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

Yersiniosis

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.

(Courtesy of Laura W. Lamps, MD.)

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

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

Shigellosis

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.)

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.

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.

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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Chapter 4 – Transplantation, Immunodeficiency, and Immunosuppression Chapter 5 – Drug-Induced Gastrointestinal Disease Chapter 14 – Duodenitis Chapter 15 – Coeliac Disease Chapter 25 – Ileal Pouch Anal Anastomosis Chapter 19 – Jejunitis and Ileitis

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