% of patients have detectable antibody titers on presentation, and convalescent titers develop in more than 90% of patients. Because antiamebic antibodies can persist for years, however, a positive result must be interpreted with caution.³⁴ For persons with known epidemiologic risks (e.g., emigration from or prior travel to an endemic region), a positive result might simply represent infection in the distant past. In the setting of recent travel to an endemic region and a positive antibody titer, diagnosis is confirmed by an appropriate symptomatic response to anti-amebic treatment.

The most specific clinically available test for diagnosis of amebiasis is a stool ELISA to detect the E. histolytica adherence lectin. Only one of the many ELISA tests developed thus far (the E. histolytica II test, TechLab, Blacksburg, Va.) accurately distinguishes E. histolytica from E. dispar.^53,60,61 This test’s specificity, when compared with the gold standard of stool culture followed by isoenzyme analysis, was greater than 90%, and it was greater than 85% sensitive for diagnosis of intestinal amebiasis when fresh fecal samples were analyzed without delay.⁶¹ In other studies, the sensitivity of this method has been less impressive, emphasizing the need for rapid processing of stool samples.^66,67 It also may be possible to use this antigen detection test to diagnose amebic liver abscess, because before treatment is initiated, amebic lectin antigen can be detected in the serum of greater than 90% of patients who have amebic liver abscess.⁶⁸

TREATMENT

Drugs for treatment of amebiasis are categorized as luminal or tissue amebicides on the basis of the location of their anti-amebic activity (Table 109-2).

Table 109-2 Amebicidal Agents Currently Available in the United States

The luminal amebicides include iodoquinol, diloxanide furoate, and paromomycin.^69,70 Of these, paromomycin, a nonabsorbable aminoglycoside, is preferred because of its safety, short duration of required treatment, and superior efficacy. Its major side effect is diarrhea. Approximately 85% of asymptomatic patients are cured with one course of paromomycin, and, because it is nonabsorbable and has moderate activity against trophozoites that have invaded the colonic mucosa, it might also be useful for single-drug treatment of mild invasive disease during pregnancy.^71,72

The tissue amebicides include metronidazole, tinidazole, nitazoxanide, erythromycin, and chloroquine.^70,73 Of these, metronidazole and tinidazole are the drugs of choice, with cure rates greater than 90%.⁷⁴ Nitazoxanide, a new antiparasitic agent, appears to be efficacious, with similar cure rates in several randomized, placebo-controlled trials.^73,75–77 Erythromycin has no activity against amebic liver disease, and chloroquine has no activity against intestinal disease.⁷⁸

Because approximately 10% of asymptomatic cyst passers develop invasive amebiasis, E. histolytica carriers should be treated.^1,4 For noninvasive disease, treatment with a luminal agent alone is adequate (e.g., paromomycin 25-35 mg/kg/day in three divided doses for seven days).⁷⁰ Patients with amebic colitis should first be treated with an oral nitroimidazole (either metronidazole [500-750 mg three times daily for 10 days] or tinidazole [2 grams once daily for three to five days]) to eliminate invasive trophozoites. Metronidazole and tinidazole are believed to be less effective against organisms in the colonic lumen, and subsequent treatment with a luminal agent such as paromomycin is recommended to prevent recurrent disease.^70,74

It is also for this reason that the familiar tissue amebicides (e.g., metronidazole) are not recommended as first-line agents for treatment of asymptomatic infection. At the recommended doses of metronidazole and tinidazole, gastrointestinal side effects including nausea and vomiting develop in approximately 30% of patients.⁷⁴ Because of severe gastrointestinal side effects, simultaneous treatment with a nitroimidazole and a luminal agent generally is not recommended.

Most patients with colitis respond promptly with resolution of diarrhea in two to five days.²

Despite conflicting reports on the safety of the nitroimidazoles for the developing fetus during pregnancy, women with severe disease during pregnancy should probably be treated without delay. As discussed in Chapter 82, metronidazole (750 mg three times a day for 10 days) followed by a luminal agent is also the treatment of choice for amebic liver abscess.^70,78

CONTROL AND PREVENTION

Prevention and control of E. histolytica infection depends on interruption of fecal-oral transmission. Water can be made safe for drinking and food preparation by boiling it for one minute, by halogenation (with chlorine or iodine), or by filtration.⁷ In the United States and Europe, modern water treatment facilities effectively remove E. histolytica. The importance of safe drinking water is highlighted by an outbreak of amebiasis in Tblisi, Republic of Georgia, where there was a water-borne epidemic due to decay of the water treatment facilities following the demise of the Soviet Union.⁷⁹ In the vast majority of the developing world, however, no modern water treatment facilities exist and none are likely to be constructed in the foreseeable future. Naturally acquired immunity to intestinal amebiasis provides short-lived protection against reinfection, giving hope that a vaccine may be feasible.^5,31,32 Because humans and some higher nonhuman primates are the only known hosts for E. histolytica, a vaccine that successfully prevents colonization might enable eradication of the disease.⁸⁰

