Pseudomembranous Pseudomembranous colitiscolitis

PathophysiologyPathophysiology

Pseudomembranous Pseudomembranous colitiscolitis

PathophysiologyPathophysiology

Jien Ni ChengJien Ni Cheng

• Pseudomembranous colitis (PMC) is a toxin-mediated enteric disease caused by Clostridium difficile.

• first described in 1893 when a patient with severe diarrhea was found to have "diphtheritic colitis" at autopsy

• Only in 1977 was C. difficile identified as the causal organism for the cytotoxin responsible for PMC

Clostridium difficile• survives well in nature and is widely

distributed in the environment• can be cultured from stool in 5% of

healthy adults• 10- 30% of symptomatic hospital and

nursing home patients• 30- 50% of healthy infants. • Therefore, the mere presence of C. difficile

does not necessarily indicate disease.

Incidence• Incidence of antibiotic-associated

diarrhea varies from 5-39% depending on the antibiotic type.

• Pseudomembranous colitis complicates 10% of the cases of antibiotic-associated diarrhea.

• C difficile is found in the stool of 15-25% of asymptomatic, antibiotic-treated, hospitalized adults.

• Most cases of PMC over the last three decades have occurred in association with antimicrobial therapy. Nearly all antimicrobial agents have been implicated in causing PMC

• Most frequently associated antimicrobials are: – Clindamycin, – cephalosporins, and – penicillins

Other risk factors• advanced age,• hospitalization,• inflammatory bowel disease, • chemotherapy, and • immunosuppression.

Clinical presentation• watery diarrhea, with as many as 15 to 30

stools per day. • abdominal pain or cramps (often have

lower quadrant tenderness in association with fever and leukocytosis.)

• Fever - absent, low-grade, or quite high.• oligoarticular, asymmetric, large joint

arthropathy.(most common gastrointestinal symptom)

• peripheral leukocyte count (10,000 to 20,000/mm3, but it may be much higher.)

• hypoalbuminemia – due to loss of protein in the stool

• The mucosal surface of the colon seen here is hyperemic and is partially covered by a yellow-green exudate. The mucosa itself is not eroded. Broad spectrum antibiotic usage (such as clindamycin) and/or immunosuppression allows overgrowth of bacteria such as Clostridium dificile

Pathophysiology• disruption of the normal bacterial

flora of the colon• colonization with C. difficile• release of toxins • mucosal damage and

inflammation.

Colonization resistance• Definition - ability of the normal intestinal

microflora to resist overgrowth by pathogenic organisms

• Mechanisms- competition for nutrients, production of bacteriocins and receptor site competition

• disruption of this barrier effect by antibiotics or medical procedures decreases the normal colonization resistance and allows pathogens to overgrow in the colon

• Broad-spectrum antibiotics that have a grater impact on normal flora populations are associated with higher rates of intestinal

disease

toxin production by pathogens

• toxin A (or enterotoxin) • toxin B (or cytotoxin). • Both are heat-labile proteins that activate

the release of cytokines from human monocytes.

• Work in tandem - one disrupting the cell cytoskeleton and the other involving the activation of the signal transduction pathways of the immune system

• Toxins are released by C.difficile and internalised by endocystosis

• Inactivate rhoA, a protein responsible for the maintenance of cytoskeleton of cells

• Widening of junctions of enteroctyes leading to fluid loss and diarrhea

• Toxin A will cause release of viscous hemorrhagic fluid like diarrhea

attraction of cytokines • Caused by activation of components of

immune system• toxins A and B cause mast cell degranulation,

upregulation of leukocyte adhesion and release of cytokines from granulocytes

• Toxin A attracts neutrophils and both toxins stimulate the release of cytokines, such as interleukin (IL) 1, IL-6, IL-8 and tumor necrosis factor from human monocytes

• Both toxins A and B act on mast cells to release histamine

• Both toxins activate phospholipase A2 leading to calcium influx and the production of arachidonic acid metabolites. The arachidonic acid cascade leads to the production of prostaglandins and leukotrienes

• Prostaglandins and leukotrienes produce increased blood flow in local capillary beds and an increase in capillary permeability. Prostaglandins can also induce chemokinesis and cellular infiltration by phagocytes

• release of leukocytes, mucin, fibrin and cellular debris results in the formation of a pseudomembrane.

neurologic interactions • toxin A has been found to increase

myoelectric activity before causing mucosal damage in rabbit colonic loop models

• The interaction between and the intestinal disease is still not understood fully

Medical Treatment• In mild or moderate cases, supportive therapy

alone is sufficient. This includes discontinuing or changing the offending antibiotics, avoiding narcotics and antidiarrheal agents, maintaining fluid and electrolyte intake, and enteric isolation.

