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Giardia intestinalis (also known as G. lamblia or G. duodenalis) is a cosmopolitan protozoal parasite that inhabits the small intestines of humans and other mammals. Giardiasis is one of the most common parasitic diseases in both developed and developing countries worldwide, causing both endemic and epidemic intestinal disease and diarrhea.
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Life Cycle and Epidemiology
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Infection follows the ingestion of environmentally hardy cysts, which excyst in the small intestine, releasing flagellated trophozoites (Fig. 224-1), (Fig. 224-2) that multiply by binary fission. Giardia remains a pathogen of the proximal small bowel and does not disseminate hematogenously. Trophozoites remain free in the lumen or attach to the mucosal epithelium by means of a ventral sucking disk. As a trophozoite encounters altered conditions, it forms a morphologically distinct cyst, which is the stage of the parasite usually found in the feces. Trophozoites may be present and even predominate in loose or watery stools, but it is the resistant cyst that survives outside the body and is responsible for transmission. Cysts do not tolerate heating or desiccation, but they do remain viable for months in cold fresh water. The number of cysts excreted varies widely but can approach 107 per gram of stool.
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Ingestion of as few as 10 cysts is sufficient to cause infection in humans. Because cysts are infectious when excreted, person-to-person transmission occurs where fecal hygiene is poor. Giardiasis is especially prevalent in day-care centers; person-to-person spread also takes place in other institutional settings with poor fecal hygiene and during anal–oral contact. If food is contaminated with Giardia cysts after cooking or preparation, food-borne transmission can occur. Waterborne transmission accounts for episodic infections (e.g., in campers and travelers) and for major epidemics in metropolitan areas. Surface water, ranging from mountain streams to large municipal reservoirs, can become contaminated with fecally derived Giardia cysts. The efficacy of water as a means of transmission is enhanced by the small infectious inoculum of Giardia, the prolonged survival of cysts in cold water, and the resistance of cysts to killing by routine chlorination methods that are adequate for controlling bacteria. Viable cysts can be eradicated from water by either boiling or filtration.
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In the United States, Giardia (like Cryptosporidium; see below) is a common cause of waterborne epidemics of gastroenteritis. Giardia is common in developing countries, and infections may be acquired by travelers.
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There are several recognized genotypes or assemblages of G. intestinalis. Human infections are due to assemblages A and B, whereas other assemblages are more common in other animals, including cats and dogs. Like beavers from reservoirs implicated in epidemics, dogs and cats have been found to be infected with assemblages A and B; this finding suggests both that these animals may have been infected from human sources and that they might be sources of further human infections.
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Giardiasis, like cryptosporidiosis, creates a significant economic burden because of the costs incurred in the installation of water filtration systems required to prevent waterborne epidemics, in the management of epidemics that involve large communities, and in the evaluation and treatment of endemic infections.
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The reasons that some, but not all, infected patients develop clinical manifestations and the mechanisms by which Giardia causes alterations in small-bowel function are largely unknown. Although trophozoites adhere to the epithelium, they are not invasive but may elicit apoptosis of enterocytes, epithelial barrier dysfunction, and epithelial cell malabsorption and secretion. Consequent lactose intolerance and, in a minority of infected adults and children, significant malabsorption are clinical signs of the loss of brush-border enzyme activities. In most infections, the morphology of the bowel is unaltered; however, in chronically infected, symptomatic patients, the histopathologic findings (including flattened villi) and the clinical manifestations at times resemble those of tropical sprue and gluten-sensitive enteropathy. The pathogenesis of diarrhea in giardiasis is not known.
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The natural history of Giardia infection varies markedly. Infections may be aborted, transient, recurrent, or chronic. G. intestinalis parasites vary genotypically, and such variations might contribute to different courses of infection. Parasite as well as host factors may be important in determining the course of infection and disease. Both cellular and humoral responses develop in human infections, but their precise roles in disease pathogenesis and/or control of infection are unknown. Because patients with hypogammaglobulinemia suffer from prolonged, severe infections that are poorly responsive to treatment, humoral immune responses appear to be important. The greater susceptibilities of the young than of the old and of newly exposed persons than of chronically exposed populations suggest that at least partial protective immunity may develop.
