When evaluating a colonic biopsy for possible infectious processes, the surgical pathologist must first attempt to differentiate histologic changes suggesting infectious colitis from other inflammatory processes, especially chronic idiopathic inflammatory bowel disease (ulcerative colitis or Crohn’s disease). Following this determination, dedicated attempts must be made to diagnose the specific infectious organism or organisms. The surgical pathologist’s ability to detect infectious processes in tissue sections has grown exponentially with the advent of new histochemical and immunohistochemical stains, in situ hybridization, and polymerase chain reaction (PCR) analysis. As these techniques have developed and become more widely available for diagnostic use, our knowledge of the pathologic spectrum that specific infectious organisms can cause has also grown, including our knowledge of those infectious processes that can closely mimic Crohn’s disease, ulcerative colitis, and ischemic colitis.
Most enteric infections are self-limited. Patients who undergo endoscopic evaluation and biopsy generally have unusual clinical features such as chronic or debilitating diarrhea, evidence of systemic disease, or a history of immunocompromise. One of the most valuable (and least expensive) diagnostic aids for the surgical pathologist is a discussion with the gastroenterologist regarding specific symptoms, colonoscopic findings, travel history, food intake history (e.g., sushi, poorly cooked beef), sexual practices, and immune status.
Despite the large number of infectious agents that may affect the colon, the histologic features that they produce may be generally categorized as follows:
- 1.
Organisms producing very mild or no histologic changes (e.g., enteroadherent Escherichia coli )
- 2.
Organisms producing the histologic features of acute infectious/self-limited colitis (ASLC) or focal active colitis (FAC), such as Campylobacter species
- 3.
Organisms producing suggestive or diagnostic histologic features, such as pseudomembranes, granulomas, or viral inclusions
The pattern of ASLC or FAC is one of the most common seen in infectious colitis. Typical histologic features include focal cryptitis, with or without increased neutrophils in the lamina propria and crypt abscesses; preservation of crypt architecture; and lack of basal plasmacytosis. The acute inflammatory component may be most prominent in the mid to upper crypts. The lack of crypt distortion and basal lymphoplasmacytosis helps distinguish ASLC from early ulcerative colitis. Details of specific viral, bacterial, fungal, and parasitic infections of the colon are given in the following sections.
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Viral infections of the colon
A wide variety of viruses affect the colon. Manifestations of disease vary with the type of virus, specific site of infection, and immune status of the patient.
Cytomegalovirus
Cytomegalovirus (CMV) infection occurs in both immunocompromised and immunocompetent persons, and may be found anywhere in the large bowel. The pathogenesis in truly healthy patients is poorly understood. Underlying immunocompromise should be considered when CMV infection is diagnosed, because it is an opportunistic pathogen in patients with many types of immune compromise, including those with acquired immunodeficiency syndrome (AIDS) and those who have undergone solid organ or bone marrow transplantation.
Clinical features
Symptoms vary with the immune status of the patient and the specific site of infection. The most common clinical symptoms are diarrhea (either bloody or watery), abdominal pain, fever, and weight loss; however, primary infections in healthy, immunocompetent persons are often self-limited. CMV is well known as a secondary pathogen superimposed on other chronic gastrointestinal (GI) diseases, such as ulcerative colitis and Crohn’s disease; in such cases, CMV superinfection has been associated with high mortality, toxic megacolon, and exacerbations of the underlying GI disease.
Definition
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Viral infection
Incidence and location
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Anywhere in GI tract
Clinical features
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Most common in, but not limited to, immunocompromised patients
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Frequent symptoms are diarrhea (with or without blood), abdominal pain, fever, weight loss
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May cause an ischemic picture, both clinically and pathologically
- ■
May superinfect Crohn’s disease or ulcerative colitis
Prognosis and therapy
- ■
Infections in healthy persons are usually self-limiting
- ■
Ganciclovir is first line of medical therapy, but now is often used in combination with newer drugs
Pathologic features
Gross findings
CMV causes a wide variety of gross lesions in the colon. Ulcers are the most common finding ( Fig. 9-1 ); they may be single or multiple, and either superficial or deep. The ulcers often have a well-demarcated, “punched out” appearance. Other gross findings include hemorrhagic colitis, pseudomembranous colitis (PMC), and obstructive mass lesions.
Segmental ulcerative lesions and linear ulcers mimicking Crohn’s disease have been well documented in colonic CMV infection. Complications of severe ulcerative CMV infection include toxic megacolon and perforation.
Microscopic findings
The histologic spectrum of CMV infection also varies widely, ranging from a minimal inflammatory reaction to deep ulcers with prominent granulation tissue and necrosis at the base ( Fig. 9-2 ). Typical histologic features include cryptitis, a mixed inflammatory infiltrate in the lamina propria with numerous neutrophils, and mucosal ulceration. Crypt abscesses, crypt atrophy and loss, and numerous apoptotic enterocytes may be seen as well. Characteristic inclusions with virtually no associated inflammatory reaction may be seen, particularly in severely immunocompromised patients. Inclusions are preferentially found in endothelial cells and stromal cells, and only rarely in epithelial cells. The characteristic “owl’s eye” inclusions are visible on routine hematoxylin and eosin (H&E) preparations, and may be present within both the cytoplasm and the nucleus of the cell. Unlike adenovirus and herpes infections, CMV inclusions are characteristically found deep within ulcer bases, rather than at the edges of ulcers or in superficial mucosa ( Fig. 9-3 ).
