Clostridium difficile (C. diff) Infection

Clostridium difficile (C. diff) is a type of bacteria that can cause diarrhea. It often affects people who have been taking antibiotics. It can usually be treated with a different type of antibiotic.

Epidemiologic Features:

Clostridium difficile is a spore-forming gram-positive anaerobic bacillus that can be found in the feces of 5% of healthy adults and 30% to 70% of infants. The organism was first isolated in 1935 from the feces of healthy newborns and named Bacillus difficilis because it was difficult to culture; it was not associated with antibiotic-associated diarrhea until the 1970s. C. difficile spores can survive for long periods in the environment. The spores are ingested but are resistant to stomach acid and convert to a vegetative form in the intestine. Most hospital patients in whom C. difficile can be found are asymptomatic but serve as reservoirs of environmental contamination. Only when there is an imbalance of the intestinal microbiota, mainly due to antibiotics such as clindamycin, cephalosporins and fluoroquinolones, does the vegetative form cause the disease by producing two exotoxins: TcdA and TcdB. TcdA causes the recruitment of inflammatory cells and the release of interleukins by intestinal epithelial and inflammatory cells, while TcdB has cytotoxic effects and is essential for virulence. A third toxin, CDT (C. difficile transferase) or binary toxin, has been described and is believed to depolymerize actin in the cytoskeleton and increase adherence of bacteria to epithelial cells.

In addition to the duration, type, and amount of antibiotics used, other risk factors for C. difficile disease include being hospitalized in an intensive care or long-term care facility, older age, use of inhibitors, proton pump or H2 antagonists, immunosuppressive treatments and gastrointestinal diseases such as inflammatory bowel disease. However, the number of patients with community-acquired C. difficile infection has increased and they tend to be younger, healthier women who have not taken antibiotics. During the first decade of the 21st century, there was a dramatic increase in the incidence and severity of C. difficile infections in North America and Europe. In 2008, in the southeastern United States, C. difficile infections surpassed healthcare-associated infections caused by methicillin-resistant Staphylococcus aureus.

Similarly, in England and Wales, C. difficile infections outnumber healthcare-associated infections with methicillin-resistant S. aureus. The increase has been attributed to a hypervirulent strain that produces higher amounts of TcdA and TcdB. Normally, the two toxins are downregulated by the TcdC protein; however, in the hypervirulent strain, the TcdC protein is truncated, leading to unregulated toxin production. The hypervirulent strain is known as group BI by restriction endonuclease analysis, NAP1 by pulsed-field gel electrophoresis, and 027 by ribotyping. In addition, the 027 strains are resistant to fluoroquinolones and some have the CDT toxin, increasing virulence. Although many outbreaks have been attributed to strain 027, other strains have also been implicated.

Clinical Features:

A commonly used definition of C or Clostridium difficile infection includes the presence of more than three unformed stools in 24 hours, with a positive test (toxins or toxin genes), or the colonoscopic/histopathologic presence of pseudomembranes. However, C. difficile causes a wide spectrum of gastrointestinal illness, from mild diarrhea to toxic megacolon with perforation. Symptoms usually begin shortly after antibiotic treatment, but can occur several weeks after the antibiotics are given. Some patients present with mild to moderate watery diarrhea that may be accompanied by lower abdominal cramps and resolves after discontinuation of the antibiotic. The most common presentation is fever, malaise, nausea, anorexia, abdominal pain, and watery diarrhea, which may have some blood. In affected patients there is endoscopic evidence of erythematous colitis without the presence of pseudomembranes. Pseudomembranous colitis is a well-known presentation of C. difficile infection. It consists of fever, abdominal pain and tenderness, severe diarrhea, and laboratory findings of leukocytosis and hypoalbuminemia. Scattered raised yellow plaques (pseudomembranes) are seen on the mucosa of the rectosigmoid area.

Although less common, involvement of the right colon, including the small intestine, can also be found. However, it must be remembered that not all pseudomembranous colitis infections are due to C. difficile. The most serious presentation of C difficile disease is toxic megacolon, which may be complicated by perforation. Affected patients present with fever, chills, hypotension, tachypnea, and diffuse abdominal pain, and may or may not have diarrhea. They show marked leukocytosis. In these patients, imaging shows ileus. Concurrent with the increase in hypervirulent strains, there has been an increase in mortality associated with C. difficile infections reported in different surveillance systems in North America and Europe. Although C. difficile appears to be a major contributor to death, in the setting of hospitalized elderly patients with multiple comorbidities, it may not be the only contributing factor. Note that most patients with antibiotic-associated diarrhea do not have C. difficile infection (see section on differential diagnosis). Important clues to the diagnosis of C. difficile infection include fever and leukocytosis. White blood cell (WBC) counts of more than 20,000 cells/μL are associated with increased mortality. Other predictors of severe disease include albumin less than 2.5 g/dl, creatinine greater than 2 mg/dl, and the presence of ileus or intestinal obstruction.

For treatment purposes, the Infectious Diseases Society of America and the Hospital Epidemiology Society of America define severe disease as white blood cells above 15,000 cells/μL or creatinine above 1.5 times baseline, and severe complicated disease if shock, hypotension, or ileus are present. The epidemiology of C. difficile infection in children has not been well studied. This bacterium is frequently found as a colonizer in children under 1 year of age and testing in this age group is not recommended. However, older children with comorbidities such as cancer, transplants, gastrostomies, or jejunostomies are at higher risk for the disease.