EPIDEMIOLOGY

Giardia intestinalis (also called G. lamblia and G. duodenalis) is a ubiquitous flagellated intestinal protozoan. Van Leeuwenhoek accurately described its motile trophozoite form in his own stools in 1681, but it was not until 1915 that Stiles named the species.⁷

The life cycle of Giardia consists of an infectious cyst form and a motile trophozoite (Fig. 109-6). The cyst is oval (8 to 12 µm long by 7 to 10 µm wide), contains four nuclei, and has a rigid outer wall that protects it from dehydration, extremes of temperature, and chlorination (Fig. 109-7). Giardia cysts can survive in cold water for several weeks.^7,91 Ingestion of as few as 10 to 25 cysts can result in infection.⁹¹ After ingestion, excystation occurs following exposure to stomach acid and intestinal proteases, each cyst giving rise to two trophozoites. Giardia trophozoites (see Fig. 109-3B) are pear-shaped (10 to 20 µm long by 7 to 10 µm wide), contain two nuclei, have eight flagellae for locomotion, and replicate by binary fission. The trophozoites live in the duodenum, where they adhere to enterocytes. Eventually they encyst, following exposure to alkaline conditions or bile salts, and are excreted in the stool to complete their life cycle.⁹¹

Figure 109-6. Life cycle of Giardia intestinalis.

(From Hill DR, Nash TE. Intestinal flagellate and ciliate infections. In: Guerrant RL, Walker DH, Weller PF, editors. Tropical Infectious Diseases: Principles, Pathogens, and Practice. Philadelphia: WB Saunders; 1999.)

Figure 109-7. Giardiasis. High-power view of a duodenal biopsy specimen showing many trophozoites near the surface of the epithelium between villi.

(Courtesy of the Carlo Denegri Foundation, Turin, Italy.)

G. intestinalis, which was defined originally as a species by morphology, is more accurately defined as a species complex with at least seven major genotypes (assemblages A through G).⁹² Of these, only assemblages A and B are known to infect humans. Both of these genotypes also commonly infect cats and dogs, highlighting the importance of these pets as reservoirs for human disease.⁹² New data suggest that assemblage A isolates may be more virulent than assemblage B isolates.^93,94

G. intestinalis is the most commonly identified intestinal parasite in the United States and was identified in 7.2% of stool samples examined by state health departments in 1987.⁹⁵ Giardiasis occurs in both endemic and epidemic forms via water-borne, food-borne, and person-to-person transmission.^96–102 Worldwide, Giardia infects infants more commonly than adults, and in highly endemic regions, essentially all children are infected by two to three years of age.^103,104 In the developing world, it is likely that recurrent infantile diarrhea from giardiasis contributes significantly to malnutrition.¹⁰³ In the United States, children in daycare and sexually active homosexual men have the greatest risk of infection.^95,105 During a year-long longitudinal study at a U.S. daycare center, Giardia cysts were identified at some time in the stool of more than 30% of children.¹⁰² Additional risk factors for infection include drinking untreated surface water, a shallow well as a residential water source, swimming in any natural body of fresh water, and contact with a person who has giardiasis or contact with a child in daycare.⁹⁷

PATHOGENESIS, PATHOLOGY, AND IMMUNOLOGY

Giardia causes malabsorptive diarrhea by an unknown mechanism. Trophozoites adhere (perhaps by suction) to the epithelium of the upper small intestine using a disk structure located on their anterior ventral surface.^7,91 There is no evidence that trophozoites invade the mucosa,¹⁰⁶ but electron microscopy has shown they damage the mucosal brush border.^91,107 On biopsy, pathologic changes range from an entirely normal-appearing duodenal mucosa (except for adherent trophozoites), as was found in more than 96% of biopsy specimens in one large study, to severe villus atrophy with a mononuclear cell infiltrate that resembles celiac sprue.^106,108,109 The severity of diarrhea appears to correlate with the severity of the pathologic change.⁹¹

The host immune response plays a critical role in limiting the severity of giardiasis. When infected with Giardia, persons with common variable immunodeficiency develop severe, protracted diarrhea and malabsorption with sprue-like pathologic changes that resolve with treatment of the Giardia.¹⁰⁹ Both systemic and mucosal humoral immune responses can be measured consistently following Giardia infection. High serum anti-giardia IgM, IgG, and IgA titers can be detected, and anti-giardia secretory IgA (s-IgA) can be detected in saliva and in breast milk of infected mothers.^110–112 Animal studies suggest that both early and late immune responses are important for control of Giardia infections. Interleukin-6 (IL-6) is important in the early immune response to Giardia in mice, as are mast cells, which might function as IL-6 producers or via another mechanism.^113–115 In a B-cell-deficient transgenic mouse model, infection with Giardia does not resolve, confirming the importance of the humoral immune response for clearance of established infections.¹¹⁶ In culture, Giardia

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