A more recently described sequel of CMV infection is segmental bowel ischemia. Mucosal changes are identical to those seen in ischemia of other causes (hemorrhagic necrosis and crypt withering). Numerous endothelial cells containing CMV inclusions are seen in the vessels of the mucosa and submucosa; vessel walls are inflamed and necrotic, and microthrombi are present within the lumen ( Fig. 9-4 ). Presumably, viral infection of numerous endothelial cells initiates inflammatory mediators, leading to thrombosis and subsequent bowel ischemia.
Gross findings
- ■
Most commonly ulcers, single or multiple, shallow or deep
- ■
May also manifest as colitis (hemorrhagic or pseudomembranous) or obstructive mass
- ■
Segmental or linear ulceration may mimic Crohn’s disease grossly
Microscopic findings
- ■
Colitis featuring cryptitis, mixed inflammatory infiltrate in the lamina propria with numerous neutrophils, mucosal ulceration, crypt abscesses, crypt atrophy, and numerous apoptotic enterocytes
- ■
Characteristic inclusions: “Owl’s eye” inclusions are visible on routine hematoxylin and eosin preparations and are present in both cytoplasm and nucleus
- ■
Inclusions are within mesenchymal and endothelial cells, often deep within ulcer bases
- ■
No associated inflammatory reaction may be seen, particularly in severely immunocompromised patients
- ■
Severe endothelial infection may cause ischemia
Differential diagnosis
- ■
Other viral infections, particularly adenovirus
- ■
Crohn’s disease
- ■
Graft-versus-host disease
- ■
Ischemic colitis
Ancillary studies
Examination of multiple levels and use of immunohistochemical stains is recommended when evaluating colonic biopsy specimens for CMV infection, for the diagnosis may be easily missed when only rare inclusions are present. Other useful diagnostic aids include viral culture, PCR assays, in situ hybridization, and serologic studies. Isolation of CMV in culture, however, does not imply active infection, because virus may be excreted for months to years after a primary infection.
Differential diagnosis
The differential diagnosis is primarily that of other viral infections, particularly adenovirus. CMV inclusions have the characteristic owl’s eye morphology, are generally located within endothelial or stromal cells, and exist within both nucleus and cytoplasm. Adenovirus inclusions, by comparison, are crescent shaped or have irregular outlines, are generally within surface epithelium, and are only intranuclear in location. As mentioned previously, CMV may mimic Crohn’s disease both grossly and microscopically, and a careful search for inclusions should confirm the diagnosis of CMV infection (although the two may coincide; Fig. 9-5 ). The distinction between CMV infection and graft-versus-host disease (GVHD) in bone marrow transplant patients may be particularly difficult, because both clinical and histologic features are similar. Immunohistochemistry or in situ hybridization studies should be employed to rule out CMV infection in this setting, because failure to identify CMV infection could result in delay of antiviral therapy.
Prognosis and therapy
The vast majority of infections in healthy persons are self-limiting. Ganciclovir has historically been the mainstay of medical therapy, but this drug has problems with toxicity and poor oral bioavailability, and resistant strains are evolving. Newer drugs such as foscarnet are now often used in combination with ganciclovir.
Herpesvirus
Herpetic infection of the large bowel is most commonly seen in the anorectum. Although colonic herpes infections are often seen in immunocompromised patients, they are by no means limited to this group. The symptoms and pathologic features of herpes simplex virus type 1 (HSV-1) versus HSV-2 are indistinguishable. In immunocompetent patients, herpetic infection is often self-limiting; immunocompromised persons may be at risk for dissemination and life-threatening illness.
Clinical features
Herpetic proctitis is the most common cause of nongonococcal proctitis in homosexual men. Herpes infection in this area generally presents with severe anorectal pain, bloody discharge or frank bleeding, tenesmus, constipation, and fever. Concomitant neurologic symptoms (difficulty in urination and paresthesias of the buttocks and upper thighs) are well described, as is inguinal lymphadenopathy. Herpes colitis is most often seen in immunocompromised patients. Patients present with diarrhea, fever, abdominal pain, and lower GI bleeding. Fulminant, life-threatening colitis with perforation may occur rapidly in immunocompromised patients. Similar to CMV, HSV may superinfect and complicate preexisting Crohn’s disease or ulcerative colitis.
Definition
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Viral infection, often in immunocompromised patients
Incidence and location
- ■
Predominantly anorectal; rarely colon
- ■
Most common cause of nongonococcal proctitis in homosexual men
Clinical features
- ■
Most common in, but not limited to, immunocompromised patients
- ■
Frequent symptoms
- ■
Proctitis—Anorectal pain, discharge, spasm, and fever, often with neurologic symptoms (paresthesias, difficulty urinating) and inguinal lymphadenopathy; perianal vesicles often present
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Colitis—Diarrhea, abdominal pain, fever, lower GI bleeding; fulminant colitis with perforation may develop
- ■
May superinfect Crohn’s disease or ulcerative colitis
- ■
Prognosis and therapy
- ■
Acyclovir is first line of medical therapy; surgery may be required if fulminant colitis or perforation develops
Pathologic features
Gross findings
In herpetic colitis, the most typical finding is ulceration. Ulcers are often multiple and confluent. Surrounding mucosa is often hemorrhagic and friable, and “cobblestoning” of the mucosa may be seen. In herpetic proctitis, perianal vesicles are common, and they may extend up into the anal canal and rectum. Associated proctoscopic findings include anorectal ulceration and mucosal friability.