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Clinical Manifestations
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Disease manifestations of giardiasis range from asymptomatic carriage to fulminant diarrhea and malabsorption. Most infected persons are asymptomatic, but in epidemics the proportion of symptomatic cases may be higher. Symptoms may develop suddenly or gradually. In persons with acute giardiasis, symptoms develop after an incubation period that lasts at least 5–6 days and usually 1–3 weeks. Prominent early symptoms include diarrhea, abdominal pain, bloating, belching, flatus, nausea, and vomiting. Although diarrhea is common, upper intestinal manifestations such as nausea, vomiting, bloating, and abdominal pain may predominate. The duration of acute giardiasis is usually >1 week, although diarrhea often subsides. Individuals with chronic giardiasis may present with or without having experienced an antecedent acute symptomatic episode. Diarrhea is not necessarily prominent, but increased flatus, loose stools, sulfurous belching, and (in some instances) weight loss occur. Symptoms may be continual or episodic and may persist for years. Some persons who have relatively mild symptoms for long periods recognize the extent of their discomfort only in retrospect. Fever, the presence of blood and/or mucus in the stools, and other signs and symptoms of colitis are uncommon and suggest a different diagnosis or a concomitant illness. Symptoms tend to be intermittent yet recurring and gradually debilitating, in contrast with the acute disabling symptoms associated with many enteric bacterial infections. Because of the less severe illness early on and the propensity for chronic infections, patients may seek medical advice late in the course of the illness; however, disease can be severe, resulting in malabsorption, weight loss, growth retardation, and dehydration. A number of extraintestinal manifestations have been described, such as urticaria, anterior uveitis, and arthritis; whether these are caused by giardiasis or concomitant processes is unclear.
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Giardiasis can be severe in patients with hypogammaglobulinemia and can complicate other preexisting intestinal diseases, such as that occurring in cystic fibrosis. In patients with AIDS, Giardia can cause enteric illness that is refractory to treatment.
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Giardiasis is diagnosed by detection of parasite antigens in the feces, by identification of cysts in the feces or of trophozoites in the feces or small intestines, or by nucleic acid amplification tests (NAATs) (Table 224-1). Cysts are oval, measure 8–12 μm × 7–10 μm, and characteristically contain four nuclei. Trophozoites are pear-shaped, dorsally convex, flattened parasites with two nuclei and four pairs of flagella (Fig. 224-2). The diagnosis is sometimes difficult to establish. Direct examination of fresh or properly preserved stools as well as concentration methods should be used. Because cyst excretion is variable and may be undetectable at times, repeated examination of stool, sampling of duodenal fluid, and biopsy of the small intestine may be required to detect the parasite. Tests for parasitic antigens in stool are at least as sensitive and specific as good microscopic examinations and are easier to perform. Newer NAATs are highly sensitive but are not always available for clinical use at present.
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TREATMENT Giardiasis
Cure rates with metronidazole (250 mg thrice daily for 5 days) are usually >90%. Tinidazole (2 g once by mouth) may be more effective than metronidazole. Nitazoxanide (500 mg twice daily for 3 days) is an alternative agent for treatment of giardiasis. Paromomycin, an oral aminoglycoside that is not well absorbed, can be given to symptomatic pregnant patients, although information is limited on how effectively this agent eradicates infection.
Almost all patients respond to therapy and are cured, although some with chronic giardiasis experience delayed resolution of symptoms after eradication of Giardia. For many of the latter patients, residual symptoms probably reflect delayed regeneration of intestinal brush-border enzymes. Continued infection should be documented by stool examinations before treatment is repeated. Patients who remain infected after repeated treatments should be evaluated for reinfection through family members, close personal contacts, and environmental sources as well as for hypogammaglobulinemia. In cases refractory to multiple treatment courses, prolonged therapy with metronidazole (750 mg thrice daily for 21 days) or therapy with varied combinations of multiple agents has been successful.
