Chapter 18 – Infectious Disorders of the Lower Gastrointestinal Tract


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.

Chapter 18 Infectious Disorders of the Lower Gastrointestinal Tract

Nicole C. Panarelli


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

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).

Fact Sheet 18.1 Cytomegalovirus

Clinical Features

  • Clinical disease usually limited to immunocompromised patients

  • Bloody or watery diarrhea, fever, weight loss

  • Vasculitis may cause ischemia

  • May exacerbate inflammatory bowel disease

Gross Pathology

  • Sharply demarcated ulcers

  • Inflammatory masses

  • Ischemic-type changes with pseudomembranes

Microscopic Pathology

  • 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

Cytomegalovirus: Differential Diagnosis

  • Graft-versus-host disease

    • Usually milder inflammation than CMV

  • Mycophenolate mofetil-induced injury

    • Immunosuppressive agent given to transplant recipients

    • Samples may show more eosinophils, fewer endocrine cell nests12

  • Other viruses (see Table 18.1)

Practice Points 18.1 Cytomegalovirus

  • Multiple levels or immunohistochemical stains may aid the diagnosis of CMV infection in cases with rare inclusions or when severe inflammation obscures viral cytopathic changes.

Adenovirus: Differential Diagnosis

  • Other viruses (see Table 18.1)

  • Nonspecific degenerative nuclear changes

Table 18.1 Pathologic features of common viral gastrointestinal infections

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

  • Intranuclear: amphophilic surrounded by clearing “owl’s eye”

  • Intracytoplasmic: eosinophilic granules

Amphophilic, replace nucleus, crescentic or targetoid contour

  • Mono or multinucleated cells

  • Cowdry A: glassy, eosinophilic

  • Cowdry B: powdery, basophilic, peripheral rim of marginated chromatin

  • May coexist in the same cell

Associated changes Ulcers, necrosis, apoptotic crypt epithelial cells, crypt drop-out

  • Epithelial cell disarray

  • Little or no increase in inflammation

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

Figure 18.1

(A) Cytomegalovirus colitis shows crypt damage with apoptotic debris in crypt lumina.

(B) Nuclear inclusions have a surrounding zone of rarified chromatin; cytoplasmic inclusions are red and granular (arrows).

(A and B courtesy of James Pullman, MD, PhD.)


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.1619

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).

Figure 18.2 Amphophilic adenovirus inclusions replace the epithelial cell nuclei (arrows).

(Courtesy of Kathryn Tanaka, MD.)

Practice Points 18.2 Adenovirus

  • Adenovirus may coexist with graft-versus-host disease and causes similar degenerative changes.

  • Adenovirus inclusions may be overlooked without careful searching.

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.

Figure 18.3 Herpes inclusions in squamous epithelial cell nuclei appear red (black arrow) or blue with marginated chromatin at the periphery (green arrow).

Fact Sheet 18.2 Herpes Simplex Virus

Clinical Features

  • Sexually transmitted proctitis

  • Immunocompetent and immunocompromised patients

  • Lifelong infection with periodic outbreaks

Gross Pathology

  • Ruptured and intact perianal vesicles

  • Ulcerative proctitis

Microscopic Pathology

  • Cryptitis, crypt abscesses, ulcers

  • Intranuclear inclusions in squamous epithelial cells

  • Multinucleation of infected cells with “molded” nuclei

Herpes Simplex Virus: Differential Diagnosis

  • 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

Bacterial Enterocolitis

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.

Table 18.2 Pathologic features of bacterial enterocolitides

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 Species

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).3941 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.

(Courtesy of Laura W. Lamps, MD.)

