Clinical Features

Primary cytomegalovirus (CMV) infections in immunocompetent persons are usually asymptomatic. CMV infection may develop anywhere in the GI tract, from mouth to anus, in both immunocompromised and immunocompetent persons. CMV is best known as an opportunistic pathogen in patients with a suppressed immune system, most commonly in those with the acquired immunodeficiency syndrome (AIDS) and in patients who have undergone solid organ or bone marrow transplantation. In fact, CMV remains the most common GI pathogen overall in patients with AIDS.

Primary infections in healthy persons are typically asymptomatic. When symptomatic disease does occur, it is usually self-limited and may manifest as a mononucleosis-like syndrome. In most of these cases, GI involvement is subclinical. Symptomatic GI infection has been reported occasionally in immunocompetent patients, although many of these were elderly or were eventually found to have underlying malignancies or hematologic disorders and therefore may not have had entirely competent immune systems.

Symptoms vary with site of infection. The most common clinical symptoms are diarrhea (either bloody or watery), abdominal pain, fever, and weight loss. Patients with esophageal infection often have dysphagia and odynophagia. A rare, but important, entity associated with pediatric CMV infection is hypertrophic gastropathy and protein-losing enteropathy resembling Ménétrier disease.

In addition, secondary CMV infection may be superimposed on chronic GI diseases such as ulcerative colitis and Crohn’s disease. In such cases, CMV superinfection is associated with exacerbations of the underlying disease, steroid-refractory disease, toxic megacolon, and a higher mortality rate. Some authorities recommend immunohistochemical evaluation for CMV as part of the routine evaluation of biopsies in patients with steroid-refractory ulcerative colitis.

Pathologic Features

CMV causes a remarkable variety of gross lesions. Ulceration is the most common; the ulcers may be single or multiple, and superficial or deep. They can be quite large (>10 cm), and often have a well-circumscribed, “punched-out” appearance. Segmental ulcerative lesions and linear ulcers may mimic Crohn’s disease. Other gross lesions include mucosal hemorrhage, pseudomembranes, and inflammatory polyps or masses.

The histologic spectrum of CMV infection is extremely variable, ranging from minimal inflammation to deep ulcers with prominent granulation tissue and necrosis. Frequently observed histologic features include mucosal ulceration, a neutrophil-rich mixed inflammatory infiltrate, and cryptitis of glandular epithelium. Crypt abscesses, crypt atrophy and loss, and numerous apoptotic enterocytes may be seen as well. CMV may also cause a vasculitis featuring numerous endothelial viral inclusions with associated inflammation, necrosis, and thrombosis of the affected vessel and resultant mucosal ischemia.

Infected cells show both nuclear and cytoplasmic enlargement (hence the name, “cytomegalovirus”) ( Fig. 4.1, A ). Characteristic “owl’s-eye” intranuclear viral inclusions and basophilic granular intracytoplasmic inclusions may be seen on routine hematoxylin and eosin (H&E) preparations (see Fig. 4.1, B and C ). Inclusions are preferentially found in endothelial cells, stromal cells, and macrophages, and, rarely, in glandular epithelial cells. In contrast to adenovirus or herpes, CMV inclusions are often found deep within ulcer bases rather than at the edges of ulcers or in the superficial mucosa. Adjacent nuclei may be enlarged, appear smudged, or have a “ground-glass” appearance, but they lack typical inclusions. Characteristic inclusions with virtually no associated inflammatory reaction may occur in severely immunocompromised patients.

A, Polyp removed from the gastric antrum contains innumerable cytomegalovirus (CMV) inclusions within endothelial and stromal cells. CMV causes both nuclear enlargement and enlargement of the entire cell. B, Characteristic “owl’s-eye” nuclear inclusion is seen within an endothelial cell at the base of an ulcer. C, Granular, basophilic cytoplasmic inclusions may also be seen.

In biopsy specimens, the diagnosis are easily missed when only rare inclusions are present. Examination of multiple levels and use of immunohistochemistry can be invaluable in detecting the rare cells containing an inclusion. Other diagnostic aids include viral culture, polymerase chain reaction (PCR) assays, in situ hybridization, serologic studies, and antigen tests. Serologic studies often have limited usefulness because of the persistence of latent CMV infection. In addition, isolation of CMV in culture does not imply active infection, because the virus can be excreted for months to years after a primary infection.

Differential Diagnosis

The differential diagnosis of CMV includes primarily other viral infections ( Table 4.1 ), particularly adenovirus. Adenovirus inclusions are usually crescent shaped, located in surface epithelium, and only intranuclear in location. CMV inclusions typically have an owl’s-eye morphology, are typically located in endothelial or stromal cells, and exist in either the nucleus or cytoplasm. The ballooning degeneration phase of adenovirus infection, just before cell lysis, most closely resembles CMV.

The distinction between CMV infection and graft-versus-host disease in bone marrow transplant recipients can be particularly difficult because the clinical and histologic features are similar. Immunohistochemistry or in situ hybridization studies should be used to rule out CMV infection in this setting, because failure to identify CMV infection could result in delay of antiviral therapy. Furthermore, these conditions may coexist. Graft-versus-host disease is favored when there is abundant apoptosis associated with crypt necrosis and dropout in the setting of minimal inflammation. The presence of viable nests of endocrine cells favors graft-versus-host disease.