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Giardiasis can be prevented by consumption of uncontaminated food and water and by personal hygiene during the provision of care for infected children. Boiling or filtering potentially contaminated water prevents infection.
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The coccidian parasite Cryptosporidium causes diarrheal disease that is self-limited in immunocompetent human hosts but can be severe in persons with AIDS or other forms of immunodeficiency. Two species of Cryptosporidium, C. hominis and C. parvum, cause most human infections.
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Life Cycle and Epidemiology
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Cryptosporidium species are widely distributed in the world. Cryptosporidiosis is acquired by the consumption of oocysts (50% infectious dose: ~132 C. parvum oocysts in nonimmune individuals), which excyst to liberate sporozoites that in turn enter and infect intestinal epithelial cells. The parasite’s further development involves both asexual and sexual cycles, which produce forms capable of infecting other epithelial cells and of generating oocysts that are passed in the feces. Cryptosporidium species infect a number of animals, and C. parvum can spread from infected animals to humans. Since oocysts are immediately infectious when passed in feces, person-to-person transmission takes place in day-care centers and among household contacts and medical providers. Waterborne transmission (especially that of C. hominis) accounts for infections in travelers and for common-source epidemics. Oocysts are quite hardy and resist killing by routine chlorination. Both drinking water and recreational water (e.g., pools, waterslides) have been increasingly recognized as sources of infection.
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Although intestinal epithelial cells harbor cryptosporidia in an intracellular vacuole, the means by which secretory diarrhea is elicited remain uncertain. No characteristic pathologic changes are found by biopsy. The distribution of infection can be spotty within the principal site of infection, the small bowel. Cryptosporidia are found in the pharynx, stomach, and large bowel of some patients and at times in the respiratory tract. Especially in patients with AIDS, involvement of the biliary tract can cause papillary stenosis, sclerosing cholangitis, or cholecystitis.
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Clinical Manifestations
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Asymptomatic infections can occur in both immunocompetent and immunocompromised hosts. In immunocompetent persons, symptoms develop after an incubation period of ~1 week and consist principally of watery nonbloody diarrhea, sometimes in conjunction with abdominal pain, nausea, anorexia, fever, and/or weight loss. In these hosts, the illness usually subsides after 1–2 weeks. In contrast, in immunocompromised hosts (especially those with AIDS and CD4+ T cell counts <100/μL), diarrhea can be chronic, persistent, and remarkably profuse, causing clinically significant fluid and electrolyte depletion. Stool volumes may range from 1 to 25 L/d. Weight loss, wasting, and abdominal pain may be severe. Biliary tract involvement can manifest as mid-epigastric or right-upper-quadrant pain.
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Evaluation starts with fecal examination for small oocysts, which are smaller (4–5 μm in diameter) than the fecal stages of most other parasites (Table 224-1). Because conventional stool examination for ova and parasites (O+P) does not detect Cryptosporidium, specific testing must be requested. Detection is enhanced by evaluation of stools (obtained on multiple days) by several techniques, including modified acid-fast and direct immunofluorescent stains and enzyme immunoassays. Newer NAATs are being employed. Cryptosporidia can also be identified by light and electron microscopy at the apical surfaces of intestinal epithelium from biopsy specimens of the small bowel and, less frequently, the large bowel.
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TREATMENT Cryptosporidiosis
Nitazoxanide, approved by the U.S. Food and Drug Administration (FDA) for the treatment of cryptosporidiosis, is available in tablet form for adults (500 mg twice daily for 3 days) and as an elixir for children. This agent has not been effective for the treatment of HIV-infected patients, in whom improved immune status due to antiretroviral therapy can lead to amelioration of cryptosporidiosis. Otherwise, treatment includes supportive care with replacement of fluids and electrolytes and administration of antidiarrheal agents. Biliary tract obstruction may require papillotomy or T-tube placement. Prevention requires minimizing exposure to infectious oocysts in human or animal feces. Use of submicron water filters may minimize acquisition of infection from drinking water.
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The coccidian parasite Cystoisospora belli causes human intestinal disease. Infection is acquired by the consumption of oocysts, after which the parasite invades intestinal epithelial cells and undergoes both sexual and asexual cycles of development. Oocysts excreted in stool are not immediately infectious but must undergo further maturation.
