Infectious diseases of the lower gastrointestinal tract are caused by a vast array of viral, bacterial, fungal, and parasitic organisms. Pathologists are often called upon to distinguish infectious enterocolitis from other inflammatory disorders and, when possible, identify the causative pathogen or group of pathogens. Thus, pathologists should be aware of the patterns of injury and morphologic features that suggest infectious enterocolitides and should be able to generate a reasonable but narrow differential diagnosis that guides clinical management. This chapter reviews the clinical, gross, and, microscopic features of common and emerging infectious diseases of the lower gastrointestinal tract and emphasizes the pathologic findings that aid the appropriate classification of these diseases in daily practice.
Infectious enterocolitis is a major cause of morbidity and mortality worldwide. Some infectious diseases are ubiquitous, whereas others exhibit characteristic geographic distributions or are related to sanitation and food preparation practices. Still others show a predilection for immunocompromised patients, the very young or elderly, or those with medical comorbidities. Advances in detection of microorganisms have led to increased understanding of the pathologic changes that they cause and, consequently, a greater role for pathologists in the evaluation of patients with intestinal infections. This chapter covers common and emerging infectious diseases of the lower intestinal tract, including the patterns of injury that they produce, morphologic features of organisms that may be apparent in tissue, and ancillary techniques that aid the surgical pathologists in their identification.
Viral enterocolitis is one of the most frequent causes of illness worldwide. Adenovirus, rotavirus, enterovirus, coronavirus, astrovirus, and Norwalk virus are among the most common pathogens to cause disease in humans, and novel viruses are continuously being identified.1 Most infections are self-limited and patients rarely come to clinical attention; even fewer are evaluated with mucosal biopsies or require surgical resections. Those who are evaluated often have comorbidities, especially immunocompromise. This section focuses on viral infections that produce diagnostic findings in biopsy and resection specimens.
Cytomegalovirus (CMV) is a major cause of morbidity in immunosuppressed patients, including patients with HIV/AIDS, transplant recipients, and those with illnesses that alter immune function (e.g. diabetes, chronic kidney disease).2 CMV infection is common, showing a seroprevalence of up to 60% in adults older than 50.3 It causes primary infection followed by lifelong latent infection that may be reactivated. Despite this, CMV rarely causes overt disease in immunocompetent hosts. Patients with CMV colitis experience bloody or watery diarrhea, abdominal pain, fever, and weight loss.4 CMV colitis also complicates Crohn disease and ulcerative colitis, especially steroid refractory disease.5 In this setting, perforation and emergent colectomy are potentially serious complications.
Gross findings include multiple superficial and deep ulcers with sharply demarcated, “punched out” borders that may span up to 10 cm.2 They usually occur on a background of hemorrhagic mucosa. CMV-associated colitis may also produce inflammatory masses that simulate malignancy or present with pseudomembranes reminiscent of Clostridioides difficile infection6 (Fact Sheet 18.1 and Practice Points 18.1).