Clinical Features

Herpetic infection can occur throughout the GI tract but is most common in the esophagus and anorectum. Although herpes infection of the gut is often seen in immunocompromised patients and remains one of the most common infections in patients with human immunodeficiency virus (HIV), it is not limited to this group. In immunocompetent patients, infection is often self-limited. Immunocompromised patients, however, are at risk for disseminated infection and life-threatening illness.

Patients with herpetic esophagitis are seen with odynophagia, dysphagia, chest pain, nausea, vomiting, fever, and GI bleeding. Many have disseminated herpes infection at the time of diagnosis. Herpetic proctitis is the most common cause of nongonococcal proctitis in homosexual men. Patients typically are seen with severe anorectal pain, tenesmus, constipation, discharge, hematochezia, and fever. Concomitant neurologic symptoms (difficulty in urination and paresthesias of the buttocks and upper thighs) are also well described, as is inguinal lymphadenopathy.

Pathologic Features

Ulcers are the most common gross finding in the esophagus, and these are usually associated with an exudate. The ulcers are often shallow and well-circumscribed. Some patients have vesicles surrounding the ulcers. Many patients have a nonspecific erosive esophagitis without discrete ulcers, however. In herpetic proctitis, the presence of perianal vesicles is common, often in association with pustules or shallow ulcers. Proctoscopic findings include ulceration and mucosal friability. Vesicles may extend into the rectum or anal canal.

Typical histologic findings, regardless of site, include ulceration, neutrophils in the lamina propria, and an inflammatory exudate that often contains sloughed epithelial cells ( Fig. 4.2, A ). Prominent aggregates of macrophages may also be present. In the anorectum, perivascular lymphocytic cuffing and crypt abscesses may be seen as well.

A, Esophageal biopsy shows dyshesion and sloughing of squamous epithelial cells, intraepithelial neutrophils, and herpetic inclusions within squamous cells. B, Higher-power view shows the homogeneous basophilic “ground-glass” inclusions of herpes simplex virus with peripherally marginated chromatin. C, Multiple inclusions may be present within a single cell, known as a polykaryon.

Characteristic viral inclusions and multinucleate giant cells are present in only a minority of biopsy specimens (see Fig. 4.2, B and C ). The best place to search for viral inclusions is in the squamous epithelium at the edges of ulcers and in sloughed cells in the exudate. Two types of nuclear inclusions may be found: the homogeneous ground-glass inclusions and the acidophilic inclusions with a surrounding clear halo and peripheral chromatin margination (Cowdry type A inclusions). Inclusions may be single or multinucleate. The histologic findings for herpes simplex virus 1 (HSV-1) and HSV-2 are indistinguishable.

Differential Diagnosis

The differential diagnosis predominantly contains other viral infections, including CMV and varicella-zoster, that may infect the GI tract (see Table 4.1 ). Varicella produces histologic findings identical to those of HSV, but patients often have a rash. Mixed infections are common in many situations in which herpetic infection is found. Immunohistochemistry and in situ hybridization are very useful, and viral culture is a valuable diagnostic aid as well. Serologic studies may be useful if there is a very high or rising antibody titer, but serologic testing has limited use because latent infections can persist for years.

Vibrio cholerae and Related Species

V. cholerae (specifically the toxigenic O1 strain) is the causative agent of cholera, an important worldwide cause of watery diarrhea and dysentery that may lead to significant dehydration, electrolyte imbalance, and death within hours. Most infections result from consumption of raw or undercooked seafood, especially shellfish. Other vibrios, including non-O1 strains of V. cholerae , Vibrio hollisae, and Vibrio parahaemolyticus , also can cause severe gastroenteritis. Symptoms of cholera include the abrupt onset of diarrhea, usually profusely watery and rarely bloody, accompanied by abdominal pain, vomiting, muscle cramps, and fever. Disseminated infection is a particularly important risk with immunocompromised patients; patients with underlying liver disease, partial or total gastrectomy, and diseases of iron metabolism are also at risk for more serious Vibrio infections.

Despite the severity of the illness, V. cholerae O1 is a noninvasive toxin-producing organism that cause minimal or no histologic change to the intestinal mucosa. Nonspecific findings such as small bowel mucin depletion, degenerative surface epithelial changes, and a mild increase in lamina propria mononuclear cells have been rarely reported. Non-toxigenic O1 and other non- cholerae Vibrio species may show an erosive enterocolitis with active neutrophilic inflammation and associated hemorrhage. Useful ancillary diagnostic tests include culture, PCR, and serologic studies. A history of travel to or emigration from an endemic or epidemic area also can be invaluable.

