Clostridium difficile infection overview

# Overview
Clostridium difficile infection is caused by the bacterium C. difficile, a a spore-forming, toxin-producing, obligate anaerobic, gram-positive bacillus. The incidence of C. difficile infection is estimated to be 140 per 100,000 individuals. In USA, the majority (65%) of cases are associated with healthcare settings, and 25% of cases are associated with previous hospitalizations. The most important risk factor for the development of C. difficile infection is history of antibiotic use within the past 12 weeks. Other important risk factors include recent hospitalization ( 65 years), immunodeficiency (primary or secondary causes), inflammatory bowel disease, and exposure to colonized/infected individuals. C. difficile spores are transmitted via the fecal-oral route. Following ingestion, spores germinate to the vegetative form in the small intestine and eventually colonize in the large intestine in susceptible patients. C. difficile does not result in clinical manifestations in the majority of cases, whereby normal GI flora resists the growth of C. difficile, and the host immune responses adequately clear the infection before the development of clinical manifestations. However, in susceptible patients, C. difficile releases 2 major virulence factors: Exotoxins A and B (TcdA and TcdB), which act synergically and mediate adhesion to the colonic mucosa, luminal fluid accumulation, and development of clinical manifestations. The onset of clinical manifestations may occur within 2 hours up to several months following antibiotic administration. Patients typically develop mild/moderate watery diarrhea (possibly bloody) associated with colicky diffuse abdominal pain, nausea, malaise, and low-grade fever. If left untreated, patients may develop colitis (with or without pseudomembrane formation). Approximately 3% of patients develop complications, which might be colonic (fulminant colitis) or extracolonic. The majority of patients with C. difficile infection recover without sequelae and are responsive to antimicrobial therapy. Nonetheless, C. difficile infection is associated with a high lifetime recurrence rate that ranges between 20% to 60%, and most recurrences occur a few weeks following the successful completion of antimicrobial therapy. The gold standard for the diagnosis of C. difficile infection is cell culture cytotoxic assay, but it is rarely used clinically (difficult technique and time consuming). Among symptomatic patients, C. difficile infection is diagnosed either by enzyme immunoassay (ELISA) for toxins A and/or B in stools or by DNA-based tests (PCR). C. difficile infection may be classified based on the clinical severity of the disease. and the severity of the infection dictates the choice of antimicrobial therapy and the need for surgical consultation/management. Administration of oral metronidazole is recommended for patients with mild symptoms, whereas oral vancomycin is recommended for severe disease.

# Historical Perspective
Clostridium difficile was first isolated in 1935 during an experiment from fecal extracts of healthy neonates. The association between C. difficile and antibiotic-associated pseudomembranous colitis was first made in 1978. In 2003, a resistant, hypervirulent strain of C. difficile (NAP/BI/027 strain) with increased synthesis of toxins A and B was first identified.

# Pathophysiology
Spores of C. difficile are transmitted via the fecal-oral route to the human host. Spore ingestion may be community-acquired (soil and food) or healthcare-associated (hospitals and clinics). Following ingestion, the acid-resistant spores of C. difficile are able to survive the human gastric acidity. C. difficile does not result in clinical manifestations in the majority of cases, whereby normal GI flora resists the growth of C. difficile, and the host immune responses adequately clear the infection before the development of clinical manifestations. However, in susceptible patients, C. difficile releases 2 major virulence factors: Exotoxins A and B (TcdA and TcdB), which act synergically and mediate adhesion to the colonic mucosa, luminal fluid accumulation, and development of pseudomembranous colitis. These toxins are able to glycosylate Rho GTPase (involved in actin cytoskeleton) and cause the formation of abnormal G-actin (leading to characteristic rounding of cells). Additionally, they stimulate macrophage-induced cytokine production and subsequent neutrophilic infiltration to the site of inflammation, which in part contributes to the disruption of the intestinal barrier and the development of clinical manifestations associated with the infection. On gross examination, colonic pseudomembranes with yellow colored plaque formation are typical. On microscopic examination, erosions within colonic crypts or formation of mushroom-like exudates with hemorrhage and necrosis are characteristic features.

# Causes
C. difficile infection is caused by Clostridium difficile, a spore-forming, toxin-producing, oligate anaerobic, gram-positive bacillus.

# Classification
C. difficile infection may be classified based on the clinical severity of the disease. The severity of the infection dictates the choice of antimicrobial therapy and the need for surgical consultation/management. Mild disease is defined as isolated diarrhea, whereas severe/complicated disease is defined as either delirium, shock, organ failure, high-grade fever, or marked leukocytosis.

# Differential Diagnosis
Clostridium difficile infection must be differentiated from other diseases that cause acute inflammatory diarrhea, abdominal pain, fever, and ileus, including other causes of colitis (ischemic, collagenous, ulcerative), malabsorptive syndromes, diverticulitis, appendicitis, malignancies, drug-induced causes, and infections, such as salmonellosis, shigellosis, or gastrointestinal infections with Escherichia coli or Campylobacter jejuni.

# Epidemiology and Demographics
The incidence of C. difficile infection is estimated to be 20 per 100,000 person-years. In USA, the majority (65%) of cases are associated with healthcare settings, and 25% of cases are associated with previous hospitalizations. Although patients of all age groups may develop C. difficile infection, elderly patients > 65 years may have up to eight-fold increased risk of developing C. difficile infection compared with younger patients. Whites and female patients are more predisposed to develop C. difficile infections. Although C. difficile is abundantly reported in Europe and the United States, the infection is a global burden.