Fact Sheet 18.3 Yersiniosis

Clinical Features

  • Diarrhea, right-sided abdominal pain mimicking appendicitis

Gross Pathology

  • Thickened, edematous, and nodular distal ileum and right colon

  • Ulcers overlying hyperplastic Peyer’s patches

  • Enlarged appendix

  • Bulky mesenteric lymph nodes

Microscopic Pathology

  • Transmural inflammation, lymphoid hyperplasia

  • Suppurative granulomas with lymphoid cuffing

Yersiniosis: Differential Diagnosis

  • Crohn disease

    • Granulomas lack central inflammation/necrosis.

    • Architectural distortion, muscularis mucosa hypertrophy, and neural hypertrophy are more pronounced in Crohn disease.

  • Mycobacterial infections

    • Acid-fast stains, culture results, and PCR assays can help to differentiate Yersinia from mycobacterial infection.

Salmonella Species

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

Fact Sheet 18.4 Salmonellosis

Clinical Features

  • Typhoid fever

    • Systemic disease heralded by bacteremia, headache, rose spots

    • Diarrhea, first watery then bloody

    • Toxic megacolon, perforation

  • Non-typhoid salmonellosis

    • Self-limited watery diarrhea, vomiting, cramps

Gross Pathology

  • Typhoid fever

    • Thickened right colon, terminal ileum

    • Bulky mesenteric lymph nodes

    • Mucosal nodularity over hyperplastic Peyer’s patches

    • Aphthous ulcers

  • Non-typhoid salmonellosis

    • Erythema and erosions

Microscopic Pathology

  • Typhoid fever

    • Hyperplastic lymphoid follicles in Peyer’s patches eventually become obliterated by macrophages

    • Crypt architectural distortion simulates inflammatory bowel disease

  • Non-typhoidal salmonellosis

    • ASLC

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.

(Courtesy of Laura W. Lamps, MD.)

Typhoid Fever: Differential Diagnosis

  • Other infections

    • Yersiniosis

    • Shigellosis

  • Inflammatory bowel disease

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.

(Courtesy Laura W. Lamps, MD.)

Non-typhoid Salmonellosis: Differential Diagnosis

  • Other causes of ASLC


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.

(Courtesy of Laura W. Lamps, MD.)

Fact Sheet 18.5 Shigellosis

Clinical Features

  • Abdominal pain, fever

  • Diarrhea, first watery then bloody

  • May cause hemolytic uremic syndrome

Gross Pathology

  • Continuously involves distal colon and rectum

  • Hemorrhage, ulcers, exudate, mural thickening

  • May have pseudomembranes

Microscopic Pathology

  • Early infection

    • ASLC

  • Later stages

    • Lymphoplasmacytic inflammation

    • Mucosal architectural distortion

Shigellosis: Differential Diagnosis

  • Early infection

    • Other causes of acute self-limited colitis

  • Late infection

    • Inflammatory bowel disease

  • Clostridioides difficile infection when pseudomembranes are present

Escherichia coli

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.

(Courtesy of Laura W. Lamps, MD.)

Fact Sheet 18.6 Enterohemorrhagic Escherichia coli

Clinical Features

  • Bloody diarrhea, abdominal pain, usually in the absence of fever

  • Hemolytic uremic syndrome

  • Thrombotic thrombocytopenic purpura

Gross Pathology

  • Proximal colon preferentially involved

  • Mucosal hemorrhage, longitudinal ulcers

Microscopic Pathology

  • Mucosal necrosis and hemorrhage, more severe superficially

  • Ischemic features

  • Fibrin thrombi in mucosal blood vessels

  • May have pseudomembranes

Enterohemorrhagic Escherichia coli: Differential Diagnosis

  • Other causes of ischemia

    • Vasculitis, hypovolemia, and hypercoagulable states

      • “Watershed distribution”: splenic flexure and rectosigmoid colon

  • Other infections

    • Clostridioides difficile

    • Klebsiella oxytoca

Practice Points 18.3 Enterohemorrhagic Escherichia coli

  • Detection of enterohemorrhagic E. coli in culture requires plating on Sorbitol–MacConkey agar and, thus, this agar should be used for culturing bloody stools.

