Clostridium difficile infection pathophysiology: Difference between revisions
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===Gross Pathology=== | |||
===Microscopic Pathology=== | |||
===Bacteriology=== | ===Bacteriology=== | ||
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Pathophysiology
Transmission
Spores of C. difficile are transmitted via the fecal-oral route to the human host.
Pathogenesis
- Following ingestiona, the acid-resistant spores of C. difficile are able to survive the human gastric acidity. Both C. difficile virulence strain and host susceptibility factors are needed for the development of clinical manifestations.
- The spores germinate to the vegetative form in the small intestine and eventually colonize in the large intestine among patients with a recent history of antibiotic administration and disruption of the normal GI flora. The normal GI flora normally prevents the growth of C. difficile (colonization resistance phenomenon).
- In susceptible patients, C. difficile releases 2 major virulence factors: Exotoxins A and B (TcdA and TcdB), both of which mediate the development of pseudomembranous colitis.
- Exotoxins A and B are cytotoxic virulence factors that are able to glycosylate and inactivate Rho GTPases and cause colonocyte death and loss of intestinal barrier.
- In the majority of individuals, the toxin production is countered by adequate host antitoxin responses.
- Among susceptible patients, however, the infectious injury is extensive, resulting in diarrhea and colitis.
- Following the development of clinical manifestations, host immune responses may be either adequate (leading to complete resolution of the infection) or inadequate (leading to recurrence of clinical manifestations).
Virulence Factors
- In susceptible patients, C. difficile releases 2 major virulence factors: Exotoxins A and B (TcdA and TcdB), both of which mediate the development of pseudomembranous colitis.
- Not all strains of C. difficile are equally virulent.[1][2]
- The virulence of an individual strain is directly associated with the amount of toxin A and B produced.[1]
- Toxin A mass is 308 kDa, whereas toxin B mass is 269 kDa.
- Although both toxins may be expressed from a single promoter, each toxin has its individual set of promoters and ribosomal binding sites along the toxic genes within the toxicon.
- Both toxins act synergically and both induce vascular permeability and hemorrhage by binding to specific host receptors.[3]
- Both toxins have monoglucosyltransferase activity at the N-terminus. Toxins are able to glycosylate Rho GTPase (involved in actin cytoskeleton) and cause the formation of abnormal G-actin (normally F-actin). In turn, G-actin induces the development of cell rounding, which is characteristic of toxin-induced cytopathy.[4][5][6]
- Toxin A, but not toxin B, is associated with luminal fluid accumulation and may be responsible for the diarrhea associated with C. difficile infection.[3]
- Toxin A is thought to stimulate cytokine production by macrophages (Il-1, IL-8, leukotrienes), which may be responsible for the subsequent neutrophilic migration and inflammation.
- Although toxin A has been studied more extensively than toxin B, virulence by strains with toxin B only virulence factor has been reported.[7] The mechanism by which toxin B acts is yet to be understood.
- Other less clinically important virulence factors that have been isolated include the following:
- Enterotoxic protein
- High-molecular weight protein
- Actin-specific ADP-ribosyl-transferase
Adhesion
- Although some C. difficle strains contain fimbriae or flagellae, the main adhesin component of the organism is thought to be exotoxin A.[1]
- Since, C. difficile toxin A mediates the adhesion of the organism to the host intestinal wall, more virulent strains with more exotoxin A are able to adhere better than strains of reduced virulence.[8]
- Typically, C. difficile adheres to the wall of the terminal ileum and the cecum, which justifies the development of ileocecitis in the majority of patients.[8]
- The role of other adhesive properties of C. difficile, including hydrophobic surfaces and charge interactions with the human host, have been studied to a lesser extent.[9]
Chemotaxis
- Chemotaxis is further facilitated by the organism's motility, which is mediated by flagellae.[1]
Hydrolytic Enzymes
C. difficile expresses several enzymes that help in the breakdown of host mucosal integrity and organism growth[12][13]:
- Hyaluronidase: Major enzyme that converts hyaluronic acid from mucus glycoproteins into N-acetylglucosamine needed for nutritional growth
- Chondroitin-4-sulphatase
- Heparinase (weak activity)
- Collagenase (weak activity)
Gross Pathology
Microscopic Pathology
Bacteriology
Clostridia are motile bacteria that are ubiquitous in nature and are especially prevalent in soil. Under the microscope after Gram staining, they appear as long drumsticks with a bulge located at their terminal ends. Clostridium difficile cells are Gram positive. Clostridium shows optimum growth when plated on blood agar at human body temperatures. When the environment becomes stressed, however, the bacteria produce spores that tolerate the extreme conditions that the active bacteria cannot. First described by Hall and O'Toole in 1935, "the difficult clostridium" was resistant to early attempts at isolation and grew very slowly in culture.[14] C. difficile is a commensal bacterium of the human intestine in a minority of the population. . In small numbers it does not result in disease of any significance. Antibiotics, especially those with a broad spectrum of activity, cause disruption of normal intestinal flora, leading to an overgrowth of C. difficile. This leads to pseudomembranous colitis.