Microscopic findings
Ulceration is the most frequent finding, accompanied by increased neutrophils in the lamina propria, and an inflammatory exudate that often contains sloughed epithelial cells. Perivascular lymphocytic cuffing and crypt abscesses may also be seen. Two types of characteristic nuclear inclusions may be found: (1) the more common smudged, ground-glass nuclear inclusion with peripheral darker, marginated chromatin ( Fig. 9-6 ), and (2) the acidophilic inclusions with a surrounding clear halo and peripheral chromatin margination (Cowdry type A inclusion). Inclusions are detectable in less than half of biopsy specimens, and ancillary studies may be required if HSV is suspected. The best place to search for the atypical cells of herpetic infection is within the mucosa at the edges of ulcers ( Fig. 9-7 ) and in sloughed cells within the exudate. If present, inclusions are often multiple.
Ancillary studies
Viral culture is the most valuable diagnostic aid to diagnosis; immunohistochemistry, in situ hybridization, and PCR assays may also be of use.
Gross findings
- ■
Anorectal or colonic ulcers, often multiple
- ■
Associated mucosal friability and hemorrhage, sometimes “cobblestoned” mucosa
Microscopic findings
- ■
Ulceration, accompanied by increased neutrophils in lamina propria, and inflammatory exudate with sloughed epithelial cells
- ■
Characteristic viral inclusions, consisting of a smudged, ground-glass nucleus with peripheral darker, marginated chromatin
- ■
Often found in epithelium of mucosa at the edges of ulcers and in sloughed cells in exudate
Differential diagnosis
- ■
Other viral infections, particularly varicella
- ■
Crohn’s disease
Differential diagnosis
The differential diagnosis predominantly includes other viral infections, such as CMV and varicella zoster. Morphology and location of the inclusions usually resolve the differential diagnosis, but ancillary studies may be required. Herpetic inclusions are most often in the epithelial cells of the mucosa, whereas CMV preferentially involves the endothelial and mesenchymal cells. It is also important to remember that mixed infections are common in many situations in which herpetic infection is found. Rarely, segmental ulceration and cobblestoning of mucosa may mimic Crohn’s disease, and as in the case of CMV infection, HSV infection should be considered when patients with idiopathic inflammatory bowel disease experience disease flare-ups and relapses.
Prognosis and therapy
Acyclovir is the mainstay of medical therapy. Segmental resection to control bleeding and prevent perforation may be required in severe cases of herpetic colitis.
Adenovirus
Adenovirus infection is second only to rotavirus as a cause of generally self-limiting childhood diarrhea. However, it has recently gained much attention as a cause of diarrhea in immunocompromised patients, especially those with AIDS and patients who have undergone transplantation (particularly bone marrow transplantation). Adenovirus infection of the GI tract is strongly associated with concomitant acute GVHD.
Clinical features
Virtually all patients present with diarrhea, sometimes accompanied by fever, weight loss, lower GI bleeding, and abdominal pain.
Pathologic features
Gross findings
Endoscopic findings typically include evidence of colitis, such as erythematous, friable, and granular mucosa.
Microscopic findings
Histologic features of adenovirus infection include epithelial changes such as superficial cellular degeneration, apoptosis of epithelial cells, and focal acute inflammation. Severe cases may show ulceration and exudate. Characteristic homogeneous, smudgy, eosinophilic inclusions may be seen filling the nucleus. Adenovirus inclusions are, except in rare circumstances, limited to epithelial cells; inclusions are most common within surface epithelium ( Fig. 9-8 ) but are also seen in the colonic crypts. Inclusions are particularly common in surface goblet cells, in which they are often crescent shaped ( Fig. 9-9 ). Cowdry type A inclusions are rarely seen, but the owl’s eye morphology of CMV inclusions is absent in adenovirus infection.
Gross findings
- ■
Evidence of colitis including erythematous, friable, and granular mucosa
Microscopic findings
- ■
Superficial cellular degeneration, apoptosis of epithelial cells, and focal acute inflammation; severe cases may show ulceration and exudate
- ■
Inclusions
- ■
Characteristic homogeneous, smudgy, eosinophilic inclusions fill the nucleus
- ■
Inclusions can be crescent shaped or targetoid
- ■
Most common within surface epithelium, particularly goblet cells, but can be seen in crypt epithelial cells; almost never in endothelial and mesenchymal cells
- ■
Differential diagnosis
- ■
Other viral infections, particularly CMV
Ancillary studies
Useful aids to diagnosis of adenovirus infection include immunohistochemistry, stool examination by electron microscopy, and viral culture.
Differential diagnosis
The differential diagnosis primarily includes other viral infections, especially CMV. Morphologic differences between the two viruses, as well as differences in location within the gut (epithelium versus endothelium/mesenchymal cells) usually help resolve the differential diagnosis. Because adenovirus often coexists with GVHD, it may be overlooked if a careful search for inclusions is not undertaken.
Prognosis and therapy
The antiviral drug ribavirin is the mainstay of therapy.