Aeromonas and Related Species

Initially believed to be nonpathogenic gram-negative bacteria, Aeromonas and related species are increasingly recognized as causes of gastroenteritis in both children and adults. Aeromonas hydrophila and Aeromonas sobria most often cause GI disease in humans. Infection usually is caused by exposure to untreated water but also may result from consumption of contaminated foods such as produce, meat, and dairy products. Infections most frequently occur in the late spring, summer, and early fall, and children are most commonly affected. A mild, self-limited diarrheal illness is most common, sometimes accompanied by nausea, vomiting, and cramping abdominal pain. A more severe, dysentery-like illness occurs in 15% to 25% of patients, featuring bloody or mucoid diarrhea and fecal leukocytes. This variant is most likely to mimic chronic idiopathic IBD endoscopically.

Endoscopically, findings include mucosal edema, friability, erosions, exudates, and loss of vascular pattern. The distribution is often segmental, either right- or left-sided, and may mimic ischemic colitis, Crohn’s disease, or ulcerative colitis macroscopically. A severe pancolitis mimicking fulminant ulcerative colitis has also been described. The histologic features are usually those of ASLC, including cryptitis, crypt abscesses, and a neutrophilic infiltrate in the lamina propria. However, ulceration and focal architectural distortion may be seen in some cases ( Fig. 4.6 ).

Focal cryptitis and architectural distortion are seen in a right colon biopsy specimen in a case of culture-proven Aeromonas infection that was initially thought to be Crohn’s disease based on the endoscopic appearance.

The differential diagnosis includes other infectious colitides, ischemic colitis, and chronic idiopathic IBD. When architectural distortion is present in a patient with more chronic symptoms or macroscopic features mimicking chronic idiopathic IBD, it may be difficult to resolve the issue of Aeromonas infection versus Crohn’s disease or ulcerative colitis. Although there are no histologic features specific for Aeromonas infection (as with many infections of the GI tract), it is important for the surgical pathologist to realize that this is one of the bacteria that can most closely mimic chronic idiopathic IBD. Stool cultures are critical to diagnosis, and certain selective media may be required.

Escherichia coli

Escherichia coli is the most common gram-negative human pathogen. The diarrheogenic E. coli are classified into five groups, based primarily on serotyping. If pathogenic E. coli is suspected, the clinical laboratory should be notified to search for it specifically, because it may be missed on routine culture. In addition, because pathogenic E. coli strains are often cleared rapidly from stool (often within 4 to 7 days), cultures should be taken as early as possible.

Enteroadherent E. coli

This noninvasive strain of enteroadherent E. coli (EAEC) is similar to EPEC. Both have been increasingly recognized as causes of chronic diarrhea and wasting in AIDS patients. Although endoscopic findings are usually unremarkable, right colon biopsies more often yield pathologic findings. Histologic examination shows degenerated surface epithelial cells with associated intraepithelial inflammatory cells. A coating of adherent bacteria at the surface epithelium is the most prominent feature ( Fig. 4.7 ). The bacteria may be tightly or loosely adherent. The histologic findings can be patchy and can resemble an exaggerated brush border; they may easily be missed at low power. In addition, specimens from infected patients may show no associated inflammatory reaction whatsoever. The main entities in the differential diagnosis are normal mucosa and spirochetosis; the bacteria in EPEC and EAEC are not spirillar, in contrast to spirochetosis, and in general, they stain gram negative.

Enteroadherent Escherichia coli in a patient with AIDS. A coating of gram-negative rods with little inflammatory reaction is seen at the surface of the colonic mucosa (Gram stain).

(Courtesy of Dr. Mary Bronner, University of Utah School of Medicine.)

Enterohemorrhagic E. coli

The most common strain of enterohemorrhagic E. coli (EHEC) is O157 : H7. This pathogen gained national attention in 1993 when a massive outbreak in the western United States was linked to contaminated ground beef. Although contaminated meat is the most frequent mode of transmission, infection may also occur through contaminated water, milk, and produce and through person-to-person contact. EHEC produces a cytotoxin similar to that of Shigella dysenteriae , but there is no invasion. Hemolytic-uremic syndrome or thrombotic thrombocytopenic purpura may develop in affected persons, and children and the elderly are at particular risk for grave illness. In some studies, the use of antibiotics to treat EHEC appears to increase the risk for hemolytic-uremic syndrome. Symptoms usually consist of bloody diarrhea with severe abdominal cramps and mild or no fever. Nonbloody, watery diarrhea may occur, however. Only one third of patients have fecal leukocytes.

Endoscopically, patients typically have severe mural edema with associated hemorrhage. The mucosa is eroded and ulcerated, and ulcers often have an overlying purulent exudate. The edema may be so marked as to cause obstruction, and surgical resection may be required to relieve this or to control bleeding. The right colon is usually most severely affected. The histologic features closely resemble ischemic colitis of other causes, including marked edema and hemorrhage in the lamina propria and submucosa with associated mucosal acute inflammation, crypt withering, and lamina propria hyalinization ( Fig. 4.8 ). Microthrombi may be present within small-caliber blood vessels, and pseudomembranes resembling antibiotic-associated pseudomembranous colitis (PMC) are occasionally present as well. Mucosal necrosis is frequently seen, often involving the upper portion of the mucosa but sparing the deeper crypts.

