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Intestinal infections can be divided into 3 broad groups (Table 40-1):
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Enterotoxin-mediated, where the disease is caused by a bacterial exotoxin; the organism does not invade the tissues and in some cases does not even enter the body (staphylococcal toxin, botulism), as the exotoxin is preformed in food.
Invasive infections, where the organism invades the intestinal mucosa.
Noninvasive infections, where the organism exists in the intestinal lumen and does not invade the tissues.
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Most intestinal infections are transmitted by fecal contamination of food or drinking water. They are common in parts of the world where public health sanitary measures such as disposal of feces and purification of water supplies are not adequate.
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Clinically, infections that involve the small intestine result in profuse watery diarrhea, while those that involve the colon produce dysentery (frequent small-volume diarrhea with blood and mucus). Fever is present in most invasive infections but is often absent in enterotoxin-mediated diseases.
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Diagnosis of intestinal infection is largely by stool culture (eg, Shigella, Salmonella, Campylobacter, Escherichia coli) or by observation of organisms in smear preparations of stool (eg, Entamoeba, Giardia, Cryptosporidium, Isospora). Serologic diagnosis is of value in certain instances (eg, rising titers of antibody to lipopolysaccharide cell wall O antigens in Salmonella infections). In diseases produced by toxins, identification of the toxin is often the only means of diagnosis (eg, Clostridium difficile enterocolitis).
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With intestinal worm infections, stool specimens may reveal whole worms, body segments, larvae, or eggs depending upon the species.
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Enterotoxin-Mediated Diseases
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Cholera is caused by Vibrio cholerae. The original classic strain has been supplanted by the El Tor variant, which is presently endemic in several Southeast Asian countries and occurs also in the southeastern United States. Infection occurs when the organism is ingested with fecally contaminated food or water.
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The organism multiplies in the intestinal lumen and produces an exotoxin that binds irreversibly to ganglioside receptors on the surface membranes of small intestinal mucosal cells (Figure 40-1). Toxin binding results in activation of adenylyl cyclase and increased cyclic adenosine monophosphate (cAMP) synthesis in the cell. The cAMP is a stimulus for increased secretion of fluid and electrolytes by the cell into the intestinal lumen and causes secretory diarrhea. The toxin acts for about 24 hours but does not permanently damage the cell. Pathologic examination reveals a normal small-intestinal mucosa on gross, light microscopic, and electron microscopic examination—even in fatal cases.
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Clinically, there is a severe secretory diarrhea, often without abdominal pain or fever. Patients become rapidly dehydrated, hypovolemic, and electrolyte-depleted. Shock and death may occur within 24 hours. The diagnosis is made by demonstrating the vibrio in a stool sample.
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Cholera is theoretically easy to treat. The diarrhea subsides when the organism has been killed (tetracycline is highly effective) and when the cells bearing bound toxin have been replaced by regenerating cells. Correction of dehydration with fluid therapy is vital in the acute phase. Glucose-containing fluids can be administered orally because the mucosal cell retains the ability to absorb fluid and electrolytes in the presence of glucose; this is important in underdeveloped regions of the world, where intravenous fluid therapy may not be available. The mortality rate in epidemics of cholera is high, partly because of the rapidity with which dehydration occurs and partly because epidemics commonly occur in regions where medical facilities are inadequate.
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Toxigenic Escherichia Coli Infection
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Certain strains of E coli produce a heat-labile enterotoxin similar to cholera toxin in its mode of action. Others produce a heat-stable enterotoxin. The ability to produce toxin is plasmid-induced and may therefore be transferred to other organisms. Toxigenic E coli causes (1) traveler's diarrhea in adults exposed to toxigenic strains of the bacillus against which they have no immunity and (2) diarrhea epidemics in neonatal units.
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The disease is usually mild, although in neonates diarrhea may result in dangerous fluid and electrolyte depletion. The diagnosis is difficult to establish. E coli is a normal commensal in the colon and is present in normal stools. Although specific serotypes of E coli have been reported as being toxigenic, the correlation between serotypes and toxigenicity is not completely accurate. Techniques using tissue culture systems for identifying the heat-labile toxin of E coli are not widely available.
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Staphylococcal Food Poisoning
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Staphylococcal food poisoning is a common form of epidemic food poisoning all over the world. It is caused by enterotoxin-producing strains of Staphylococcus aureus (Table 40-3). The organism multiplies in food that has been prepared and kept without refrigeration for several hours before it is eaten, leading to accumulation of the enterotoxin. Heating the food before ingestion destroys staphylococci but not the heat-stable toxin. The toxin causes severe nausea and vomiting of short duration, usually accompanied by abdominal cramps and diarrhea. The disease is self-limited. Death almost never occurs.