C. difficile is resistant to most antibiotics. It flourishes under these conditions. It is transmitted from person to person by the fecal-oral route. Because the organism forms heat-resistant spores, it can remain in the hospital or nursing home environment for long periods of time. It can be cultured from almost any surface in the hospital. Once spores are ingested, they pass through the stomach unscathed because of their acid-resistance. They change to their active form in the colon and multiply. It has been observed that several disinfectants commonly used in hospitals may fail to kill the bacteria, and may actually promote spore formation. However, disinfectants containing bleach are effective in killing the organisms[15].
Patients are rarely infected unless the normal flora of the intestinal tract has been altered by antibiotics. Following colonization C. diff releases two cytotoxins, A and B:
- The cytotoxins bind to receptors on intestinal epithelial cells.
- The cytotoxins usually result in acute inflammatory infiltrate, leading to cell necrosis and shedding.
- A shallow ulcer results, from which serum proteins, mucus, and inflammatory cells emanate, leading to the appearance of a pseudomembrane.
- Some strains do not produce toxin.
Toxins
Pathogenic C. difficile strains produce various toxins. The most well-characterized are enterotoxin (toxin A) and cytotoxin (toxin B). These two toxins are both responsible for the diarrhea and inflammation seen in infected patients, although their relative contributions have been debated by researchers. Another toxin, binary toxin, has also been described, but its role in disease is not yet fully understood.[16]
Role in Disease
With the introduction of broad-spectrum antibiotics in the latter half of the twentieth century, antibiotic-associated diarrhea became more common. Pseudomembranous colitis was first described as a complication of C. difficile infection in 1978,[17] when a toxin was isolated from patients suffering from pseudomembranous colitis and Koch's postulates were met.
Clostridium Difficile Infection (CDI), can range in severity from asymptomatic to severe and life threatening, and many deaths have been reported, especially amongst the aged. People are most often infected in hospitals, nursing homes, or institutions, although C. difficile infection in the community, outpatient setting is increasing. Clostridium difficile associated diarrhea (aka CDAD) has been linked to use of broad-spectrum antibiotics such as cephalosporins and clindamycin, though the use of quinolones is now probably the most likely culprit, which are frequently used in hospital settings. Frequency and severity of C. difficile colitis remains high and seems to be associated with increased death rates. Immunocompromised status and delayed diagnosis appear to result in elevated risk of death. Early intervention and aggressive management are key factors to recovery.
The rate of Clostridium difficile acquisition is estimated to be 13 percent in patients with hospital stays of up to two weeks and 50 percent in those with hospital stays longer than four weeks.
Increasing rates of community-acquired Clostridium difficile-associated infection/disease (CDAD) has also been linked to the use of medication to suppress gastric acid production: H2-receptor antagonists increased the risk twofold, and proton pump inhibitors threefold, mainly in the elderly. It is presumed that increased gastric pH, (alkalinity), leads to decreased destruction of spores.[18]
References
- ↑ 1.0 1.1 1.2 1.3 Borriello SP (1998). "Pathogenesis of Clostridium difficile infection". J Antimicrob Chemother. 41 Suppl C: 13–9. PMID 9630370.