Clinical disease usually limited to immunocompromised patients
Bloody or watery diarrhea, fever, weight loss
Vasculitis may cause ischemia
May exacerbate inflammatory bowel disease
Sharply demarcated ulcers
Ischemic-type changes with pseudomembranes
Cryptitis, crypt abscesses, ulcers
Pauci-inflammatory in immunocompromised hosts
Apoptosis, crypt injury, and crypt dropout
Inclusions in endothelial and stromal cells
Intranuclear “owl’s eye” inclusions
Intracytoplasmic granular eosinophilic inclusions
Other viruses (see Table 18.1)
Nonspecific degenerative nuclear changes
|Features||Cytomegalovirus||Adenovirus||Herpes simplex virus|
|Infected cell type(s)||Endothelial, stromal, rarely glandular epithelium||Glandular epithelium||Squamous epithelium|
|Locus of inclusions||Intranuclear, intracytoplasmic||Intranuclear||Intranuclear|
|Morphology of inclusions||Amphophilic, replace nucleus, crescentic or targetoid contour|
|Associated changes||Ulcers, necrosis, apoptotic crypt epithelial cells, crypt drop-out||Neutrophil-rich inflammation and ulcers|
The associated inflammatory response depends on the immune status of the patient and ranges from a mild neutrophilic inflammatory infiltrate with patchy cryptitis and crypt abscesses to ulcers and mucosal and mural necrosis. The intact mucosa shows apoptotic crypt epithelial cells, injured crypts lined by attenuated epithelial cells, crypt drop-out, and nests of residual endocrine cells (Figure 18.1A). CMV produces both nuclear and cytoplasmic enlargement and inclusions. Inclusions are usually identifiable in endothelial cells, stromal cells, and macrophages, but rarely in epithelial cells. Thus, infection is most readily diagnosed in biopsy samples from the ulcer bed, which is rich in granulation tissue. Nuclear inclusions are amphophilic and surrounded by a zone of rarified chromatin, resulting in an “owl’s eye” appearance, whereas cytoplasmic inclusions are granular and eosinophilic (Figure 18.1B). Severe CMV vasculitis may cause vascular necrosis and thrombosis, resulting in segmental ischemia.7 Viral cytopathic changes are apparent on hematoxylin and eosin (H&E), but cytomegalovirus immunohistochemical stains may facilitate the diagnosis, particularly in cases where inflammatory and reactive changes obscure the characteristic morphology.8, 9 For example, some authors suggest that CMV immunohistochemistry should be used routinely to evaluate biopsies from patients with steroid-refractory inflammatory bowel disease.10, 11
Adenovirus is a DNA virus with>50 serotypes that infect human tissues, some of which show tropism for gastrointestinal (GI) mucosae.13 It is a leading cause of diarrhea among children, in whom it represents a risk factor for intussusception.14 Acute infection is usually self-limited in immunocompetent adults, but the virus may establish asymptomatic persistent infection.15 Immunosuppressed individuals may develop nephritis, enteritis, hepatitis, pneumonia, and encephalitis, any of which may be fatal.16–19
Adenovirus colitis produces cellular disorder, loss of orientation in goblet cells, and degenerative changes, especially in surface epithelial cells. Nuclear viral inclusions are present in goblet and absorptive cells, are amphophilic, and replace the entire nucleus. They are crescentic or target-shaped (Figure 18.2). Immunohistochemical stains are available to aid their identification (Practice Points 18.2).
Herpes Simplex Virus
Herpes simplex virus (HSV) causes chronic, lifelong infection and may be transmitted sexually or through any other mucous membrane contact. The disease affects immunocompetent and immunocompromised individuals. Most cases of anorectal HSV infection are attributable to HSV2, but HSV1 infection is increasingly common at this site, and the two are histologically indistinguishable.20 HSV is second only to chlamydia and gonorrhea as a cause of proctitis in men who have sex with men.21 HSV outbreaks cause anorectal pain and systemic symptoms including fever, lymphadenopathy, and parasthesias. Proctoscopic exam reveals intact and/or ruptured perianal vesicles and diffuse ulceration of the distal rectal mucosa.22
Histologic features of HSV proctitis include ulcers with neutrophilic infiltrates and crypt abscesses. Viral inclusions are best identified in sloughed anal squamous epithelium or in squamous cells at the edges of ulcers. Two types of inclusions may be present: Cowdry A inclusions are acidophilic with a surrounding halo of chromatin clearing; Cowdry B inclusions are homogeneous, powder blue, ground glass inclusions with a peripheral rim of marginated chromatin (Figure 18.3). Infected cells are often multinucleated and display nuclear molding. See Fact Sheet 18.2.