# Risk Factors
The most important risk factor for the development of C. difficile infection is antibiotic use. Although C. difficile infection has been described with almost all antibiotics, ampicillin, amoxicillin, cephalosporins, clindamycin, and fluoroquinolones are most classically and most commonly associated with development of C. difficile infection. Other important risk factors include recent hospitalization (65 years), immunodeficiency (primary or secondary causes), inflammatory bowel disease, and exposure to colonized/infected individuals. The association between gastric acid suppression and C. difficile infection has not been well established.

# Natural History, Complications & Prognosis
Following ingestion of C. difficile spores, patients are colonized with the organism. Typically, young healthy individuals with adequate immune responses are able to clear the organism without development of any clinical manifestations. But patients with risk factors, such as recent antibiotic use, recent hospitalization, advanced age, or immunodeficiency, are at an increased risk of developing persistent colonization and/or developing signs and symptoms of the infection. The onset of clinical manifestations may occur within 2 hours up to several months of antibiotic use. Patients typically develop mild/moderate watery diarrhea (possibly bloody) associated with colicky diffuse abdominal pain, nausea, malaise, and fever.  If left untreated, patients may develop colitis (with or without pseudomembrane formation). Approximately 3% of patients develop complications, which might be colonic (fulminant colitis) or extracolonic (small intestine involvement, bacteremia, skin infections, reactive arthritis, abscess formation, empyema, or death). The majority of patients with C. difficile infection recover without sequelae and are responsive to antimicrobial therapy. Nonetheless, C. difficile is associated with a high lifetime recurrence rate that ranges between 20% to 70%, most of which occur a few weeks following the successful completion of antimicrobial therapy.

# Diagnosis

## History and Symptoms
Clinical manifestations may range from an asymptomatic course to a severe/fatal presentation. Common symptoms include acute-onset, foul-smelling watery diarrhea, crampy diffuse or lower abdominal pain, low-grade fever, malaise, anorexia, nausea, and weight loss. Alarming symptoms that may be suggestive of colonic complications of C. difficile infection include worsening abdominal pain and diarrhea, high-grade fever, dry mucus membranes, and peripheral edema.

## Physical Examination
Patients with C. difficile infection typically have low-grade fever and abdominal tenderness on physical examination. Additional signs on physical examination may be suggestive of worsening infection, complicated disease, or failure of antimicrobial therapy. Significant findings on physical examination include significant derangements in vital signs, including high-grade fever, tachycardia, or hypotension, signs of dehydration, peripheral edema which might be suggestive of hypoalbuminemia, or worsening abdominal tenderness, distention, palpable masses, or inactive bowel sounds, which may suggest toxic megacolon, abscess development, or ileus.

## Laboratory Findings
Testing is generally not necessarily for patients with formed stools (no diarrhea). The gold standard for diagnosis of C. difficile infection is cell culture cytotoxic assay, but it is rarely used clinically (difficult technique and time consuming). Among patients with diarrhea,C. difficile infection is diagnosed either by enzyme immunoassay (ELISA) for toxins A and/or B in stools or by DNA-based tests (PCR) that detect bacterial toxin genes in stools. Although both ELISA and DNA-based tests may be performed sequentially, only one positive test is sufficient to diagnose C. difficile infection. Both ELISA and DNA-based tests also have a high negative predictive value > 95% among average-risk patients, and generally negative results warrants the search for alternative diagnoses. The advantage of DNA-based tests over ELISA is that it may detect the presence of BI/NAP1/027 strain, which alters the management plan. However, DNA-based tests may also detect clinically irrelevant findings that may delay the diagnosis. Stool culture requires anaerobic culture and may not be available. Although not diagnostic, additional blood testing may be necessary to monitor for possible development of complications or the success/failure of antimicrobial therapy.

## Abdominal X-ray
Abdominal X-ray may be required for patients suspected to have toxic megacolon. Signs on abdominal x-ray that may be suggestive of toxic megacolon include enlarged, dilated colon > 6-7 cm, loss of colonic haustrations, small intestinal dilation, presence of air-fluid levels, or submucosal edema with thumbprinting.

## Abdominal CT Scan
Abdominal CT scan is the imaging of choice for patients with C. difficile pseudomembranous colitis or patients with suspected complications. Abdominal CT scan findings may include marked colonic wall thickening or nodularity, irregular bowel walls, pericolonic stranding, or ascites formation.

## Other Imaging Findings
In patients with suspected C. difficile infection and inconclusive laboratory diagnostic findings, atypical presentation, or unsuccessful antimicrobial therapy, either a sigmoidoscopy or colonoscopy is indicated. During endoscopy, multiple biopsies should be obtained for microscopic histopathological analysis. On gross examination, colonic pseudomembranes with yellow colored plaque formation are typical findings.

## Biopsy
On microscopic examination, erosions within colonic crypts or formation of mushroom-like exudates with hemorrhage and necrosis are characteristic features of C. difficile infection.

# Treatment

## Medical Therapy
Treatment is generally recommended for average-risk patients who are symptomatic with positive lab findings for C. difficile infection. For patients with C. difficile risk factors, empiric therapy is recommended for symptomatic patients regardless of lab findings. Antimicrobial therapy is tailored acccording to the clinical severity of the infection. Administration of oral metronidazole is recommended for patients with mild symptoms, whereas oral vancomycin is recommended for severe disease.

## Surgery
Indications for surgery include peritoneal signs, persistent bacteremia, progressive clinical disease with organ damage (e.g. renal or pulmonary disease), or evidence on CT scan demonstrating worsening infection.

## Prevention
There are no vaccines available for the prevention of C. difficile infection. Individuals in healthcare settings may reduce the risk of C. difficile infection by washing hands using soap and water (alcohol-based products are not effective), minimizing unnecessary use of antibiotic administration, and properly isolating infected patients with adequate post-discharge room disinfection.