- ↑ Delmée M, Avesani V (1990). "Virulence of ten serogroups of Clostridium difficile in hamsters". J Med Microbiol. 33 (2): 85–90. PMID 2231680.
- ↑ 3.0 3.1 Lyerly DM, Saum KE, MacDonald DK, Wilkins TD (1985). "Effects of Clostridium difficile toxins given intragastrically to animals". Infect Immun. 47 (2): 349–52. PMC 263173. PMID 3917975.
- ↑ Just I, Selzer J, von Eichel-Streiber C, Aktories K (1995). "The low molecular mass GTP-binding protein Rho is affected by toxin A from Clostridium difficile". J Clin Invest. 95 (3): 1026–31. doi:10.1172/JCI117747. PMC 441436. PMID 7883950.
- ↑ Just I, Selzer J, Wilm M, von Eichel-Streiber C, Mann M, Aktories K (1995). "Glucosylation of Rho proteins by Clostridium difficile toxin B." Nature. 375 (6531): 500–3. doi:10.1038/375500a0. PMID 7777059.
- ↑ Just I, Wilm M, Selzer J, Rex G, von Eichel-Streiber C, Mann M; et al. (1995). "The enterotoxin from Clostridium difficile (ToxA) monoglucosylates the Rho proteins". J Biol Chem. 270 (23): 13932–6. PMID 7775453.
- ↑ Lyerly DM, Barroso LA, Wilkins TD, Depitre C, Corthier G (1992). "Characterization of a toxin A-negative, toxin B-positive strain of Clostridium difficile". Infect Immun. 60 (11): 4633–9. PMC 258212. PMID 1398977.
- ↑ 8.0 8.1 Borriello SP, Welch AR, Barclay FE, Davies HA (1988). "Mucosal association by Clostridium difficile in the hamster gastrointestinal tract". J Med Microbiol. 25 (3): 191–6. PMID 3346902.
- ↑ Krishna MM, Powell NB, Borriello SP (1996). "Cell surface properties of Clostridium difficile: haemagglutination, relative hydrophobicity and charge". J Med Microbiol. 44 (2): 115–23. PMID 8642572.
- ↑ Dailey DC, Kaiser A, Schloemer RH (1987). "Factors influencing the phagocytosis of Clostridium difficile by human polymorphonuclear leukocytes". Infect Immun. 55 (7): 1541–6. PMC 260555. PMID 3596798.
- ↑ Davies HA, Borriello SP (1990). "Detection of capsule in strains of Clostridium difficile of varying virulence and toxigenicity". Microb Pathog. 9 (2): 141–6. PMID 2277588.
- ↑ Seddon SV, Hemingway I, Borriello SP (1990). "Hydrolytic enzyme production by Clostridium difficile and its relationship to toxin production and virulence in the hamster model". J Med Microbiol. 31 (3): 169–74. PMID 2156075.
- ↑ Wilson KH, Perini F (1988). "Role of competition for nutrients in suppression of Clostridium difficile by the colonic microflora". Infect Immun. 56 (10): 2610–4. PMC 259619. PMID 3417352.
- ↑ Hall I, O'Toole E (1935). "Intestinal flora in newborn infants with a description of a new pathogenic anaerobe, Bacillus difficilis". Am J Dis Child. 49: 390.
- ↑ "Cleaning agents 'make bug strong'". BBC News Online. 3 April 2006. Retrieved 2007-01-11.
- ↑ Barth H, Aktories K, Popoff M, Stiles B (2004). "Binary bacterial toxins: biochemistry, biology, and applications of common Clostridium and Bacillus proteins". Microbiol Mol Biol Rev. 68 (3): 373–402, table of contents. PMID 15353562.
- ↑ Larson H, Price A, Honour P, Borriello S (1978). "Clostridium difficile and the aetiology of pseudomembranous colitis". Lancet. 1 (8073): 1063–6. PMID 77366.
- ↑ Dial S, Delaney J, Barkun A, Suissa S (2005). "Use of gastric acid-suppressive agents and the risk of community-acquired Clostridium difficile-associated disease". JAMA. 294 (23): 2989–95. PMID 16414946.