Enterohemorrhagic Escherichia coli . A, Transmural hemorrhagic necrosis and an acute inflammatory exudate are seen in this right colon resection from a patient with E. coli O157 : H7 infection. B, The crypt withering and lamina propria hyalinization are very similar to the features of ischemic colitis.

The differential diagnosis primarily includes Clostridium difficile –related PMC and ischemic colitis of other causes, from which EHEC may be histologically indistinguishable. The clinical history, including the possibility of consumption of contaminated food, the age of the patient, and macroscopic findings may aid in distinguishing ischemia from E. coli infection. The C. difficile antigen test or PCR assays, or both, may be very helpful in distinguishing C. difficile –related colitis from EHEC.

An antibiotic-associated hemorrhagic colitis has been reported in association with Klebsiella oxytoca . This colitis is hemorrhagic, segmental, most common in the right and transverse colon, and lacks pseudomembranes. A history of antibiotic usage, especially penicillins, may help distinguish this infection from EHEC. Stool culture is invaluable in making the diagnosis; however, routine stool cultures cannot distinguish O157 : H7 from normal intestinal flora, because microbiologic diagnosis requires screening on selective agar. An immunohistochemical stain for the EHEC organism has been described, and molecular assays exist but are not widely available.

Salmonella

Salmonellae are gram-negative bacilli that are transmitted through food and water and are prevalent where sanitation is poor. They are an important cause of both food poisoning and traveler’s diarrhea. The majority of medically important salmonellae are in the species Salmonella enterica. They are differentiated by their serotyping, but the nomenclature has changed. For example, the bacterium Salmonella enteritidis is now designated Salmonella enterica ser. Enteritidis , or simply S. enteritidis .

Discussion of Salmonella infection can generally be divided into infection by typhoid and nontyphoid species. Enteric (typhoid) fever is usually caused by the serovar S. Typhi but may also be caused by S. paratyphi ; the most common nontyphoid species include S. enteritidis, S. typhimurium, S. muenchen, S. anatum, S. paratyphi. , and S. give . Although historically enteric fever was considered a much more severe disease and nontyphoid salmonellosis a milder one, more recent literature suggests a greater degree of overlap (both clinically and pathologically) than previously thought. Patients with low gastric acidity are at increased risk of salmonellosis, and patients with AIDS have a greater risk of Salmonella infection as well as a greater likelihood of severe infection and septicemia.

Typhoid (Enteric) Fever

Typhoid fever typically manifests with abdominal pain, headache, an elevation in fever over several days, and occasionally constipation. An abdominal rash and leukopenia are often seen. Diarrhea, which begins in the second or third week of infection, is initially watery but may progress to severe GI bleeding. Perforation and toxic megacolon may complicate typhoid fever.

Any level of the alimentary tract may be involved, but the characteristic pathology is associated with lymphoid aggregates and Peyer patches and therefore is most prominent in the ileum, appendix, and colon. Grossly, the bowel wall is thickened, and raised nodules may be seen corresponding to hyperplastic lymphoid tissue. Aphthous ulcers overlying lymphoid aggregates, linear ulcers, discoid ulcers, and full-thickness ulceration and necrosis are common as the disease progresses. Associated suppurative mesenteric lymphadenitis may occur. Occasionally, the mucosa is grossly normal or only mildly inflamed and edematous.

The histiocyte is the predominant inflammatory cell. Hyperplasia of Peyer patches leads to acute inflammation of the overlying epithelium ( Fig. 4.9, A and B ). Eventually, macrophages, mixed with occasional lymphocytes and plasma cells, infiltrate and obliterate the lymphoid follicles; neutrophils are not prominent. Necrosis then begins in the Peyer patch and spreads to the surrounding mucosa, which eventually ulcerates. Ulcers are typically very deep. Architectural distortion that may mimic ulcerative colitis or Crohn’s disease is well described (see Fig. 4.9, C ). Typhoid fever occasionally shows features more consistent with ASLC, including prominent neutrophils, cryptitis, crypt abscesses, and overlying fibrinous exudate. Granulomas are occasionally seen.

A, The typical histologic lesion of typhoid fever is ulceration overlying a lymphoid aggregate or Peyer patch. (Courtesy of Dr. A. Brian West, Yale University.) B, The typical inflammatory infiltrate is predominantly mononuclear, featuring plasma cells, lymphocytes, and histiocytes, with inconspicuous neutrophils. C, Architectural distortion can mimic that of chronic idiopathic inflammatory bowel disease. D, Nontyphoid Salmonella infection often shows features of acute infectious-type colitis but can also exhibit mild architectural disarray and gland loss.

Shigella

Shigella species are virulent, invasive, gram-negative bacilli that cause severe watery and bloody diarrhea and are a major cause of infectious diarrhea worldwide. Infection is transmitted by water contaminated with feces, and person-to-person transmission is also possible. It has the highest infectivity rate of the enteric gram-negative bacteria; symptoms may result from ingestion of a very low number of organisms. Children younger than 6 years of age are commonly affected, as are homosexual men and malnourished or debilitated patients. Constitutional symptoms are the earliest manifestation and include abdominal pain, malaise, and fever. The diarrhea is often watery initially; this is followed by the onset of bloody diarrhea containing mucus or pus and accompanied by tenesmus. Complications include severe dehydration, sepsis, perforation, toxic megacolon, reactive arthritis, Reiter syndrome, and hemolytic-uremic syndrome. Chronic disease is rare.