AIDS enterocolopathy
AIDS enterocolopathy has been loosely defined as the morphologic changes seen in the gut of patients with HIV/AIDS and chronic diarrhea, for which no other infectious cause has been identified. Some workers believe that these changes represent either primary infection of gut epithelial cells with HIV or a secondary autoimmune reaction to viral infection. Others believe that this is a poorly understood term that does not clearly represent a specific disease entity, and thus should not be used at all. The controversy arises because asymptomatic patients may have similar morphologic findings on biopsy, and conversely severely symptomatic patients may have normal biopsy findings. In addition, there is always the added concern that a causative pathogen simply has been missed. Because patients with HIV/AIDS do have severe impairments of GI function including diarrhea, malabsorption, and weight loss, even in the absence of any demonstrable pathogen, some authors support using the term AIDS enterocolopathy to describe the morphologic findings, provided that the bowel has been adequately sampled and all other infectious causes have been excluded.
Clinical features
Patients with these abnormalities often have chronic diarrhea, but some are asymptomatic. Colonoscopy is usually normal.
Pathologic features
The histologic findings are more commonly described in the small bowel, but may also affect the colon. Histologic features include increased apoptotic enterocytes ( Fig. 9-10 ) and decreased numbers of mitotic figures relative to extent of mucosal injury; the changes resemble those seen in mild GVHD and chemotherapy-related mucosal injuries.
Differential diagnosis
The differential diagnosis includes GVHD, chemotherapy- and drug-related injury, and other viral infections such as CMV. Once other infectious agents have been rigorously excluded, the clinical history of HIV infection usually resolves the differential.
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Bacterial infections of the colon
Diarrhea resulting from bacterial infection is a significant worldwide health problem. E. coli , Salmonella , Shigella , and Campylobacter are the most commonly identified pathogens, and many bacterial infections of the gut are related to ingestion of contaminated water or food, or travel to foreign countries. Although bacteria are often recovered by culture, surgical pathologists may play a valuable role in diagnosis. A general classification of colonic bacterial infections by histologic pattern is given in Table 9-1 .
| Minimal or No Inflammatory Change | Acute Self-Limited Colitis Pattern | Pseudomembranous Pattern | Predominantly Granulomatous | Diffuse Histiocytic | Predominantly Lymphohistiocytic | Marked Architectural Distortion | Ischemic Pattern |
|---|---|---|---|---|---|---|---|
| Enteropathic Escherichia coli Enteroadherent E. coli Spirochetosis Neisseria species | Shigella Campylobacter Aeromonas Salmonella (nontyphoid) Occasionally Clostridium difficile Syphilis (± increased plasma cells) | Enterohemorrhagic E. coli C. difficile Occasionally Shigella | Yersinia Mycobacterium tuberculosis Actinomycosis (mixed suppurative and granulomatous) MAI (immunocompetent patients) Rarely syphilis | Rhodococcus equi MAI (immuno-compromised patients) | LGV Salmonella typhimurium | S. typhimurium Shigella | Enterohemorrhagic E. coli |
Escherichia coli
Diarrheagenic E. coli organisms are classified into five groups: enterotoxigenic, enteropathogenic, enteroadherent, enteroinvasive, and enterohemorrhagic. If pathogenic E. coli is suspected, the clinical laboratory should be notified to search for it specifically, because cultures may be a valuable diagnostic aid.
Enterohemorrhagic E. coli (EHEC) is discussed in detail later, because it is more commonly encountered by surgical pathologists than the other groups. Enterotoxigenic E. coli is a major cause of traveler’s diarrhea, but patients are seldom examined via biopsy, and the pathology has not been well characterized in humans. Enteropathogenic E. coli (EPEC) predominantly affects infants and neonates. Biopsy is not generally performed and is not diagnostically useful, although occasionally gram-negative rods may be seen at the surface of the mucosa. Enteroadherent E. coli (EAEC) is similar to the enteropathogenic group and is also an important cause of traveler’s diarrhea and pediatric diarrhea worldwide. Both EPEC and EAEC have been increasingly recognized as causes of chronic diarrhea and wasting in AIDS patients. Endoscopic findings are usually unremarkable, but histologic examination shows a coating of adherent bacteria at the surface epithelium, which may stain gram negative ( Fig. 9-11 ). Degenerated surface epithelial cells with associated intraepithelial inflammatory cells may also be present. Enteroinvasive E. coli (EIEC) is similar to Shigella both genetically and in its clinical presentation and pathogenesis. Given its capacity for invasion, EIEC produces a severe dysentery-like diarrheal illness that can be a particular problem in patients with AIDS. The gross and microscopic pathology of EIEC has not been well described.
Enterohemorrhagic escherichia coli
The most common strain of EHEC is 0157:H7. This infectious disease is probably markedly underdiagnosed. EHEC gained national attention in 1993 when a massive outbreak in the Western United States was linked to contaminated hamburger patties served at a fast-food restaurant. This organism adheres to intestinal epithelial cells and produces a cytotoxin similar to that produced by Shigella dysenteriae; however, there is no invasion. Although contaminated meat is the most frequent mode of transmission, infection may also occur through contaminated water, milk, produce, and person-to-person contact.
Clinical features
GI 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. Rarely, this infection leads to frank lower GI bleeding. Affected persons may develop hemolytic-uremic syndrome or thrombotic thrombocytopenic purpura, and children and the elderly are at particular risk for serious, systemic illness.
Definition
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Diarrheagenic E. coli strain producing hemorrhagic colitis
Incidence and location
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Preferentially involves right colon
Clinical features
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Bloody diarrhea (rarely nonbloody) with severe abdominal cramps
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Mild or no fever
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One third of patients have fecal leukocytes
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Sometimes leads to obstructive edema or massive bleeding
- ■
Patients at risk for hemolytic-uremic syndrome and thrombotic thrombocytopenic purpura
Prognosis and therapy
- ■
Mainly supportive care
- ■
Role of antibiotics controversial
- ■
Surgery may be required to relieve obstruction or control bleeding
Pathologic features
Gross findings
Endoscopically, patients have colonic edema, erosions, ulcers, and hemorrhage, and the right colon is usually more severely affected. The edema may be so marked as to cause obstruction.