Sexually transmitted proctitis
Immunocompetent and immunocompromised patients
Lifelong infection with periodic outbreaks
Ruptured and intact perianal vesicles
Cryptitis, crypt abscesses, ulcers
Intranuclear inclusions in squamous epithelial cells
Multinucleation of infected cells with “molded” nuclei
Other viruses (see Table 18.1)
Varicella zoster infection
Histologically indistinguishable from HSV, but immunohistochemical stains can distinguish the two
Human Immunodeficiency Virus
HIV/AIDS enterocolopathy describes diarrhea in HIV-positive patients without an identifiable infectious cause. Proposed etiologies include occult infection, direct effects of HIV on GI mucosae, and indirect effects of altered local immunity. Villous blunting, crypt hyperplasia, and apoptosis occur in the distal small intestine.23 This is a controversial entity because similar changes are seen in asymptomatic patients with HIV infection, whereas some patients with diarrhea have normal-appearing mucosa.24, 25
Patterns of Injury in Bacterial Enterocolitis
Bacterial colitides can be grouped based on the histologic patterns of injury that they produce (Table 18.2). Many manifest the acute self-limited colitis (ASLC) pattern, characterized by neutrophil-rich lamina propria inflammation, active cryptitis, crypt abscesses, and erosions (Figure 18.4). Because patients with diarrhea usually do not undergo colonoscopy until late in the course of an infectious illness, if at all, ASLC is often patchy or focal. In its resolving stage, ASLC may include lamina propria plasmacytosis with only mild cryptitis or increased intraepithelial lymphocytes, mimicking inflammatory bowel disease (IBD) or lymphocytic colitis. The presence of crypt architectural distortion and basal lymphoplasmacytosis in IBD help to distinguish it from ASLC.1, 7 Other infections typically produce crypt architectural distortion and lymphoplasmacytic lamina propria inflammation that simulates IBD; some include transmural inflammation with granulomas that may be indistinguishable from Crohn disease. Ischemic-type changes result from some infections and appear similar to those from other vascular insults. Finally, some infections produce minimal or no histologic changes.
|Inflammatory pattern||Organism||Disease Distribution||Other Pathologic Features|
|Acute self-limited colitis||Campylobacter spp.||Ileocecal region, appendix, mesenteric lymph nodes||Occasional crypt architectural distortion|
|Salmonella spp., non-typhoidal strains||Terminal ileum, right colon||Occasional crypt architectural distortion|
|Shigella spp., early stages||Extends proximally from rectum||Inflammatory bowel disease-like pattern in later stages; see below|
|Aeromonas spp.||Segmental pancolitis||Occasional crypt architectural distortion|
|Inflammatory bowel disease-like||Yersinia spp.||Terminal ileum, appendix, right colon, mesenteric lymph nodes||Epithelioid granulomas with lymphoid cuffing and central suppurative inflammation and necrosis|
|Salmonella typhi||Terminal ileum, right colon||Deep ulcers, reactive lymphoid follicles infiltrated by macrophages, lacks granulomas|
|Shigella spp., late stages||May be patchy||Occasional pseudomembranes|
|Mycobacterium tuberculosis||Ileocecal region, mesenteric lymph nodes||Large, confluent centrally necrotic granulomas; most common in submucosa|
|Mycobacterium avium intracellulare complex||Duodenum, rectum||Necrotizing granulomas (immunocompetent hosts), diffuse histiocytic inflammation, abundant intracellular organisms (immunocompromised hosts)|
|Treponema pallidum (syphilis)||Anorectum||Rare, poorly formed granulomas, spirochetes subjacent to squamous epithelium on immunostains|
|Chlamydia trachomatis||Anorectum||Rare, poorly formed granulomas|
|Ischemic colitis||Enterohemorrhagic Escherichia coli||Ascending and transverse colon||Fibrin thrombi, pseudomembranes|
|Clostridioides difficile||Pancolitis, more severe distally||Pseudomembranes, apoptosis|
|Clostridium septicum||Terminal ileum, right colon||Pseudomembranes, absence of neutrophils|
|Clostridium perfringens||Jejunum, ileum||Pneumatosis|
|Klebsiella oxytoca||Ascending and transverse colon||Usually lacks pseudomembranes|
|Minimal changes||Vibrio cholerae||Small intestine||Mucin depletion, degenerative epithelial changes, increased lamina propria mononuclear inflammation|
|Brachyspira spp. (spirochetosis)||Any segment of colon||Adherent organisms produce basophilic fringe on mucosal surface|
Figure 18.4 Acute self-limited colitis showing neutrophilic cryptitis, lamina propria neutrophils, and preserved mucosal architecture.