Grossly, the large bowel is typically affected (the left side usually more severely), but the ileum may be involved. The mucosa is hemorrhagic, with exudates that may form pseudomembranes. Ulcerations are variably present. Histologically, early disease has the features of ASLC with cryptitis, crypt abscesses (often superficial), and ulceration ( Fig. 4.10 ). Pseudomembranes similar to those of C. difficile infection may be seen, as may aphthous ulcers similar to those seen in Crohn’s disease. As the disease continues, increased mucosal destruction occurs with many neutrophils and other inflammatory cells in the lamina propria. Marked architectural distortion mimicking idiopathic IBD is well described.

This biopsy from a patient with Shigella sonnei infection shows cryptitis, a crypt abscess, and a mucin granuloma centered on a damaged gland.

(Courtesy of Dr. Mary Bronner, University of Utah School of Medicine.)

The differential diagnosis of early shigellosis is primarily that of other infections, particularly EIEC and C. difficile . Shigellosis, especially later in the disease course, can be extremely difficult to distinguish from Crohn’s disease or ulcerative colitis, both endoscopically and histologically. Stool cultures and clinical presentation may be helpful in this instance. Multiple stool cultures may be necessary, because the organism dies rapidly and prolonged transit time may affect culture yield.

Campylobacter

Campylobacter (the name is derived from the Greek for “curved rod”) is a genus of gram-negative bacteria that are major causes of diarrhea worldwide and are the most common stool isolate in the United States. Infection is most commonly associated with consumption of undercooked poultry, raw milk, or untreated water. Campylobacter jejuni is more frequently associated with food-borne gastroenteritis ; Campylobacter fetus and the other, less common species are more often seen in immunosuppressed patients and homosexual men. Campylobacter infects patients of all ages, but infants, children, and young adults are most often affected. The incidence in HIV-positive patients is higher than in the general population, and severe, chronic, recurrent, or disseminated infections are more common in this group. Campylobacter infection is associated with the subsequent development of several autoimmune disorders, including Guillain-Barré syndrome, Henoch-Schönlein purpura, and reactive arthropathy. Campylobacter infection may also cause exacerbations of underlying chronic idiopathic IBD. Patients typically have fever, malaise, abdominal pain (often severe), and watery diarrhea that may contain blood and fecal leukocytes. Nausea, vomiting, tenesmus, myalgias, and headache are variably present. Symptoms typically resolve within 1 to 2 weeks, but relapse is common.

Endoscopic findings include friable colonic mucosa with associated erythema and hemorrhage. Histologic examination shows features of ASLC. Mild crypt distortion may occasionally be seen, although the architecture overall is preserved ( Fig. 4.11 ). The differential diagnosis primarily includes other forms of infectious enterocolitis that produce the acute infectious-type colitis or focal active colitis pattern. Occasionally, when crypt distortion is seen, Campylobacter colitis can mimic chronic idiopathic IBD. Cultures are useful in resolving the differential diagnosis.

This case of culture-proven Campylobacter jejuni colitis shows a neutrophilic infiltrate with overlying surface mucosal erosion and hemorrhage. The architecture is largely preserved.

Yersinia

Yersinia are among the most common agents of bacterial enteritis in western and northern Europe, and the incidence is rising in both Europe and the United States. These gram-negative coccobacilli may cause appendicitis, ileitis, colitis, and mesenteric lymphadenitis. Although yersiniosis is usually a self-limited process, chronic infections (including chronic colitis) have been well documented. Immunocompromised and debilitated patients, as well as patients who are taking desferrioxamine or have iron overload, are at risk for serious disease. Yersinia enterocolitica and Yersinia pseudotuberculosis are the species that cause human GI disease.

Yersinia organisms preferentially involve the ileum, right colon, and appendix and may cause a pseudoappendicular syndrome. In addition, they are responsible for many cases of isolated granulomatous appendicitis. Grossly, the involved bowel has a thickened, edematous wall with nodular inflammatory masses centered on Peyer patches. Aphthous and linear ulcers may be seen. Involved appendices are enlarged and hyperemic, as in suppurative appendicitis; perforation is often seen. Involved lymph nodes may show gross foci of necrosis.

Both suppurative and granulomatous patterns of inflammation are common, and these are often mixed. Significant overlap is seen between the histologic features of infection with either species, and either may show epithelioid granulomas with prominent lymphoid cuffing ( Fig. 4.12, A ), lymphoid hyperplasia, transmural lymphoid aggregates, mucosal ulceration, and lymph node involvement. GI infection with Y. pseudotuberculosis has characteristically been described as a granulomatous process with central microabscesses, almost always accompanied by mesenteric adenopathy (see Fig. 4.12, B ). Gram stains are usually not helpful, but cultures, serologic studies, and PCR assays may be useful in confirming the diagnosis.