Microscopic findings
The histopathologic features are those of ischemic colitis, because the toxin is believed to induce an ischemic insult. These features include marked edema and hemorrhage in the lamina propria and submucosa ( Fig. 9-12 ), with associated mucosal acute inflammation, crypt withering, and necrosis ( Fig. 9-13 ). Microthrombi may be seen within small vessels, and pseudomembranes may occasionally be present.
Gross findings
- ■
Colonic edema, erosions, ulcers, and hemorrhage
Microscopic findings
- ■
Mimics ischemic colitis of other causes
- ■
Marked edema and hemorrhage in the lamina propria and submucosa
- ■
Mucosal acute inflammation, crypt withering, and necrosis
- ■
Microthrombi may be seen within small vessels
- ■
Pseudomembranes may be present
Differential diagnosis
- ■
Ischemic colitis of other causes
- ■
C. difficile– related PMC
- ■
Rarely, idiopathic inflammatory bowel disease
Ancillary studies
Routine stool cultures will not distinguish 0157:H7 from normal intestinal flora, and successful culture may be impossible more than 4 days after onset of symptoms. Microbiologic diagnosis requires screening on special agar. An immunohistochemical stain for this organism has recently been described, and molecular assays for use on routinely processed tissue are being developed. If this organism is suspected, the microbiology lab should be notified so that special media and serotyping assays may be employed in a timely manner.
Differential diagnosis
The differential diagnosis includes Clostridium difficile– related colitis, idiopathic inflammatory bowel disease, and especially ischemic colitis. Histologic features of ischemia in the right colon, particularly in patients who are not at risk for atherosclerotic disease, should prompt consideration of EHEC and the appropriate cultures. If pseudomembranes are present, differentiation from C. difficile– related colitis may be difficult, and cultures or the C. difficile toxin assay may be required. The histologic features of ischemia generally serve to distinguish EHEC from idiopathic inflammatory bowel disease.
Prognosis and therapy
There is no proven therapy for EHEC, and the role of antibiotic treatment is controversial, although most strains are susceptible. Surgical resection of the affected colon may be required to relieve obstruction from edema or to control bleeding.
Salmonellosis
Salmonella, which are gram-negative bacilli, are transmitted through food and water and are particularly prevalent where sanitation is poor. They are an important cause of both food poisoning and traveler’s diarrhea. The discussion of Salmonella species may be generally divided into typhoid and nontyphoid species. Enteric (typhoid) fever is usually caused by S. typhi ; 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 was previously thought. The infective dose is relatively low (approximately 10 3 organisms may cause human disease). Patients with low gastric acidity are at increased risk for salmonellosis, and patients with AIDS have a greater risk for Salmonella infection as well as a greater likelihood of severe infection and septicemia.
Clinical features
There are numerous manifestations of Salmonella infection, including an asymptomatic carrier state (often the organism is harbored in the gallbladder), a self-limited gastroenteritis, typhoid fever, and septicemia. Patients with typhoid (enteric) fever typically present with fever (which generally rises over several days), abdominal pain, headache, and occasionally initial constipation. Abdominal rash (“rose spots”), delirium, hepatosplenomegaly, and leukopenia are fairly common. The diarrhea, which begins in the second or third week of infection, is first watery but may progress to severe GI bleeding and perforation. Nontyphoid Salmonella species generally causes a milder, self-limited gastroenteritis with vomiting, nausea, fever, and watery diarrhea. Occasionally these species cause bloody diarrhea or toxic megacolon.
Definition
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Gram-negative enteric bacterium causing typhoid (enteric) fever or milder gastroenteritis; may mimic idiopathic inflammatory bowel disease
Incidence and location
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Any level of colon; typhoidal form typically involves ileum, right colon, and appendix most dramatically
Clinical features
- ■
Typhoidal form
- ■
Fever (rising over several days), abdominal pain, headache, and occasionally constipation
- ■
Abdominal rash (rose spots) and leukopenia
- ■
Diarrhea begins in the second or third week
- ■
Diarrhea is initially watery but may progress to severe GI bleeding
- ■
Nontyphoidal form
- ■
Milder, self-limited gastroenteritis with vomiting, nausea, fever, and watery diarrhea
- ■
More clinical and pathologic overlap between the typhoidal and nontyphoidal forms than previously thought
Prognosis and therapy
- ■
Antibiotics, supportive care
Pathologic features
Gross findings
In enteric fever, any level of the alimentary tract may be involved, but the characteristic pathology is most prominent in the ileum, appendix, and colon and is associated with Peyer’s patches. Grossly, the bowel wall is thickened, and raised nodules may be seen corresponding to hyperplastic Peyer’s patches. Aphthoid ulcers overlying Peyer’s patches, linear ulcers, discoid ulcers, or full-thickness ulceration and necrosis are common as disease progresses. Perforation and toxic megacolon may also be seen, as may suppurative mesenteric lymphadenitis. Occasionally, the mucosa is grossly normal or only mildly inflamed and edematous. Endoscopic findings in nontyphoid salmonellosis include mucosal redness, ulceration, and exudates, but the characteristic nodularity and marked edema are not generally seen.