Pathologic Features of Clostridium difficile:

Few studies correlate evidence of the presence of C. difficile or its toxins in feces and endoscopic and histopathologic findings. In adults with diarrhea associated with C. difficile, pseudomembranes were detected in 51% to 89% of patients by endoscopy and in 63% by histology. In patients with the presence of C. difficile toxin in stool, approximately one third had pseudomembranous colitis histologically, while 42% had suspicious histology. Correlation of positive C. difficile polymerase chain reaction (PCR) tests, presence of toxin in stool, and histopathologic changes in biopsies have also shown a variety of morphologies including significant changes to ulcers covered by pseudomembranes

H&E stains of patients
H&E stains of patients with Clostridium difficile having stool EIA and PCR positivity. Apparent is a spectrum of disease from minimal changes in the colon (A), to pseudomembranous colitis (B), to complete necrosis of the colonic wall (C).

The histopathology of children with positive C. difficile toxin in stool has ranged from minimal pathology in most cases to moderate colitis, granulomatous inflammation, intestinal necrosis, and pseudomembranous colitis. Immunohistochemical and PCR tests of pediatric tissues only showed evidence of clostridia in the patient with pseudomembranes. Pseudomembranous colitis is characterized by discrete yellow plaques on the mucosa of the colon and rectum. Histologically, the colonic crypts are dilated due to the abundance of inflammatory cells and debris, and when they discharge this exudate into the colonic lumen, they appear as erupting volcanoes. In severe cases of C. difficile-associated diarrhea, the presence of pseudomembranes may not occur if the patient is neutropenic or immunocompromised and therefore unable to produce the inflammatory response that creates the characteristic pseudomembranes. Lack of pseudomembrane formation with evidence of C. difficile toxins has been described in patients who have received hematopoietic stem cell transplantation and those with ulcerative colitis.

Differential Diagnosis:

Nosocomial diarrhea is defined as having three or more unformed stools during one day that occur 3 or more days after being hospitalized. Although C. difficile is a common concern in patients with nosocomial diarrhea, it accounts for less than 20% of nosocomial diarrhea. Most cases of diarrhea in hospitalized patients are due to medications, enteral feeding, and underlying disease. The use of antibiotics can alter the intestinal flora and eliminate bacteria that produce butyrate, which is an important nutrient for epithelial cells, or eliminate bacteria that break down complex carbohydrates or bile salts, leading to diarrhea that is not associated with C. difficile infections. Most nosocomial diarrhea is clinically mild to moderate.

However, severe diarrhea can be caused by drugs in patients receiving chemotherapy for neoplasms and transplant recipients, or caused by norovirus or toxin-producing Clostridium perfringens and Klebsiella oxytoca. The vast majority of cases of pseudomembranous colitis are associated with C. difficile infection; however, other infectious agents have been found to display similar macroscopic and microscopic characteristics, including viruses (cytomegalovirus), parasites (Entamoeba histolytica), and other bacteria (enterotoxin-producing C. perfringens, S. aureus, Shigella dysenteriae, Escherichia coli O157: H7 and K. oxytoca). Interestingly, before C. difficile was associated with antibiotic diarrhea, S. aureus was thought to be the etiologic agent of antibiotic-associated diarrhea and the presence of pseudomembranes in the colon and rectum. Some authors have commented that pseudomembranes difficile appear when they are not C., which are actually ulcerated lesions covered by inflammatory membranes. Also, in the case of cytomegalovirus and amoeba, the presence of viral or protozoan inclusions should alert the pathologist to the proper diagnosis.

Prognosis and Treatment:

Treatment of Clostridium difficile C. difficile diarrhea begins with discontinuation of the offending antibiotic. For patients with mild to moderate disease, metronidazole is suggested, while for those with severe disease, vancomycin is the drug of choice. Fidaxomicin, a macrocyclic antibiotic with minimal systemic absorption that has anti-C. difficile coverage but little effect on normal flora, has been used as an alternative to vancomycin. In some cases, a colectomy may be necessary; however, mortality is very high in patients who require this treatment. Asymptomatic carriage of C. difficile decreases the risk of infection, suggesting that nontoxigenic strains may confer natural immunity, and monoclonal antibodies against toxins A and B have been used for treatment. Other treatment modalities have included the use of probiotics and microbiota transplantation.

Patients who use a room that was previously occupied by another patient with C. difficile are at high risk of acquiring the disease. Multiple measures must be implemented to prevent transmission of the disease in hospitals. These include isolation of symptomatic patients, use of barrier precautions and disposable patient equipment, specific cleaning and disinfection of rooms and all surfaces in them, and antimicrobial stewardship. Patients with the mild and moderate disease have a good prognosis with cure rates greater than 90%. Patients with severe diseases have lower cure rates (about 70%) with more recurrences. Continued use of antibiotics during treatment of C. difficile infections or immediately after treatment is also associated with disease recurrence.


Pathology of Infectious Diseases  (Book) by

Gary W. Procop, MD, MS
Medical Director, Enterprise Test Utilization and
Pathology Consultative Services
Director, Molecular Microbiology, Parasitology, and
Mycology Laboratories
Professor of Pathology
Cleveland Clinic Lerner College of Medicine
Cleveland Clinic
Cleveland, Ohio

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