Vibrio cholerae and Related Species
Vibrio spp. are gram-negative bacilli found in saltwater environments.26 Consequently, infection is acquired from consumption of contaminated seafood. “Cholera” is caused by toxigenic serogroups of V. cholerae O1 and O139, which have been responsible for several global pandemics of life-threatening gastroenteritis. Voluminous watery diarrhea and vomiting, sometimes exceeding 1 liter per hour, in the absence of pain or fever is characteristic. “Rice water stool” results from white flecks of shed mucosa in watery diarrhea. The copious release of fluids can lead to severe dehydration and electrolyte imbalance.
Vibrio spp. are noninvasive; thus, colonoscopy is usually unremarkable. Histologic changes are also minimal; mucin depletion of the small intestinal epithelium, increased chronic inflammation in the lamina propria, and epithelial cell disarray are observed.27 Enterocolitis caused by some non-O1 strains of V. cholerae and other Vibrio spp. (V. parahaemolyticus, V. vulnificus, V. alginolyitcus) assumes an ASLC pattern.28
Campylobacter are a genus of gram-negative bacilli that are a leading cause of infectious diarrhea worldwide.29 The most frequently implicated is C. jejuni.30 The main reservoir for Campylobacter is birds, including chickens; thus infection is acquired from consuming undercooked poultry and cross-contaminated food or water. Symptoms develop one to five days after exposure and include fever, abdominal pain, and watery or bloody diarrhea; some patients develop mesenteric adenitis mimicking acute appendicitis. Postinfectious complications include Guillain–Barré syndrome, reactive arthropathy, and hemolytic uremic syndrome.31 Patients who are exposed to Campylobacter, particularly C. jejuni and C. concisus, seem to be at increased risk for development of inflammatory bowel disease.32 Colonoscopic findings range from normal to hemorrhagic and friable mucosa with shallow ulcers.33, 34 Histologically, a pattern of ASLC is apparent, with occasional crypt architectural distortion.33
Yersinia spp. include two enteric pathogens, Y. enterocolitica and Y. pseudotuberculosis.35 These gram-negative bacilli are found in deli meats, pork, chicken, beef, fish, and raw milk. Enterocolitis and mesenteric lymphadenitis develop four to seven days after exposure and can last from one to three weeks. Right-sided abdominal pain is common and may mimic appendicitis clinically. Complications include erythema nodosum, polyarthritis, and endocarditis.36 Infections are more common in winter and children are more susceptible.37 Patients with iron overload disorders, those receiving iron chelation, and immunocompromised individuals are at risk for development of bacteremia.35, 38
The distal ileum and right colon are thickened and nodular. Sections reveal transmural inflammation, and lymphoid hyperplasia underlying linear and aphthous ulcers; epithelioid granulomas with lymphoid cuffing, central necrosis, and suppurative inflammation, found in the ileum, appendix, and mesenteric lymph nodes, are characteristic (Figure 18.5).39–41 Cases of isolated granulomatous appendicitis have been associated with Yersinia infection (Fact Sheet 18.3).
Figure 18.5(A) Lymphoid aggregates in a patient with yersiniosis mimic Crohn disease.
(B) A granuloma underlying an aphthous ulcer.
(C) The granuloma contains epithelioid histiocytes surrounded by a lymphocytic cuff.
Diarrhea, right-sided abdominal pain mimicking appendicitis
Thickened, edematous, and nodular distal ileum and right colon
Ulcers overlying hyperplastic Peyer’s patches
Bulky mesenteric lymph nodes
Transmural inflammation, lymphoid hyperplasia
Suppurative granulomas with lymphoid cuffing
Granulomas lack central inflammation/necrosis.
Architectural distortion, muscularis mucosa hypertrophy, and neural hypertrophy are more pronounced in Crohn disease.
Acid-fast stains, culture results, and PCR assays can help to differentiate Yersinia from mycobacterial infection.