Microscopic findings
The histiocyte is the predominant inflammatory cell in typhoid fever ( Fig. 9-14 ). Peyer’s patches become hyperplastic, and then acute inflammation of the overlying epithelium is seen ( Fig. 9-15 ). Eventually the lymphoid follicles are infiltrated and obliterated by macrophages. Occasional lymphocytes and plasma cells are seen, but neutrophils are not prominent. Necrosis begins in the Peyer’s patch and spreads to surrounding mucosa, which eventually ulcerates. The ulcers are typically deep, with the base at the muscularis propria. Typhoid fever may also show features more consistent with acute self-limited colitis, including prominent neutrophils, cryptitis, crypt abscesses, and overlying fibrinous exudate. Granulomas are occasionally seen. In nontyphoid salmonellosis, the pathologic features are those of acute self-limited colitis of any infectious cause. Occasionally, significant crypt distortion may be seen ( Fig. 9-16 ).
Gross findings
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Typhoid
- ■
Characteristic pathology most prominent in ileum, appendix, and colon
- ■
Markedly thickened bowel, raised nodules correspond to hyperplastic Peyer’s patches
- ■
Aphthoid ulcers overlying Peyer’s patches, linear ulcers, discoid ulcers, or full-thickness ulceration and necrosis are common
- ■
Perforation and toxic megacolon rarely seen
- ■
Suppurative mesenteric lymphadenitis may be present
- ■
Nontyphoid
- ■
Generally milder findings including mucosal redness, ulceration, and exudates
Microscopic findings
- ■
Typhoid
- ■
Histiocyte is the predominant inflammatory cell
- ■
Hyperplastic Peyer’s patches with overlying acute inflammation; eventually frank ulceration begins in Peyer’s patch and spreads to surrounding mucosa
- ■
Lymphoid follicles are infiltrated and obliterated by macrophages
- ■
Neutrophils are not prominent
- ■
Ulcers are typically very deep, with the base at the muscularis propria
- ■
Rare granulomas
- ■
Occasionally significant crypt distortion
- ■
Nontyphoid
- ■
Features of acute self-limited colitis, variable exudate
Differential diagnosis
- ■
Other bacterial infections ( Yersinia, Shigella )
- ■
Crohn’s disease
- ■
Ulcerative colitis
Ancillary studies
Stool cultures are the most helpful ancillary study, and blood cultures may also be of use if the patient is septic.
Differential diagnosis
The differential diagnosis of typhoid fever includes yersiniosis and other infectious processes, as well as Crohn’s disease, and there may be significant histologic overlap. Prominence of neutrophils and granulomas are often more prominent in the latter two diseases. The differential diagnosis of nontyphoid Salmonella infection also includes other causes of acute self-limited infectious colitis, as well as ulcerative colitis. In addition, Salmonella infection may complicate preexisting idiopathic inflammatory bowel disease. Although significant crypt distortion has been reported in some cases of salmonellosis, it is more likely to be more pronounced in ulcerative colitis. Clinical presentation and stool culture may be helpful in resolving the differential diagnosis.
Prognosis and therapy
Although the vast majority of Salmonella infections in developed countries resolve with antibiotics and supportive care, illness may progress to septicemia and death, particularly in the elderly and the very young, or in patients who are ill for other reasons. Delayed treatment is associated with higher mortality, and antibiotics are particularly important for neonates, older patients, immunocompromised persons, and patients with cardiac valve abnormalities or indwelling prostheses. Salmonella is sensitive to several antibiotics, including ciprofloxacin, penicillins, and quinolones. Follow-up stool cultures should be obtained to exclude chronic carrier states.
Shigellosis
Shigella species are virulent, invasive, gram-negative bacilli that cause severe bloody diarrhea. They are a major cause of infectious diarrhea worldwide. Shigella dysenteriae is the most common species isolated, although S. sonnei and S. flexneri are increasingly reported in the United States. The infective dose is low (as few as 10 to 100 species in S. dysenteriae type 1). Shigella is generally ingested from water contaminated with feces, but person-to-person transmission is also possible through the fecal-oral route. Infants, young children, and malnourished, immunocompromised, or debilitated patients are most commonly affected in developed countries. Like salmonellosis, the gross and microscopic features of shigellosis may closely mimic idiopathic inflammatory bowel disease.
Clinical features
Symptoms include abdominal pain, fever, and watery diarrhea, followed by bloody diarrhea. Chronic disease is rare. Perforation and hemolytic-uremic syndrome associated with Shigella have been rarely described. Most studies of mortality in shigellosis were performed in underdeveloped nations, and figures range from 2% to 10%. The mortality rate is significantly higher (exceeding 20%) if patients become septic.
Definition
- ■
Gram-negative bacterium causing severe bloody diarrhea; may mimic ulcerative colitis or Crohn’s disease both grossly and microscopically
Incidence and location
- ■
Colon, with left colon most severely affected
Clinical features
- ■
Abdominal pain, fever
- ■
Watery diarrhea followed by bloody diarrhea
- ■
Chronic disease is rare
- ■
Perforation and hemolytic-uremic syndrome occasionally develop
- ■
Severity worse in debilitated or immunocompromised patients
Prognosis and therapy
- ■
Supportive care
- ■
Selected antibiotics, because Shigella organisms have multidrug resistance
Pathologic features
Gross findings
The large bowel is typically affected, with the left colon more severely involved. The mucosa is hemorrhagic, with exudates that may form pseudomembranes. Ulcerations may be present as well.
