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Abstract & Commentary
Synopsis: Patients who fail to mount a serum antibody response to Clostridium difficile toxin A are at high risk for recurrence.
Source: Kyne L, et al. Association between antibody response to toxin A and protection against recurrent Clostridium difficile diarrhoea. Lancet 2001;357:189-193.
Treatment of antibiotic-associated Clostridium difficile diarrhea is followed by recurrence in 5-50% of episodes; some patients experience multiple recurrences. Kyne and colleagues prospectively followed 63 patients with nosocomial C. difficile diarrhea for up to 60 days. They measured serum IgA, IgG, and IgM concentrations against toxins A and B, as well as nontoxin antigens at three-day intervals. Of 44 patients who survived, 50% had at least one recurrence. Patients with single episodes of C. difficile diarrhea had significantly higher serum concentrations of IgM against toxin A by day 3, and significantly higher concentrations of IgG against toxin A at day 12 than did patients who subsequently suffered recurrences. There was no correlation between IgG concentrations against toxin A and age, underlying disease, co-morbidity, or receipt of additional antibiotics.
Comment by Robert Muder, MD
C. difficile diarrhea is a frequent complication of antimicrobial therapy in hospitals and nursing homes. It is associated with significant morbidity, mortality, prolongation of hospital stay, and excess cost. Although most patients respond initially to therapy with metronidazole or vancomycin, recurrent diarrhea occurs in a substantial number of patients, up to 50% in some series. Clinical risk factors for recurrence include advanced age and increased severity of underlying illness.
Kyne et al found a significant association between recurrent disease and lack of antibody response to toxin A. Their observations extend previous observations on the role of serum antibody against toxin A and the clinical course of C. difficile diarrhea. Kyne et al previously reported that after the onset of colonization with C. difficile in patients receiving antibiotics, those who remained asymptomatically colonized had significantly greater increases in anti-toxin A IgG than those who developed diarrhea.1 There are reports of successful use of intravenous IgG in the treatment of C. difficile diarrhea refractory to standard antibiotic therapy,2 and in the treatment of multiple recurrences.3 Although these reports are uncontrolled and involve small numbers of patients, they are consistent with a role for serum immunoglobulin response in the clinical course of C. difficile diarrhea.
Standard approaches to control of C. difficile disease in hospitals and nursing homes has centered on restraint in antibiotic usage, contact isolation, and environmental decontamination. These measures, while theoretically sound, have proven extremely difficult to implement effectively in practice. The preceding observations raise the possibility of development of a vaccine to prevent disease. However, vaccination poses a number of problems. The first is identification of the target population and administration of the vaccine in a timely fashion. Given the near ubiquity of antibiotic administration during hospitalization, immunization at the time of hospital admission could prove to be a cost-effective strategy. The second problem is that the disease, and the severe sequelae of the disease, are more frequent in older, more debilitated patients. This is a population that typically has a suboptimal response to vaccines.
Another potential implication of these observations is the role of immunotherapy in altering the course of C. difficile diarrhea. Treatments used in refractory or relapsing disease have included combination antimicrobial therapy, anion exchange resins, administration of non-pathogenic organisms, and enemas of filtered normal stool, to name but a few. A controlled trial of immunoglobin infusion for treatment of severe or relapsing C. difficile diarrhea would appear to be a worthwhile undertaking.
1. Kyne L, et al. Asymptomatic carriage of Clostridium difficile and serum levels of IgG antibody against toxin A. N Engl J Med 2000;342:390-397.
2. Salcedo J, et al. Intravenous immunoglobulin therapy for severe Clostrium difficile colitis. Gut 1997;41:
3. Leung DY, et al. Treatment with intravenously administered gamma globulin of chronic relapsing colitis induced by Clostridium difficile toxin. J Pediatr 1991; 118:633-637.