Salmonella species are gram-negative bacilli that are a leading cause of death due to foodborne illness worldwide, especially in Africa and Southeast Asia.29 Human disease is caused by S. enterica subspecies enterica. This subspecies includes typhoidal (S. typhi, S. paratyphi) and non-typhoidal serovars (S. typhimurium, S. enteritidis) (Fact Sheet 18.4).42
Systemic disease heralded by bacteremia, headache, rose spots
Diarrhea, first watery then bloody
Toxic megacolon, perforation
Self-limited watery diarrhea, vomiting, cramps
Thickened right colon, terminal ileum
Bulky mesenteric lymph nodes
Mucosal nodularity over hyperplastic Peyer’s patches
Erythema and erosions
Salmonella typhi (Typhoid/Enteric Fever)
Typhoid fever causes bacteremia, fever, vomiting, headache, and “rose spots” on the chest. The onset of diarrhea, which is initially watery but later bloody, occurs days later. Typhoid fever preferentially affects elderly, very young, or debilitated patients. Antibiotics can be curative, but death may result from toxic megacolon and intestinal perforation.43 Humans are the only reservoir for S. typhi, which may establish lifelong asymptomatic infection; the gallbladder is a common reservoir of infection.
Salmonella typhi has a predilection for the right colon and terminal ileum owing to the abundant lymphoid tissue in that area. Hyperplastic ileal Peyer’s patches with inflammation of overlying epithelium is characteristic (Figure 18.6A). The mucosa shows aphthous and, eventually, deep ulceration with mural necrosis. Reactive lymphoid follicles eventually become infiltrated and obliterated by macrophages (Figure 18.6B). Crypt architectural distortion may be striking.
Figure 18.6(A) A lymphoid aggregate with surrounding mucosal inflammation and erosion in a case of typhoid fever.
(B) Macrophages are the predominant inflammatory cell.
Non-typhoid Salmonella enterica
Infection with non-typhoidal Salmonella serovars presents as watery diarrhea, nausea, vomiting, fever, and abdominal cramping 12–72 hours after exposure. Infection pursues a self-limited, four- to seven-day course. Systemic infection is usually limited to patients with compromised immunity. Endoscopic findings are nonspecific and include erythema, erosions and exudate. Histologically, the pattern is that of ASLC (Figure 18.7).
Figure 18.7 Non-typhoid salmonellosis is characterized by the ASLC pattern.
Shigella are gram-negative bacilli that spread via fecal–oral transmission. Symptoms include fever, watery diarrhea, cramping, and myalgia following a one- to four-day incubation period. Diarrhea becomes bloody and mucoid with tenesmus after two to three days. Most cases resolve in five to seven days. Infection with S. dysenteriae is usually the most severe form. This species produces the Shiga toxin and is more prevalent in developing countries, young children, and men who have sex with men. Infections with S. sonnei and S. flexneri are usually mild or asymptomatic and are more common in developed countries. Complications of Shigella infection include sepsis, intestinal perforation, toxic megacolon, reactive arthritis, and hemolytic uremic syndrome.44
Shigellosis extends proximally from the rectum in a continuous fashion and shows a predilection for the distal colon, although both rectal sparing and pancolitis have been observed.45 The distribution becomes patchy during recovery.46 Colonoscopic features range from mild edema, erythema, punctate hemorrhage, and diminished vascularity to diffuse hemorrhage, ulcers, and exudates resembling pseudomembranes. Early infection is marked by the ASLC pattern (Figure 18.8A). In later stages, lymphocytes and plasma cells may predominate and crypt architectural distortion is observed (Figure 18.8B).47 Occasional cases show mucosal necrosis and adherent mucin and inflammatory debris that simulates Clostridioides difficile infection (Figure 18.8C) (Fact Sheet 18.5).
Figure 18.8(A) Early Shigella infection resembles other causes of ASLC.
(B) Ongoing infection with architectural distortion that simulates inflammatory bowel disease.
(C) Some cases have pseudomembranes.