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Clostridium Difficile Pseudomembranous Enterocolitis
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Pseudomembranous enterocolitis complicates treatment with certain antibiotics—most commonly clindamycin, ampicillin, or tetracycline—that alter the intestinal bacterial flora, permitting the overgrowth of C difficile. C difficile produces a powerful exotoxin that binds to and has a cytotoxic effect on mucosal epithelial cells, resulting in superficial necrosis and acute inflammation of the intestinal mucosa. The necrotic mucosa and exudate remain adherent to the mucosal surface as yellow plaques or membranes. The colon is usually most severely involved.
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Clinically, there is an acute severe diarrhea with blood and mucus, accompanied by fever and an elevated white blood count. The disease progresses rapidly and is frequently fatal in the absence of prompt treatment. The diagnosis is based on the endoscopic and histologic features (Figure 40-2) and demonstration of C difficile exotoxin in blood and stool. Stool culture shows decreased numbers of commensal organisms; the finding of C difficile is difficult to interpret because the organism is a normal commensal. Vancomycin is effective in treatment; cholestyramine is of immediate value in that it binds with and neutralizes the toxin.
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Approximately 90% of cases of pseudomembranous enterocolitis are caused by C difficile. The causes in the other cases are unknown. Very rarely, invasive S aureus infection causes a severe pseudomembranous enterocolitis associated with the presence of large numbers of gram-positive cocci in a gram-stained smear of feces.
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Other Enterotoxic Diseases
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Clostridium perfringens and Bacillus cereus also produce toxins that give a clinical picture of food poisoning similar to staphylococcal food poisoning (Table 40-3). Vibrio parahaemolyticus, often ingested in uncooked shellfish, multiplies in the intestine much like V cholerae. The mechanism of action of the enterotoxin is not known. The disease is mild and self-limited and is characterized by abdominal pain and diarrhea. In botulism, the toxin of C botulinum is present in inadequately processed food (commonly sausage or home-canned food). The toxin is destroyed by heating for 20 minutes at 100 °C, which is achieved in commercial canning operations. Though classified as a form of “food poisoning,” botulism rarely causes diarrhea and usually presents with neuromuscular paralysis due to the systemic action of the exotoxin (see Chapter 13: Infectious Diseases: I. Mechanisms of Tissue Changes in Infection).
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Invasive Viral & Bacterial Infections
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Viral Gastroenteritis
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Viral gastroenteritis (stomach flu) is one of the most common infections of humans. It is most often caused by rotaviruses and parvoviruses, of which the best known is the Norwalk agent. Numerous other viruses, including adenoviruses, calicivirus and astrovirus, are sometimes implicated.
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The viruses infect the small intestinal epithelial cells, causing acute inflammation. The villi become blunted and infiltrated with lymphocytes and plasma cells.
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Clinically, patients present with fever, acute diarrhea, vomiting, and abdominal pain. The illness is self-limited and mild, lasting 3–4 days. Diagnosis may be made by demonstrating the virus in stools or detecting a rise in antibody titer.
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Cytomegalovirus Enterocolitis
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Cytomegalovirus is an important cause of intestinal infection in immunocompromised patients and is common in persons with acquire immunodeficiency disease (AIDS). The virus infects the entire intestinal tract, producing a severe chronic diarrhea that may cause death, and it infects mucosal epithelial cells as well as vascular endothelial cells. Cytomegalovirus vasculitis may result in focal ischemic necrosis of the wall; rarely, perforation of the intestine results. The diagnosis is established by demonstrating infected cells—greatly enlarged and containing large intranuclear inclusions and granular cytoplasmic inclusions—in biopsy specimens taken endoscopically.
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Salmonella Gastroenteritis
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Salmonella species other than Salmonella typhi are a common cause of bacterial “food poisoning” all over the world (Table 40-3). Infection results when food, water, and dairy products are contaminated with infected human or animal feces. Pasteurization of milk has decreased the incidence of this disease.
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Infection causes acute inflammation of the small intestine, with diffuse mucosal hyperemia, swelling, focal superficial ulceration, and neutrophil infiltration.
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Patients present 1–3 days after infection with an acute onset of fever, abdominal pain, and diarrhea. The disease is usually mild. Rarely, a more severe illness with bacteremia may occur.
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Typhoid fever is caused by Salmonella typhi; Salmonella paratyphi may produce a similar illness. The organism infects only humans, and infection results from contamination of food and water with feces from a symptomatic case or asymptomatic carrier of typhoid. Typhoid is uncommon in the United States but is still prevalent in Third World countries.
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Pathology & Clinical Features
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The ingested bacillus invades the small intestinal mucosa, where it is taken up by macrophages and transported to regional lymph nodes. S typhi is a facultative intracellular organism and multiplies in the intestinal lymphoid tissue during the 1- to 3-week incubation period (Figure 40-3).