• Most patients, 75% of symptomatic patients and 25% of patients with colitis, will experience complete recovery within 10 days. In fulminant or intractable cases, hospitalization for IV hydration will be necessary.

• Oral treatment with antimicrobial agents effective against C difficile is the preferred treatment. No reliable parenteral treatment for pseudomembranous colitis exists.

• In elderly patients and in severely ill patients, empirical antibiotic treatment should be started when the diagnosis is suspected.

• In severe cases, in cases where supportive therapy fails, and in cases where the offending antibiotic cannot be discontinued, a short course (7-10 d) of specific antibiotic therapy should be administered along with the supportive therapy, and the offending antibiotic should be changed to another appropriate agent when possible.

• Recurrent diseases respond well to re-treatment with vancomycin.

• In cases with multiple recurrences, a few suggested therapeutic regimens exist. A long course of oral antibiotic (4-6 wk) may be administered, followed by gradual tapering, or pulsing, of vancomycin (125 mg qid for 1 wk, 125 mg bid for 1 wk, 125 mg qd for 1 wk, or 125 mg qod for 1 wk; followed by 125 mg q72h for 2 wk).

• Another suggested regimen is administering 5-7 days of intermittent antibiotic treatment periods alternating with periods off antibiotics. Treatment with a combination of vancomycin and rifampin was reported to be successful in some cases.

• Antidiarrheal agents - Antiperistaltic drugs should be avoided. They may provide temporary symptomatic relief, but they may protract the disease by prolonging the mucosal exposure to the bacterial toxins, resulting in more severe colonic damage. Postoperative narcotics may play a similar role.

• Restoration of normal flora - In patients with multiple relapses, attempts have been made to recolonize the colon by introducing organisms to suppress C difficile. Oral Lactobacillus GG has been used. Enema with feces from healthy person, though it carries the risk of disease transmission, also has been used. Oral nonpathogenic yeast, such as Saccharomyces boulardii, also has been used effectively in treatment of multiple relapses.

Surgical Therapy• Two thirds of patients with toxic megacolon require surgical intervention. • Diverting ileostomy or resection of diseased bowel (subtotal colectomy)

– This was necessary treatment before antibiotic therapy was available. – This treatment currently is used only as a life-saving measure, such as

in cases of perforated cecum or toxic megacolon.• Colostomy or ileostomy

– This approach is used rarely for direct instillation of antibiotic into the colon lumen in patients with paralytic ileus.

– Pseudomembranous colitis could be the cause of early dysfunction of the colostomy.

– Ileal involvement in the disease has been reported as a complication of ileostomy.

• Early subtotal colectomy: It is advocated by some surgeons in fulminant toxic cases that do not respond after a week of intensive medical therapy because the risk of perforation increases after 7 days of ineffective medical therapy.

Follow up care• Many patients remain asymptomatic carriers

for C difficile, and most of them never relapse. • Ten percent to 20% of all treated patients will

have a relapse regardless of the therapeutic agent used. This could be due either to germination of spores or reinfection. Response to re-treatment with vancomycin usually is favorable.

• In patients with multiple symptomatic relapses, vancomycin pulsing is recommended

Complications• Hypovolemic shock, dehydration, and

electrolytes depletion may occur. • Hypoproteinemia as a result of

protein-losing enteropathy may occur in patients with prolonged diarrhea.

• Cecal perforation, toxic megacolon, hemorrhage, and sepsis also can occur.

Outcome and Prognosis• The overall mortality rate is 2%. • The mortality rate in untreated

elderly or debilitated patients is 10-20%.

• Even with surgical intervention, the mortality rate in patients with toxic megacolon is 35%.

• Prevention • Passive immunization, which has been effective in

animals, may be potentially useful in protecting those with high risk of acquiring the disease. Immunologic studies of toxin A, toxin B, and other virulence factors have led to toxoids that have been used for the production of antibodies that might be used to generate a vaccine in this group of patients.

• Treatment • Therapeutic strategies to inhibit toxin A-induced

colitis are being tested. APAZA, a new compound consisting of a molecule of 5-aminosalicylic acid linked to one molecule of 4-aminophenylacetic acid by an azo bond, has been found to significantly inhibit toxin A-induced myeloperoxidase activity, luminal fluid accumulation, and structural damage to the colon when administered chronically for 5 days in drinking water. – Sulfasalazine has been reported to have similar effects.