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Although C. belli infects many animals, little is known about the epidemiology or prevalence of this parasite in humans. It is most common in tropical and subtropical countries. Acute infections can begin abruptly with fever, abdominal pain, and watery nonbloody diarrhea and can last for weeks or months. In patients who have AIDS or are immunocompromised for other reasons, infections often are not self-limited but rather resemble cryptosporidiosis, with chronic, profuse watery diarrhea. Eosinophilia, which is not found in other enteric protozoan infections, may be detectable. The diagnosis (Table 224-1) is usually made by detection of the large (~25 μm) oocysts in stool by modified acid-fast staining. Oocyst excretion may be low-level and intermittent; if repeated stool examinations are unrevealing, sampling of duodenal contents by aspiration or small-bowel biopsy (often with electron microscopic examination) may be necessary. NAATs are promising newer diagnostic tools.
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TREATMENT Cystoisosporiasis
Trimethoprim-sulfamethoxazole (TMP-SMX, 160/800 mg two times daily for 10 days; and, for HIV-infected patients, then continuing three times daily for 3 weeks) is effective. For patients intolerant of sulfonamides, pyrimethamine (50–75 mg/d) can be used. Relapses can occur in persons with AIDS and necessitate maintenance therapy with TMP-SMX (160/800 mg three times per week).
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Cyclospora cayetanensis, a cause of diarrheal illness, is globally distributed: illness due to C. cayetanensis has been reported in the United States, Asia, Africa, Latin America, and Europe. The epidemiology of this parasite has not yet been fully defined, but waterborne transmission and food-borne transmission (e.g., by basil, sweet peas, and imported raspberries) have been recognized. The full spectrum of illness attributable to Cyclospora has not been delineated. Some infected patients may be without symptoms, but many have diarrhea, flulike symptoms, and flatulence and belching. The illness can be self-limited, can wax and wane, or, in many cases, can involve prolonged diarrhea, anorexia, and upper gastrointestinal symptoms, with sustained fatigue and weight loss in some instances. Diarrheal illness may persist for >1 month. Cyclospora can cause enteric illness in patients infected with HIV.
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The parasite is detectable in epithelial cells of small-bowel biopsy samples and elicits secretory diarrhea by unknown means. The absence of fecal blood and leukocytes indicates that disease due to Cyclospora is not caused by destruction of the small-bowel mucosa. The diagnosis (Table 224-1) can be made by detection of spherical 8- to 10-μm oocysts in the stool, although routine stool O+P examinations are not sufficient. Specific fecal examinations must be requested to detect the oocysts, which are variably acid-fast and are fluorescent when viewed with ultraviolet light microscopy. Newer NAATs are proving to be sensitive. Cyclosporiasis should be considered in the differential diagnosis of prolonged diarrhea, with or without a history of travel by the patient to other countries.
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TREATMENT Cyclosporiasis
Cyclosporiasis is treated with TMP-SMX (160/800 mg twice daily for 7–10 days). HIV-infected patients may experience relapses after such treatment and thus may require longer-term suppressive maintenance therapy.
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Microsporidia are obligate intracellular spore-forming protozoa that infect many animals and cause disease in humans, especially as opportunistic pathogens in AIDS. Microsporidia are members of a distinct phylum, Microspora, which contains dozens of genera and hundreds of species. The various microsporidia are differentiated by their developmental life cycles, ultrastructural features, and molecular taxonomy based on ribosomal RNA. The complex life cycles of the organisms result in the production of infectious spores (Fig. 224-3). Currently, eight genera of microsporidia—Encephalitozoon, Pleistophora, Nosema, Vittaforma, Trachipleistophora, Anncalia, Microsporidium, and Enterocytozoon—are recognized as causes of human disease. Although some microsporidia are probably prevalent causes of self-limited or asymptomatic infections in immunocompetent patients, little is known about how microsporidiosis is acquired.