Abdominal pain, fever
Diarrhea, first watery then bloody
May cause hemolytic uremic syndrome
Continuously involves distal colon and rectum
Hemorrhage, ulcers, exudate, mural thickening
May have pseudomembranes
Mucosal architectural distortion
Escherichia coli are food-borne gram negative bacilli that are the most common cause of bacteria-associated diarrhea worldwide.29, 48 Cattle are the largest reservoir for E. coli, which is transmitted to humans through animal contact or ingestion of food or water contaminated with feces. Enteropathogenic (EPEC) and enterotoxigenic E. coli (ETEC) are noninvasive organisms that cause secretory diarrhea, fever, and abdominal pain by colonizing the small intestine. ETEC is the most common cause of diarrhea among children in the developing world and travelers to developing countries.49 EPEC is a major cause of gastroenteritis in infants with high mortality in the developing world.50 Enteroinvasive E. coli is closely related to Shigella spp., yet usually causes watery diarrhea in travelers; it is found in contaminated water and cheese. Enteroadherent E. coli (EAEC) has recently been recognized as a cause of several diarrhea outbreaks worldwide.51, 52 Immunocompromised patients are at risk for persistent diarrhea due to EAEC infection. The colonic mucosa shows mild inflammatory changes and a coating of bacteria adhering to surface colonocytes (Figure 18.9).53
Figure 18.9(A) Mildly increased mucosal inflammation in EAEC infection.
(B) Adherent organisms are appreciable on the surface.
Enterohemorrhagic E. coli
Enterohemorrhagic E. coli (EHEC) are a group of Shiga toxin–producing bacteria that cause severe dysentery-like illness. In particular, the O157 strain can cause severe diarrhea and kidney damage. EHEC typically causes abdominal pain and diarrhea that becomes bloody after one to four days; fever is characteristically absent.54 Approximately 15% of infected patients develop hemolytic uremic syndrome (HUS) within five to thirteen days of disease onset. HUS is an important cause of renal failure, especially in children.55 Thrombotic thrombocytopenic purpura (TTP) is another potential complication of EHEC infection.
Enterohemorrhagic E. coli shows a predilection for the ascending and transverse colon and produces mucosal hemorrhage, longitudinal ulcers, and, sometimes, pseudomembranes. The colonic mucosa shows acute inflammation and superficial hemorrhagic necrosis with sparing of the deeper compartment. Crypt “withering” and lamina propria hyalinization mimic ischemia (Figure 18.10A). Necrosis of small and medium-sized blood vessels with intraluminal fibrin thrombi are usually seen (Figure 18.10B) (Fact Sheet 18.6 and Practice Points 18.3).56, 57
Figure 18.10(A) Ischemic-type injury with “withered” crypts and lamina propria hyalinization is characteristic of EHEC infection.
(B) Fibrin thrombi are present in mucosal blood vessels.
Bloody diarrhea, abdominal pain, usually in the absence of fever
Hemolytic uremic syndrome
Thrombotic thrombocytopenic purpura
Proximal colon preferentially involved
Mucosal hemorrhage, longitudinal ulcers
Mucosal necrosis and hemorrhage, more severe superficially
Fibrin thrombi in mucosal blood vessels
May have pseudomembranes
Other causes of ischemia
Vasculitis, hypovolemia, and hypercoagulable states
“Watershed distribution”: splenic flexure and rectosigmoid colon
Klebsiella oxytoca causes antibiotic-associated diarrhea in otherwise healthy patients who receive penicillin and its derivatives. The clinical history of antibiotic use and detection of toxins in stool help to classify this infection properly.58 K. oxytoca has also been isolated from the stools of healthy patients and thus may not be pathogenic in the absence of antibiotic treatment. Patients experience bloody diarrhea and abdominal cramps within three to seven days of starting antibiotic treatment. Most patients recover completely within approximately four days of antibiotic cessation.
Colonoscopy reveals segmental hemorrhagic colitis with rectal sparing. The right colon is preferentially affected, but disease may extend to the transverse and descending segments. Mucosal edema, erosion, and longitudinal ulcers are also typical, but pseudomembranes are not apparent. The histologic picture is that of ischemic colitis, including “withered” crypts with increased mitotic figures, crypt loss and apoptosis, and mucosal hemorrhage. Inflammation is not increased.