A, Epithelioid granulomas with prominent lymphoid cuffs are typical of Yersinia enterocolitica infection. B, Lymphoid hyperplasia with necrotizing granulomatous inflammation and prominent microabscess formation in a case of appendicitis caused by Yersinia pseudotuberculosis .

The major differential diagnosis includes other infectious processes, particularly with mycobacteria and Salmonella species. Acid-fast stains and culture results should help to distinguish mycobacterial infection; clinical features and the presence of greater numbers of neutrophils, microabscesses, and granulomas may help to distinguish yersiniosis from salmonellosis.

Crohn’s disease and yersiniosis may be difficult to distinguish from one another, and they have a long and complicated relationship ( Table 4.4 ). They may show similar histologic features, including transmural lymphoid aggregates, skip lesions, and fissuring ulcers. In fact, isolated granulomatous appendicitis has in the past frequently been interpreted as primary Crohn’s disease of the appendix. However, generalized IBD rarely develops in patients with granulomatous inflammation confined to the appendix. Features that favor a diagnosis of Crohn’s disease include cobblestoning of mucosa and creeping fat, grossly, and microscopic changes of chronicity, including crypt distortion, thickening of the muscularis mucosae, and prominent neural hyperplasia. However, some cases are indistinguishable on histologic grounds alone.

Clostridium difficile –Related Colitis

C. difficile infection is most commonly related to prior antibiotic exposure (especially orally administered antibiotics), because the organism cannot establish infection within the gut in the presence of normal flora. It is the most common nosocomial GI pathogen. The majority of patients are elderly, although infection is certainly not limited to this group. Recurrent disease is seen in as many as one half of cases, despite successful treatment. Furthermore, the incidence of severe or life-threatening C. difficile colitis in North America has increased because of the hypervirulent BI/NAP1 strain. The range of clinical disease is highly variable, from mild diarrhea to fully developed PMC to fulminant disease with perforation or toxic megacolon. Watery diarrhea is almost always present initially and may be accompanied by abdominal pain, cramping, fever, and leukocytosis. Bloody diarrhea is sometimes seen. Symptoms can occur as long as several weeks after discontinuation of antibiotic therapy.

The entire colon is often involved, but the disease may be patchy or segmental, and any segment of the bowel may be affected, including the small bowel and the appendix. Classic PMC shows yellow-white pseudomembranes, most commonly in the left side of the colon, that bleed when scraped. The distribution is often patchy, and the rectum may be spared. Atypical findings include mucosal erythema and friability without pseudomembranes, and typical histologic findings may be seen in the absence of macroscopically evident pseudomembranes.

Histologically, classic PMC features “volcano” or “mushroom” lesions with intercrypt necrosis and ballooned crypts, giving rise to the laminated pseudomembrane composed of fibrin, mucin, and neutrophils ( Fig. 4.13, A and B ). Ballooned glands are filled with neutrophils and mucin, and the superficial epithelial cells are often lost. Degenerated goblet cells may slough and spill into the lumen of degenerated and necrotic crypts (see Fig. 4.13, C ); it is important to be aware of this reactive morphologic change in the context of PMC, because it can mimic signet ring cell adenocarcinoma. Severe and prolonged PMC may lead to full-thickness mucosal necrosis. Less characteristic nonspecific lesions, usually focal active colitis with occasional crypt abscesses but lacking the pseudomembranous feature, have been well described in association with a positive C. difficile toxin assay.

A, The classic “volcano” lesion of Clostridium difficile with a laminated pseudomembrane composed of fibrin, mucin, and neutrophils. B, Higher-power view shows intercrypt necrosis and markedly dilated crypts giving rise to the pseudomembrane. C, Sloughed epithelial cells within degenerated crypts may resemble signet ring cells.

It is important to remember that the term “pseudomembranous colitis” is descriptive, not a specific diagnosis. Although most cases of PMC are related to C. difficile , other infectious entities (especially Shigella and EHEC), as well as ischemic colitis, can have a similar appearance. A hyalinized lamina propria favors the diagnosis of ischemia; other features, such as crypt withering, pseudomembranes, and mucosal necrosis, may be seen in either entity. Endoscopically, pseudomembrane formation is more frequent in PMC, although it can be seen in ischemia.

A history of antibiotic use may be important in making the diagnosis. C. difficile PCR assays are replacing the C. difficile enzyme-linked immunosorbent assays (ELISA) that detect toxins in many centers, owing to their superior sensitivity and specificity. Another approach is to screen stools by using enzyme immunoassays (EIA) that detect glutamate dehydrogenase derived from C. difficile. Unlike those that detect toxin, this immunoassay is highly sensitive, although positive results require confirmation (usually by PCR). Studies comparing the sensitivity and specificity of all of these ancillary diagnostic modalities are ongoing.