Microscopic findings
Early infection features acute self-limited colitis with cryptitis, crypt abscesses (often superficial), and ulceration. Pseudomembranes similar to C. difficile infection may be seen, as may aphthoid ulcers similar to those of Crohn’s disease. As disease progresses, there is increased mucosal destruction with a mixed inflammatory infiltrate containing many neutrophils in the lamina propria. Marked architectural distortion to an extent that mimics idiopathic inflammatory bowel disease is commonly seen.
Gross findings
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Hemorrhagic mucosa, with exudates that may form pseudomembranes
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Ulcerations may be present as well
Microscopic findings
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Early infection
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Acute self-limited colitis with cryptitis, crypt abscesses, ulceration
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Pseudomembranes or aphthoid ulcers may be seen
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Later infection
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Increased mucosal destruction with a predominantly neutrophilic inflammatory infiltrate
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Marked architectural distortion to an extent that mimics idiopathic inflammatory bowel disease
Differential diagnosis
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Other infections, especially C. difficile and enteroinvasive E. coli
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Ulcerative colitis
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Crohn’s disease
Ancillary studies
Stool culture is essential to diagnosis. Specimens should be rapidly inoculated onto appropriate culture plates, because Shigella organisms are fastidious and die quickly. Multiple cultures may be necessary. Stool cultures are more sensitive than rectal swabs. PCR, DNA probes, and serologic studies are also available.
Differential diagnosis
The differential diagnosis of early shigellosis is primarily that of other infections, particularly enteroinvasive E. coli and C. difficile . As disease progresses, it may be extremely difficult to distinguish shigellosis from Crohn’s disease or ulcerative colitis both endoscopically and histologically. Stool cultures and clinical presentation may be helpful in this instance.
Prognosis and therapy
Treatment includes supportive care with fluid and electrolyte replacement, and antibiotics, particularly in children, people who are severely ill, and HIV-positive patients. Antibiotics lessen the mortality rate and shorten the duration of the illness. Most Shigella species have at least some degree of antibiotic resistance; trimethoprim-sulfamethoxazole, third-generation cephalosporins, and some fluoroquinolones are drugs of choice.
Campylobacter
Campylobacter species, particularly C. jejuni, are major causes of diarrhea worldwide. Campylobacter is the most common stool isolate identified in the United States. It is transmitted by the fecal-oral route; is found in contaminated meat, water, and milk; and is a common animal pathogen. C. jejuni is most commonly associated with gastroenteritis; C. fetus and the other less common species are more often seen in immunosuppressed patients and homosexual men. The importance of C. fetus may be underrecognized as a result of the difficulty of culturing it under conditions used for other Campylobacter strains. The infective dose is low (ingestion of as few as 500 organisms may cause disease), and invasion may occur.
Clinical features
Patients typically have fever, malaise, abdominal pain (often severe), and watery diarrhea, often bloody and with fecal leukocytes. Symptoms generally present within 1 to 5 days of exposure, and last for 4 to 10 days. Relapse is common, although usually less severe than the original attack. Immunosuppressed patients have a higher incidence of symptomatic infection, and symptoms are more severe. Most infections are self-limited, especially in healthy patients. Of note, Guillain-Barré syndrome and reactive arthropathy are associated with Campylobacter infection.
Definition
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Gram-negative bacterium, most common stool isolate in United States
Incidence and location
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Colon
Clinical features
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Fever, malaise, abdominal pain, watery diarrhea, often bloody and with fecal leukocytes
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Symptoms generally present within 1 to 5 days of exposure and last for 4 to 10 days
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Infection generally self-limited, although relapse is frequent
Prognosis and therapy
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Supportive care in most cases
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Erythromycin in severe cases and in immunocompromised patients
Pathologic features
Gross findings
Endoscopic findings include friable colonic mucosa with associated erythema and hemorrhage.
Microscopic findings
Histologic examination most frequently shows features of acute infectious or self-limited colitis, including cryptitis ( Figs. 9-17 and 9-18 ), crypt abscesses, surface epithelial damage, and a neutrophilic infiltrate in the lamina propria. Marked edema and superficial mucosal erosion with associated hemorrhage may be seen as well. Findings may be patchy or focal. Mild crypt distortion, crypt epithelial damage, and crypt loss are occasionally present, although crypt architecture is usually well preserved overall.
Ancillary studies
The mainstay of laboratory diagnosis is culture of Campylobacter from stool or blood. Preliminary diagnosis may be made by detection of organisms in fresh stool smears by dark-field microscopy. Stool agglutination tests are less sensitive, and serologies are only useful late in the course of disease. Molecular techniques are under development and available for research purposes but are not widely available for clinical use.
Differential diagnosis
The differential diagnosis primarily includes other forms of infectious enterocolitis that produce the acute self-limited colitis pattern; stool culture may be essential to resolving the differential.
Prognosis and therapy
In most uncomplicated cases of Campylobacter infection, fluid and electrolyte replacement is the principal therapy. Antibiotics are not generally indicated unless there is high fever, severe or bloody diarrhea, symptoms of more than 1 week, or the patient is immunocompromised or septic. Erythromycin is the antibiotic of choice.
Yersinia
Yersinia enterocolitica and Y. pseudotuberculosis are the two Yersinia species pertinent to human GI disease. Yersinia is one of the most common causes of bacterial enteritis in Western and Northern Europe, and numerous cases have been documented in North America and Australia. Yersinia may be found in many food products, including meats (particularly undercooked pork), dairy products, and water.