Clostridial Diseases of the Gut
Several types of Clostridia are gut pathogens. These spore-forming anaerobic bacilli cause severe tissue damage that results in intestinal perforation, sepsis, and death.
Clostridium septicum causes neutropenic enterocolitis (“typhlitis”), especially in patients on chemotherapy. There is a strong association between C. septicum infection and malignancy with more than half of cases being associated with GI cancers.59 Patients experience abrupt onset of GI hemorrhage, fever, abdominal pain and distention, and diarrhea; perforation is a potentially serious complication. The terminal ileum and right colon are preferentially affected and show multiple, well-demarcated ulcers; pseudomembranes may be present. The inflammatory response in immunocompetent patients includes a transmural, diffuse mononuclear infiltrate and neutrophilic debris at the base of ulcers, whereas inflammatory cells may be strikingly absent in neutropenic patients.59 Bowel wall gas, myonecrosis, and organizing serosal fat necrosis should raise the possibility of C. septicum infection. Gram stains may reveal gram positive bacilli in the ulcers.
Clostridium perfringens causes a rare form of life-threatening necrotizing enteritis. The largest outbreaks have been reported in Papua New Guinea among patients who consumed inadequately cooked pork contaminated with pig intestine (C. perfringens infection has been referred to as “pigbel” in this region).60 The disease was transiently prevalent in Europe following World War II, when some populations began consuming meat after a period of starvation.61 Only a few cases have subsequently been reported in developed countries, mostly in diabetic patients.62–66
Resected small intestinal segments are dusky red with serosal exudate. The mucosa may contain pseudomembranes. Microscopic examination reveals transmural necrosis with hemorrhage and mucosal and submucosal pneumatosis. Gram stains may reveal club-shaped gram-positive organisms adherent to necrotic mucosa.67
Clostridioides difficile is a nosocomial pathogen that proliferates in the gut following changes in native intestinal flora after antibiotic use.68 Infection occurs via person-to-person transmission of spores and symptoms usually begin within four weeks of spore ingestion.69 Symptoms range from mild diarrhea to toxic megacolon, colonic perforation, and death. C. difficile infection predominantly affects hospitalized elderly patients, but the incidence of community-acquired infection is also increasing in young, otherwise healthy patients. This may be due, in part, to the emergence of the hypervirulent NAP1 strain, which has been detected in asymptomatic carriers in outpatient and community settings.70, 71 C. difficile may also complicate underlying IBD and it is linked to relapse and increased disease severity.72, 73 Suspected infection is usually confirmed via enzyme-linked immunosorbent assay (ELISA) or polymerase chain reaction (PCR) that detect toxins A and B in stool.74
The entire colon is usually affected, but the distribution may be patchy or segmental, and involve the appendix and small intestine. Pseudomembranes are denser in the distal colon and appear as confluent yellow-green to gray plaques that bleed when disrupted. Toxic megacolon is heralded by marked thinning of the colon wall and dark red to black discoloration. Rarely, C. difficile infection may not produce endoscopically appreciable pseudomembranes.75
The colonic mucosa contains dilated crypts filled with neutrophil-rich mucin and lined by attenuated epithelium (Figure 18.11A). Epithelial cells may slough into the crypt lumina or surface and simulate signet ring cell adenocarcinoma (Figure 18.11B). In severe cases, there is full-thickness mucosal necrosis. Pseudomembranes have a “mushroom” or “volcano” shape and comprise laminated aggregates of mucin, fibrin, inflammatory cells, and sloughed epithelium that emanate from the mucosal surface (Figure 18.11C and D). Mild or early cases may display nonspecific features, such as active cryptitis and crypt abscesses (Fact Sheet 18.7).
Figure 18.11(A) Dilated crypts are filled with inflammatory debris in C. difficile colitis.
(B) The damaged epithelial cells have a signet ring appearance.