C. perfringens causes a segmental necrotizing enteritis (also termed enteritis necroticans or pigbel) related to food poisoning. This bacteria also causes diarrhea unrelated to food poisoning, which is often associated with antibiotic use and hospitalization in elderly patients. Food-related infection is most common in Southeast Asia and New Guinea. The onset of disease usually follows a meal rich in infected meat and occurs in persons with malnutrition and those in endemic areas who routinely eat very-low-protein diets and foods that are high in protease inhibitors. Similar cases have been described after eating binges in Western countries. Infection also has been associated with diabetes, possibly because of the delayed gastric emptying and reduced intestinal motility seen in these patients. Symptoms include abdominal pain, bloody diarrhea, and vomiting, often with abdominal distention. Complications include perforation, obstruction, bowel gangrene, and septicemia with shock and rapid death. Mild or subacute forms have also been described. Involvement is predominantly seen in the jejunum but is not limited to that site. The bowel is often dusky gray-green, as in ischemia. Necrotic areas may be segmental and quite focal, with intervening areas of normal mucosa. The mucosal exudate can be similar to that of PMC, but inflammation and necrosis often become transmural and lead to perforation. Histologically, the mucosa is necrotic and ulcerated, with a heavy acute inflammatory infiltrate at the edges of ulcers ( Fig. 4.14, A ). Small-vessel vasculitis and microthrombi may be seen. Pneumatosis may be present in severe cases, particularly in the mucosa and submucosa (see Fig. 4.14, B ). Gram-positive bacilli typical of Clostridium can be found in the necrotic exudate. The major entities in the differential diagnosis of necrotizing enteritis include ischemia and other infections that cause an ischemic-type injury, such as EHEC. The clinical history of consumption of large quantities of meat (especially pork or pork products) may be helpful, along with exclusion of other possible causes of ischemia. Cultures can help to distinguish C. perfringens from other bacteria.

A, Mucosal hemorrhage, necrosis, ulceration, and crypt withering that mimic ischemia are seen in this case of Clostridium perfringens infection. (Courtesy of Dr. Robert D. Odze, Brigham and Women’s Hospital.) B, Pneumatosis may also be found in the submucosa.

Clostridium septicum is associated with neutropenic enterocolitis (typhlitis), a serious complication of both chemotherapy-related and primary neutropenia. Most patients have received chemotherapy within the month before the onset of colitis. Although C. septicum has been frequently reported as a causative agent of typhlitis, especially in adults, other commonly implicated bacteria include other clostridial species, E. coli, Pseudomonas species, and enterococci. C. septicum infection is also associated with malignancies (particularly adenocarcinoma) in the colon and distal ileum, and infection may be the first indication of such a tumor. Patients usually are seen with the abrupt onset of GI hemorrhage, accompanied by fever, abdominal pain and distention, and diarrhea. The pain often initially localizes to the right lower quadrant but quickly progresses to peritonitis, shock, and sepsis. Perforation is a well-described complication, and infection is often fatal.

The right colon (especially the cecum) is preferentially involved, although the ileum and other sites in the colon may be affected. Gross findings include diffuse dilatation and edema of the bowel, with varying severity of ulceration and hemorrhage. Exudates and pseudomembranes resembling C. difficile colitis are common. Microscopically, changes range from mild hemorrhage to prominent submucosal edema, ulceration, marked hemorrhage, and focal necrosis, often with a striking absence of neutrophils ( Fig. 4.15 ). However, neutrophils may sometimes be found despite peripheral neutropenia. Sometimes organisms can be detected in the wall of the bowel on Gram staining. The differential diagnosis includes ischemic colitis and PMC. The appropriate clinical setting and dearth of inflammatory cells should favor a diagnosis of neutropenic enterocolitis. Culture is the most helpful technique for confirming the diagnosis of C. septicum infection, and isolation of the organism from blood cultures may be helpful in septic patients.

Typhlitis (neutropenic enterocolitis) in a chemotherapy patient features ulceration with hemorrhage, prominent submucosal edema, mucosal ulceration and necrosis, and almost no neutrophils.

Mycobacterium tuberculosis

There has been a remarkable resurgence of tuberculosis in Western countries, due in large part to AIDS, but also to institutional overcrowding and immigrant populations. Tuberculosis remains common in developing countries as well. GI tuberculosis may be acquired through several mechanisms, including swallowing infected sputum in pulmonary tuberculosis; ingestion of contaminated milk (rare where pasteurization is common); hematogenous spread from pulmonary or military disease; and direct extension from adjacent organs.

GI symptoms (rather than pulmonary) may be the initial presentation of disease, and extrapulmonary manifestations of tuberculosis are more common in AIDS patients than in immunocompetent persons. In addition, primary GI tuberculosis in the absence of pulmonary infection has been well documented. Symptoms and signs of GI tuberculosis vary with the site or sites of involvement. The ileocecal and jejunoileal areas are most commonly involved, probably because of the abundance of lymphoid tissue at those locations. Associated mesenteric adenopathy is very common. Involvement of the ascending colon, duodenum, or rectum is less frequent. Gastroesophageal, appendiceal, or anal/perianal involvement is rare but is well documented in the literature. Peritoneal tuberculosis is slightly more common than GI tuberculosis and may cause ascites as well as clinically significant adhesions.

