Elsevier

The Lancet

Volume 357, Issue 9251, 20 January 2001, Pages 189-193
The Lancet

Early Report
Association between antibody response to toxin A and protection against recurrent Clostridium difficile diarrhoea

https://doi.org/10.1016/S0140-6736(00)03592-3Get rights and content

Summary

Background

We have reported that symptom-free carriers of Clostridium difficile have a systemic anamnestic immune response to toxin A. The aim of this study was to determine whether an acquired immune response to toxin A, during an episode of C difficile diarrhoea, influences risk of recurrence.

Methods

We prospectively studied 63 patients with nosocomial C difficile diarrhoea. Serial serum IgA, IgG, and IgM concentrations against C difficile toxin A, toxin B, or non-toxin antigens were measured by ELISA. Individuals were followed for 60 days.

Findings

19 patients died (30%). Of the 44 who survived, 22 had recurrent C difficile diarrhoea. Patients with a single episode of C difficile diarrhoea (n=22) had higher concentrations of serum IgM against toxin A on day 3 of their first episode of diarrhoea than those with recurrent diarrhoea (n=22, p=0·004). On day 12, serum IgG values against toxin A were higher in patients who had a single episode of diarrhoea (n=7) than in those who subsequently had recurrent diarrhoea (n=9, p=0·009). The odds ratio for recurrence associated with a low concentration of serum IgG against toxin A, measured 12 days after onset of C difficile diarrhoea, was 48·0 (95% CI 3·5–663).

Interpretation

A serum antibody response to toxin A, during an initial episode of C difficile diarrhoea, is associated with protection against recurrence.

Introduction

Clostridium difficile antibiotic-associated diarrhoea is a common, iatrogenic, nosocomial disease associated with substantial morbidity and mortality.1 Pathogenic strains of C difficile produce the protein exotoxins toxin A and toxin B. These cytotoxic, enterotoxic, and proinflammatory toxins induce colonic mucosal injury, diarrhoea, and in severe cases, pseudomembranous colitis.1, 2C difficile is endemic in hospitals and long-term care facilities throughout the world.3, 4, 5, 6, 7 In a previous study, we noted that 31% of patients who received antibiotics in acute-care medical wards were colonised by C difficile while in hospital. 56% of these developed C difficile diarrhoea; the remainder were symptomless carriers.3

Most patients with C difficile diarrhoea respond well to medical therapy that includes discontinuation of the inciting antibiotic and treatment with metronidazole or vancomycin.1, 8, 9 However, despite successful treatment of initial episodes, recurrence of diarrhoea after withdrawal of specific antibiotic therapy is a substantial clinical difficulty. Recurrence rates of 5-65% have been reported, dependent on definition of recurrence and population studied.10, 11, 12, 13, 14

We reported high concentrations of serum IgG against toxin A in symptomless carriers of C difficile.3 On the basis of this finding, and on results of our previous studies, we postulated that host immune response to toxin A during an episode of C difficile diarrhoea could affect risk of recurrence.15, 16

Section snippets

Patients

All patients with C difficile diarrhoea at Beth Israel Deaconess Medical Center, Boston, USA, between Jan 5, and May 22, 1998, were eligible for study enrolment. Diarrhoea was defined as a change in bowel habit with three or more unformed bowel movements per day for at least 2 days. C difficile diarrhoea was defined as diarrhoea not attributed to any other cause, that arose during or within 30 days of antibiotic therapy, and that was associated with a positive stool toxin for C difficile

Results

We prospectively identified 63 cases of C difficile diarrhoea during the 5-month study period. The study population was made up predominantly of elderly white patients, most had clinically significant comorbid disease, and almost two thirds (39, 62%) had severe or extremely severe underlying disease at hospital admission.

The presence or absence of recurrent diarrhoea could not be determined in 19 (30%) patients with C difficile diarrhoea because they died before the end of the 60-day follow-up

Discussion

In our prospective cohort study of 63 patients, we found that an acquired immune response to C difficile toxin A during an initial episode of C difficile diarrhoea is associated with a substantially reduced risk of recurrent diarrhoea. Patients with a single episode of C difficile diarrhoea have significantly higher concentrations of serum IgM against toxin A by day 3 of their illness and significantly higher serum concentrations of IgG against toxin A on day 12, than patients who later had

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