(C) Pseudomembranes coat the surface resembling a volcanic eruption
Usually hospitalized patients on antibiotic therapy
Community acquired disease is increasing
Symptoms range from mild diarrhea to toxic megacolon
Pseudomembranes are more dense distally
Thin, dilated red-black colon wall in toxic megacolon
Dilated, mucin filled crypts; attenuated epithelial cells
Pseudomembranes of aggregated mucin, fibrin, inflammatory cells, and sloughed epithelium
Mucosal and mural necrosis
Mycobacterial Diseases of the Gut
Intestinal tuberculosis is one of the most common extrapulmonary manifestations of Mycobacterium tuberculosis infection. Poverty, malnutrition, overcrowding, and HIV coinfection aid the spread of M. tuberculosis. Patients infected with HIV, in particular, are more susceptible to extrapulmonary tuberculosis.76 Intestinal tuberculosis may be a primary infection or part of disseminated disease in patients with pulmonary infections. Infection is presumed to occur via ingestion of bacteria from swallowing sputum, hematogenous spread from the lung, or direct spread from adjacent organs.77 Consumption of unpasteurized milk is a risk factor for zoonotic tuberculosis caused by Mycobacterium bovis.78 Intestinal tuberculosis presents as abdominal pain, a right iliac fossa mass, altered bowel habits, and bleeding, sometimes simulating colonic adenocarcinoma or IBD.
The ileocecal region and associated mesenteric lymph nodes are most commonly involved. The ileocecal valve appears deformed and gaping. Endoscopic findings include nodular mucosa with transverse ulcers, masses, and strictures. M. tuberculosis infection produces large, confluent, centrally necrotic epithelioid granulomas, often with a peripheral rim of lymphocytes. Granulomas may be concentrated in the submucosa (Figure 18.12). Older granulomas may become hyalinized or calcified. The intestinal wall contains deep and superficial ulcers. Over time, mural fibrosis ensues. In most cases, organisms are scarce and may not be identifiable, even when acid fast stains are used. When present, the organisms are rod shaped and have a “beaded” appearance. Transmural inflammation, lymphoid hyperplasia, fibrosis, and architectural distortion simulate IBD, particularly Crohn disease.79 Indeed, the two may coexist, as patients who undergo antitumor necrosis factor alpha therapy are at risk for reactivation of latent M. tuberculosis infection (Fact Sheet 18.8).80, 81
Abdominal pain, altered bowel habits, bleeding, palpable mass
Mycobacterium avium intracellulare complex
Abdominal pain, weight loss, fever
Ulcers, fistulae, intraaddominal abscesses
Nodular mucosa, transverse ulcers, masses, strictures
Mycobacterium avium intracellulare complex
Raised yellow-white nodules
Large, confluent, centrally necrotic granulomas, lymphocytic cuff
Mucosal architectural distortion
Mural lymphoid hyperplasia, fibrosis
Rod-shaped acid-fast organisms with “beaded” appearance
Mycobacterium avium intracellulare complex
Macrophages expand lamina propria
Abundant filamentous organisms
Acid fast and periodic acid–Schiff diastase positive
Necrotizing granulomas, scarce organisms
The incidence of disseminated Mycobacterium avium intracellulare complex (MAC) infection increased dramatically with the AIDS epidemic and was associated with high mortality; it has subsequently declined with the introduction of highly active antiretroviral therapy.82, 83 The duodenum is the most common site of MAC infection in the GI tract, followed by the rectum. Patients experience abdominal pain, weight loss, and fever. Complications include ulcers, fistulae, intraabdominal abscess, and hemorrhage.84, 85
The most common endoscopic findings are raised whitish yellow nodules.86 Infection in immunocompetent hosts is marked by necrotizing granulomas. Organisms are usually scarce, and acid-fast stains may fail to identify them. Specimens from immunocompromised hosts display expansile macrophage infiltrates in the lamina propria (Figure 18.13A). Numerous intracellular organisms impart a striated appearance to macrophages that appear pale blue on H&E stains (Figure 18.13B). Organisms are acid fast and periodic acid–Schiff diastase (PASD) positive (Figure 18.13C and D).87
Infection with Yersinia spp.
Infection with Histoplasma capsulatum
Immunocompromised hosts: other causes of diffuse histiocytic inflammation
Leishmania donovani infection
Histoplasma capsulatum infection
Whipple disease (upper gastrointestinal tract)