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Microsporidiosis is most common among patients with AIDS, less common among patients with other types of immunocompromise, and rare among immunocompetent hosts. In patients with AIDS, intestinal infections with Enterocytozoon bieneusi and Encephalitozoon (formerly Septata) intestinalis are recognized to contribute to chronic diarrhea and wasting; these infections have been found in 10–40% of patients with chronic diarrhea. Both organisms have been found in the biliary tracts of patients with cholecystitis. E. intestinalis may also disseminate to cause fever, diarrhea, sinusitis, cholangitis, and bronchiolitis. In patients with AIDS, Encephalitozoon hellem has caused superficial keratoconjunctivitis as well as sinusitis, respiratory tract disease, and disseminated infection. Myositis due to Pleistophora has been documented. Nosema, Vittaforma, and Microsporidium have caused stromal keratitis associated with trauma in immunocompetent patients.
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Microsporidia are small gram-positive organisms with mature spores measuring 0.5–2 μm × 1–4 μm. Diagnosis of microsporidial infections in tissue often requires electron microscopy, although intracellular spores can be visualized by light microscopy with hematoxylin and eosin, Giemsa, or tissue Gram’s stain. For the diagnosis of intestinal microsporidiosis, modified trichrome or chromotrope 2R–based staining and Uvitex 2B or calcofluor fluorescent staining reveal spores in smears of feces or duodenal aspirates. Definitive therapies for microsporidial infections remain to be established. For superficial keratoconjunctivitis due to E. hellem, topical therapy with fumagillin suspension has shown promise (Chap. 217). For enteric infections with E. bieneusi and E. intestinalis in HIV-infected patients, therapy with albendazole may be efficacious (Chap. 217).
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OTHER INTESTINAL PROTOZOA
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Balantidium coli is a large ciliated protozoal parasite that can produce a spectrum of large-intestinal disease analogous to amebiasis. The parasite is widely distributed in the world. Since it infects pigs, cases in humans are more common where pigs are raised. Infective cysts can be transmitted from person to person and through water, but many cases are due to the ingestion of cysts derived from porcine feces in association with slaughtering, with use of pig feces for fertilizer, or with contamination of water supplies by pig feces.
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Ingested cysts liberate trophozoites, which reside and replicate in the large bowel. Many patients remain asymptomatic, but some have persisting intermittent diarrhea, and a few develop more fulminant dysentery. In symptomatic individuals, the pathology in the bowel—both gross and microscopic—is similar to that seen in amebiasis, with varying degrees of mucosal invasion, focal necrosis, and ulceration. Balantidiasis, unlike amebiasis, only rarely spreads hematogenously to other organs. The diagnosis is made by detection of the trophozoite stage in stool or sampled colonic tissue. Tetracycline (500 mg four times daily for 10 days) is an effective therapeutic agent.
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Blastocystis hominis remains an organism of uncertain pathogenicity. Some patients who pass B. hominis in their stools are asymptomatic, whereas others have diarrhea and associated intestinal symptoms. Diligent evaluation reveals other potential bacterial, viral, or protozoal causes of diarrhea in some but not all patients with symptoms. Because the pathogenicity of B. hominis is uncertain and because therapy for Blastocystis infection is neither specific nor uniformly effective, patients with prominent intestinal symptoms should be fully evaluated for other infectious causes of diarrhea. If diarrheal symptoms associated with Blastocystis are prominent, either metronidazole (750 mg thrice daily for 10 days) or TMP-SMX (160 mg/800 mg twice daily for 7 days) can be used.
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Dientamoeba fragilis is unique among intestinal protozoa in that it has a trophozoite stage but not a cyst stage. How trophozoites survive to transmit infection is not known. When symptoms develop in patients with D. fragilis infection, they are generally mild and include intermittent diarrhea, abdominal pain, and anorexia. The diagnosis is made by the detection of trophozoites in stool; the lability of these forms accounts for the greater yield when fecal samples are preserved immediately after collection. Since fecal excretion rates vary, examination of several samples obtained on alternate days increases the rate of detection. Iodoquinol (650 mg three times daily for 20 days) or paromomycin (25–35 mg/kg per day in three doses for 7 days) is appropriate for treatment.