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At the end of the incubation period, the bacilli enter the bloodstream (bacteremic phase), resulting in fever, headache, and muscle aches. Many tissues, including liver, heart, kidney, lungs, meninges, and bone, may be infected during this phase.
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The diagnosis of typhoid fever is suggested by the following in a patient with continued fever: (1) splenomegaly; (2) a petechial skin rash (rose spots); (3) bradycardia, which is unusual in other febrile illnesses; and (4) peripheral blood neutropenia. All of these findings are present toward the end of the first week of clinical illness. The diagnosis is established at this time by blood culture, which is positive in 95% of cases.
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In the second week of illness, S typhi reenters the intestinal lumen by way of biliary excretion (intestinal phase). The organism reinfects lymphoid tissue in the small intestine and colon in large numbers, causing acute inflammation, necrosis, and ulceration. Necrosis is the result of direct invasion plus endotoxin released by the bacillus, together with delayed hypersensitivity, which has developed by this time. The mucosal ulcers tend to take the shape of the underlying lymphoid follicles and typically occur as longitudinal ulcers overlying the Peyer patches in the ileum (Figure 40-4).
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Microscopic examination shows edema and acute inflammation. The cellular infiltrate in typhoid is deficient in neutrophils and composed of macrophages, lymphocytes, and plasma cells. Necrosis and ulceration follow.
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Clinically, the intestinal phase is characterized by diarrhea and continued fever. The diagnosis can be established by stool and urine culture (Figure 40-3), which is positive at this stage. Blood culture is still positive in about 60% of patients.
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Bacteremia is common and often fatal if the patient is not treated. Hemorrhage may occur from the intestinal ulcers, and perforation may lead to peritonitis.
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There may be evidence of skin infection (rose spots) or, rarely, of meningitis, endocarditis, chondritis, osteomyelitis, or widespread focal necrosis of muscle (Zenker's degeneration).
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After clinical recovery, 5% of patients continue to excrete bacilli in urine or feces; this carrier state is believed to be due to persistent low-grade infection in the kidney and gallbladder. Carriers represent a public health hazard, particularly if they are involved in handling food.
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Shigella Colitis (Bacillary Dysentery)
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Bacillary dysentery is caused by Shigella species. Shigella sonnei and Shigella flexneri are the common species and cause a relatively mild illness. Shigella boydii is uncommon. Shigella dysenteriae type I (Shiga's bacillus) produces a severe illness and is endemic in Central America and parts of Asia. Shigella dysentery is common in the United States.
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Shigella species affect the colon, producing an acute inflammation with diffuse hyperemia, edema, and multiple superficial ulcers. Neutrophils are the dominant cells. Bacteremia is rare, occurring only in severe cases, particularly with S dysenteriae type 1.
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Clinically, bacillary dysentery is an acute illness characterized by high fever, severe diarrhea with blood and mucus in the stool, and neutrophilic leukocytosis. Passage of 10–40 stools per day is usual; individual stools are of small volume and often composed entirely of blood, mucus, and the inflammatory exudate. Diagnosis is made by stool culture.
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Enteroinvasive Escherichia Coli Infection
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Some strains of Escherichia coli have the ability to invade the intestinal mucosa and cause epidemics of necrotizing enterocolitis in neonates or invasive intestinal infections in older children and adults. Extensive necrosis of the mucosa often causes death in neonates. The disease in children and adults simulates either salmonellosis, when the small intestine is maximally involved, or Shigella dysentery when colitis predominates. Children who recover may develop fibrous strictures. The identification of serotypes of E coli that are invasive is very difficult.
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Campylobacter Fetus Infection
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Campylobacter fetus is a curved bacterium recognized recently as being a common cause of enterocolitis and responsible for about 10% of cases of bacterial diarrhea in children. The disease is acquired from infected humans and animals.
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Both small intestine and colon are affected, causing diarrhea and dysentery. The disease is usually mild. Diagnosis is by stool culture. Treatment with antibiotics is effective.
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Yersinia Enterocolitica & Yersinia Pseudotuberculosis Infection
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These two Yersinia species cause fever, diarrhea, and marked painful enlargement of mesenteric lymph nodes (mesenteric adenitis), with right lower quadrant abdominal pain. Differentiation from acute appendicitis can be difficult.
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Diagnosis is made by stool culture.
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Intestinal Tuberculosis
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Primary Intestinal Tuberculosis
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Primary tuberculous infection of the intestine has become rare as a result of pasteurization of milk and eradication of bovine tuberculosis in dairy herds. It is characterized by a small focus in the intestine and large mesenteric lymph nodes, analogous to the primary complex in the lung.