Klebsiella oxytoca

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.

Klebsiella oxytoca: Differential Diagnosis

  • Vasculitis, hypovolemia, and hypercoagulable states

  • Enterohemorrhagic E. coli (EHEC)

    • Similar histologic appearance; culture results help to make the distinction

    • EHEC is not associated with antibiotic use

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

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

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.6266

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

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

(D) and are composed of mucin, sloughed epithelial cells, and inflammatory cells.

Fact Sheet 18.7 Clostridioides difficile

Clinical Features

  • Usually hospitalized patients on antibiotic therapy

  • Community acquired disease is increasing

  • Symptoms range from mild diarrhea to toxic megacolon

Gross Pathology

  • Usually pancolitis

  • Pseudomembranes are more dense distally

  • Thin, dilated red-black colon wall in toxic megacolon

Microscopic Pathology

  • Dilated, mucin filled crypts; attenuated epithelial cells

  • Pseudomembranes of aggregated mucin, fibrin, inflammatory cells, and sloughed epithelium

  • Mucosal and mural necrosis

Clostridioides difficile: Differential Diagnosis

  • Other infections that produce pseudomembranes

    • Shigella spp.

    • Enterohemorrhagic E. coli

  • Ischemic colitis

Stool toxin assays are essential to establishing the diagnosis

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

Figure 18.12(A) Large, confluent granulomas in a patient with M. tuberculosis infection.

(B) Granulomas comprise epithelioid histiocytes and giant cells with surrounding lymphocytes

(C) and may be hyalinized.

(Courtesy of Laura W. Lamps, MD.)

Fact Sheet 18.8 Mycobacterial Diseases

Clinical Features

  • Mycobacterium tuberculosis

    • Abdominal pain, altered bowel habits, bleeding, palpable mass

  • Mycobacterium avium intracellulare complex

    • Abdominal pain, weight loss, fever

    • Ulcers, fistulae, intraaddominal abscesses

Gross Pathology

  • Mycobacterium tuberculosis

    • Ileocecal region

    • Nodular mucosa, transverse ulcers, masses, strictures

  • Mycobacterium avium intracellulare complex

    • Duodenum, rectum

    • Raised yellow-white nodules

Microscopic Pathology

  • Mycobacterium tuberculosis

    • Large, confluent, centrally necrotic granulomas, lymphocytic cuff

    • Mucosal architectural distortion

    • Mural lymphoid hyperplasia, fibrosis

    • Scant organisms

      • Rod-shaped acid-fast organisms with “beaded” appearance

  • Mycobacterium avium intracellulare complex

    • Immunocompromised host

      • Macrophages expand lamina propria

      • Abundant filamentous organisms

      • Acid fast and periodic acid–Schiff diastase positive

    • Immunocompetent hosts

      • Necrotizing granulomas, scarce organisms

Mycobacterium tuberculosis: Differential Diagnosis

  • Other infectious causes of granulomatous ileocolitis

    • Yersinia spp.

    • Mycobacterium avium intracellulare complex in immunocompetent hosts

  • Crohn disease

    • Skip lesions, cobblestoned mucosa, fissures, and fistulae are more common in Crohn disease.

    • Usually non-necrotic granulomas

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

Figure 18.13(A) The lamina propria contains a diffuse macrophage infiltrate in Mycobacterium avium intracellulare infection. The organisms impart a blue tinge to the macrophage cytoplasm

(B) and are highlighted by acid-fast

(C) and periodic acid–Schiff

(D) stains.

Mycobacterium avium intracellulare Complex: Differential Diagnosis

  • Immunocompetent hosts: other types of granulomatous colitis

    • Crohn disease

    • 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)

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Sep 2, 2020 | Posted by in GASTROENTEROLOGY | Comments Off on Chapter 18 – Infectious Disorders of the Lower Gastrointestinal Tract
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