Regardless of the site of involvement, patients often have nonspecific symptoms including weight loss, fever, abdominal pain, diarrhea, or a palpable abdominal mass. Other symptoms include night sweats, malaise, anorexia, GI bleeding, and signs of malabsorption. Symptoms have often been present for months. Laboratory abnormalities include an elevated erythrocyte sedimentation rate and mild anemia.

Strictures and ulcers (often occurring together) are the most common endoscopic findings, along with thickened mucosal folds and inflammatory nodules. The ulcers are often circumferential and transverse. Multiple and segmental lesions with skip areas are common and may mimic those of Crohn’s disease (see Table 4.4 ). Large inflammatory masses (tuberculomas), usually involving the ileocecum, may be seen, and well-described complications include obstruction, perforation, and hemorrhage. The wall of the bowel is often thickened and edematous, with transmural inflammation, lymphoid hyperplasia, and fibrosis in later stages of the disease. Ulcers may be superficial or deep and may overlie hyperplastic Peyer patches (aphthoid ulcers). The characteristic histologic lesion consists of caseating, often confluent, granulomas ( Fig. 4.16, A ) that may be present at any level of the gut wall but most commonly appear in the submucosa. A rim of lymphocytes is often present at the periphery of the granulomas, and giant cells are variably present. Older lesions are frequently hyalinized and calcified, and well-formed granulomas may be rare and difficult to find. Inflammation of submucosal vessels is common, and architectural distortion that mimics chronic idiopathic IBD is frequently seen overlying areas of granulomatous inflammation. Characteristic granulomas are often present within involved lymph nodes, with confluence and caseation.

A, Colonic Mycobacterium tuberculosis infection with mucosal and submucosal confluent, caseating granulomas. B, Acid-fast organisms are seen in the necroinflammatory infiltrate (Ziehl-Neelsen stain).

Acid-fast stains sometimes demonstrate organisms (see Fig. 4.16, B ), preferentially within necrotic areas or macrophages, but culture is usually required for definitive diagnosis. The acid-fast bacilli of Mycobacterium tuberculosis are typically rod shaped and have a “beaded” morphology. Organisms may be abundant in immunocompromised patients yet rare and difficult to detect in immunocompetent persons, and the number of organisms may vary with the age of the lesion and previous antituberculosis therapy. PCR assays are becoming more widely available, but sensitivity also suffers with this methodology if the number of organisms is very low. The purified protein derivative (PPD) tests may be helpful but are unreliable in immunocompromised or debilitated patients. Some atypical mycobacteria, such as Mycobacterium kansasii and Mycobacterium bovis, may cause similar pathologic findings.

The differential diagnosis includes other granulomatous infectious processes, especially yersiniosis and fungal disease, as well as noninfectious processes such as sarcoidosis, Behçet disease, reaction to foreign material, and granulomatous changes secondary to a delayed or interval appendectomy. The granulomas of yersiniosis are typically noncaseating with striking lymphoid cuffs, but there may be considerable histologic overlap. Crohn’s disease may be difficult to distinguish from tuberculosis ; features favoring Crohn’s disease are linear rather than circumferential ulcers, transmural lymphoid aggregates, and deep fistulas and fissures. Tuberculosis also commonly lacks mucosal cobblestoning. A further confounding factor is that tuberculosis has recently been associated with the use of infliximab, a tumor necrosis factor-α neutralizing agent used in treating Crohn’s disease and rheumatoid arthritis. The pattern of involvement in these patients is somewhat unusual, with most exhibiting extrapulmonary tuberculosis. The emergence of infection is often associated with initiation of treatment.

Mycobacterium avium-intracellulare Complex

Mycobacterium avium-intracellulare complex is the most common mycobacterium isolated from the GI tract. It is typically found in patients with AIDS and other immunocompromising conditions, although it is occasionally seen in immunocompetent persons. Symptoms include diarrhea, abdominal pain, fever, and weight loss and often reflect systemic infection. Endoscopy findings are usually normal, although white nodules, small ulcers, or hemorrhages may be seen. The small bowel is preferentially involved, but colonic and gastroesophageal involvement may be present, as may mesenteric adenopathy.

Histologic manifestations vary with the site and the immune status of the patient. Immunocompetent patients usually have a well-formed, often epithelioid granulomatous response, either with or without necrosis. Small bowel biopsies from immunocompromised patients typically show villi distended by a diffuse infiltration of histiocytes containing bacilli ( Fig. 4.17, A ), with little inflammatory response other than occasional poorly formed granulomas. The small bowel is most often involved, but similar histiocytic infiltrates may be seen in the colon and other areas of the GI tract. Bacilli stain with acid-fast stains (see Fig. 4.17, B ), as well as periodic acid–Schiff (PAS) and Gomori’s methenamine silver (GMS) stains. Mycobacteria (including M. tuberculosis and Mycobacterium leprae ) may also stain for desmin, actin, and keratin. Culture and PCR assays can be extremely helpful in diagnosis. Organisms are usually abundant in the immunocompromised host but may be harder to detect in healthy patients. The differential diagnosis includes Whipple disease and other infectious processes.

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