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Secondary Intestinal Tuberculosis
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This form of tuberculosis still occurs as a result of swallowing of infected sputum by patients with active pulmonary disease or reactivation of a dormant intestinal focus, usually in the terminal ileum or cecum.
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Typical caseous granulomas form. The organisms spread locally in the intestinal lymphatics, resulting in ulcers that are transverse because the intestinal lymphatics pass circumferentially. Fibrosis leads to strictures (Figure 40-5). Involvement of the serosa results in fibrous adhesions between loops of intestine. Fistula formation may occur.
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Clinically, intestinal tuberculosis is a chronic illness characterized by low-grade fever and diarrhea, which may be tinged with blood. A mass may be palpable in a few cases (hyperplastic cecal tuberculosis). The diagnosis is made by culturing tubercle bacilli from the stools.
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Complications of intestinal tuberculosis include intestinal obstruction, caused by strictures, fistulas, and tuberculous peritonitis.
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Atypical Mycobacteriosis
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Intestinal infection with Mycobacterium avium-intracellulare occurs in elderly or immunocompromised patients. M avium-intracellulare enteritis is one cause of severe chronic diarrhea in patients with AIDS. The organisms accumulate in large numbers in macrophages in the mucosa, and there is little or no inflammation. Spread to lymph nodes is common. The diagnosis may be established by biopsy or identification of the organism in stools by direct examination (using acid-fast stain) or culture.
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Entamoeba histolytica is a common pathogen of the colon in underdeveloped countries. In the United States it occurs mainly in cities with high immigrant populations.
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Infection occurs by ingestion of cysts in food and water contaminated with feces. Ingested cysts release active amebas (trophozoites) that invade the large intestinal mucosa and enter the submucosa, which is the site of maximal involvement. The amebas cause multiple areas of enzymatic necrosis of tissue and acute inflammation, leading to flask-shaped submucosal abscesses throughout the colon (Figure 40-6). The mucosal surface—as seen at colonoscopy—shows multiple ulcers separated by healthy-appearing mucosa which is, however, undermined by the submucosal abscesses. Confluence of mucosal ulcers results in large areas of denuded mucosa covered by a necrotic base. Amebas are found in the walls of the ulcers (Figure 40-7). The trophozoites typically contain phagocytosed erythrocytes in their cytoplasm.
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Infection is usually localized to the submucosa and mucosa. Rarely, necrosis involves the muscle, leading to intestinal perforation. Hemorrhage and toxic megacolon may also occur with severe infection, and venous spread to the liver may occur (Chapter 42: The Liver: I. Structure & Function; Infections).
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Clinically, patients with amebic colitis present with bloody and mucous diarrhea accompanied by low-grade fever. The diagnosis is made by the finding of trophozoites of E histolytica in the stools or in a biopsy specimen. Amebicidal drugs such as metronidazole are highly effective in treatment.
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Giardiasis is a common infection caused by the protozoan flagellate Giardia lamblia. Infection is by ingestion of cysts in food and water contaminated with feces. After ingestion, excystment and release of trophozoites occurs in the duodenum.
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Giardia attaches itself to the surface of the small intestinal mucosal cells by its ventral sucker. The duodenum is involved most heavily. In heavy infections, a large part of the mucosal surface area may be occupied by parasites, causing mechanical interference with absorption. Giardiasis also causes partial villous atrophy, which contributes to malabsorption. The organism does not invade tissues.
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Clinically, infected individuals develop cramping abdominal pain, with diarrhea and steatorrhea due to malabsorption. The diagnosis is made by identifying the organism in stools, duodenal aspirates (Figure 40-8), or duodenal biopsies.
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Intestinal Cryptosporidiosis, Microsporidiosis, & Isosporiasis in Aids
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Cryptosporidium, Isospora, and Microsporidium species have been identified as common causes of chronic watery diarrhea in patients with AIDS.
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Cryptosporidium and Isospora species may rarely infect healthy individuals, causing a mild self-limited acute diarrhea. In AIDS, multiplication proceeds unimpeded, leading to massive infection of the small intestine and colon, and severe diarrhea. Cryptosporidium is present in large numbers, usually attached to the surface of the epithelial cell. The diagnosis is established by identifying the organism in stool smears stained with acid-fast stains. Cryptosporidium is 2–4 μm in diameter, round, and seen only in acid-fast stained smears. Isospora is larger and may be seen in both unstained wet mounts and acid-fast stained smears. Microsporidium infects duodenal epithelial cells. They are minute organisms that are best seen by electron microscopy and silver-stained sections.
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Intestinal Helminthiasis
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Intestinal helminthiasis is extremely common in underdeveloped countries and has been estimated as afflicting about 25% of the world population. In many of these diseases, the worm lives in the lumen without causing major symptoms; in others, significant clinical manifestations occur (Table 40-4).
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