Clinical features
These gram-negative coccobacilli are causative agents in appendicitis, ileitis, colitis, and mesenteric lymphadenitis. In addition, they are responsible for many cases of isolated granulomatous appendicitis. Infection with either species may cause symptoms and signs of an acute abdomen, chronic abdominal pain, and diarrhea. Although yersiniosis is usually a self-limited process, chronic infections (including chronic colitis) and persistent abdominal pain have been well documented. Immunocompromised and debilitated patients, as well as patients on deferoxamine or with iron overload resulting from other causes, are at particular risk for serious disease.
Definition
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Common cause of granulomatous appendicitis, enterocolitis in the United States and Europe
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Found in many food products, including meats, dairy products, and water
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May be clinicopathologic mimic of Crohn’s disease
Incidence and location
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Ileum, appendix, and colon
Clinical features
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Signs and symptoms of enterocolitis, acute appendicitis
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Usually self-limiting, occasionally cause chronic disease
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May have mesenteric adenopathy
Prognosis and therapy
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Usually self-limiting
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Severe cases or debilitated patients require antibiotics
Pathologic features
Gross findings
Grossly, involved bowel has a thickened, edematous wall with nodular inflammatory masses centered around Peyer’s patches. Aphthoid and linear ulcers may be seen. Involved appendices are enlarged and mimic suppurative granulomatous appendicitis; perforation is often seen. Involved lymph nodes may show gross foci of necrosis.
Microscopic findings
Both suppurative and granulomatous patterns of inflammation may be seen, and a mixture of the two is common. GI infection with Y. pseudotuberculosis has characteristically been described as a granulomatous process with central microabscesses, almost always accompanied by mesenteric adenopathy. Infection with Y. enterocolitica has not typically been associated with discrete granulomas but has been characterized by hyperplastic Peyer’s patches with overlying ulceration and accompanying acute inflammation, hemorrhagic necrosis, and palisading histiocytes. Recent studies have shown that there is significant overlap between the histologic features of Y. enterocolitica and Y. pseudotuberculosis infection and that either species may show lymphoid hyperplasia, epithelioid granulomas with prominent lymphoid cuffing, transmural lymphoid aggregates, giant cells, mucosal ulceration, cryptitis, and concomitant lymph node involvement ( Figs. 9-19 through 9-21 ). Some cases show only nonspecific features of acute self-limited colitis.
Gross findings
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Thickened, edematous wall with nodular inflammatory masses centered around Peyer’s patches
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Aphthoid and linear ulcers may be seen
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Involved appendices are enlarged and mimic typical suppurative appendicitis; perforation is frequent
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Mesenteric lymph node involvement common
Microscopic findings
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Often mix of both suppurative and granulomatous patterns of inflammation
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Common features include lymphoid hyperplasia, epithelioid granulomas with prominent lymphoid cuffing, transmural lymphoid aggregates, giant cells, mucosal ulceration, and cryptitis
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Sometimes central microabscesses are present within granulomas
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There is significant overlap between the histologic features of Y. enterocolitica and Y. pseudotuberculosis infection
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Rare cases show only acute self-limited colitis
Differential diagnosis
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Primarily Crohn’s disease
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Other infections such as M. tuberculosis, Salmonella
Ancillary studies
Special stains are not helpful in the diagnosis of Yersinia , for the organisms are small, may be present in low numbers, and are difficult to distinguish from normal nonpathogenic colonic flora. Cultures, serologic studies, and particularly PCR assays are the most useful diagnostic aids.
Differential diagnosis
The major differential diagnoses of Yersinia infection include other similar infectious processes, particularly mycobacterial infection and salmonellosis. 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, in fact, have a long and complicated relationship. Both may show similar histologic features, and, in fact, isolated granulomatous appendicitis has in the past frequently been interpreted as primary Crohn’s disease of the appendix. However, patients with granulomatous inflammation confined to the appendix rarely develop generalized inflammatory bowel disease. Features that may favor Crohn’s disease include cobblestoning of mucosa and creeping fat grossly, and changes of chronicity microscopically, including crypt distortion, thickening of the muscularis mucosa, and prominent neural hyperplasia. However, some cases are indistinguishable on histologic grounds alone.
Prognosis and therapy
Most cases of yersiniosis resolve spontaneously. Yersinia is susceptible to many antibiotics, and therapy is recommended in patients with severe infections, bacteremia, or in the context of immunocompromise or debilitation.
Aeromonas
Aeromonas , initially thought to be nonpathogenic gram-negative bacteria, are increasingly recognized as causes of gastroenteritis in both children and adults. The motile A. hydrophila and A. sobria most often cause GI disease in humans.
Clinical features
The typical presentation is bloody diarrhea, sometimes chronic, accompanied by nausea, vomiting, and cramping pain. The diarrhea may contain mucus as well as blood. The duration of illness varies widely, ranging from a few days to several years, indicating that Aeromonas infection can cause a chronic colitis.
Definition
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Gram-negative bacterium initially believed nonpathogenic; now increasingly recognized as cause of infectious enterocolitis; may be clinicopathologic mimic of Crohn’s disease
Incidence and location
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Colon, often segmental distribution
Clinical features
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Bloody diarrhea, can be chronic; nausea, vomiting, cramping pain
Prognosis and therapy
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Most cases resolve spontaneously; susceptible to multiple antibiotics if needed
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