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The Appendix May Protect Against Clostridium difficile Recurrence

      Background & Aims

      Several risk factors have been identified for the development of recurrent Clostridium difficile infection (CDI) that alter host immunity and disrupt colonic flora. Although the function of the appendix has been debated, its active, gut-associated lymphoid tissue and biofilm production indicate potential roles in recovery from initial CDI and protection against recurrent CDI. We investigated whether the presence or absence of an appendix is associated with CDI recurrence.

      Methods

      We reviewed the medical records of adult inpatients with CDI who were admitted to a tertiary-care teaching hospital from 2005 to 2007 to identify those with and without an appendix. The primary dependent variable for statistical analysis was CDI recurrence.

      Results

      In a multivariate analysis of 11 clinical variables, the presence of an appendix was associated inversely with CDI recurrence (P < .0001; adjusted relative risk, .398). Age older than 60 years also was associated with CDI recurrence (P = .0280; adjusted relative risk, 2.44).

      Conclusions

      The presence of an appendix has a significant and independent, inverse association with CDI recurrence, but this finding requires validation in a prospective study. Assessing the presence or absence of an appendix might be useful in predicting CDI recurrence.

      Keywords

      Abbreviations used in this paper:

      CDI (Clostridium difficile infection), CI (confidence interval), CT (computed tomography), GALT (gut-associated lymphoid tissue), Ig (immunoglobulin)
      See editorial on page 1017.
      Clostridium difficile is a gram-positive, spore-forming, anaerobic bacillus first isolated in 1935, that was identified as the agent involved in pseudomembranous colitis in 1978.
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      • et al.
      Recurrent Clostridium difficile disease: epidemiology and clinical characteristics.
      Studies have identified several important risk factors for the development of recurrent CDI, including inadequate antibody response to toxin A, persistent disruption of colonic flora, age older than 65 years, prolonged hospital stays, severe or fulminant illness by the modified Horn severity index, use of antibiotics other than C difficile therapy during or after an episode of CDI and use of antacid or immunosuppressive medications.
      • Aslam S.
      • Musher D.M.
      An update on diagnosis, treatment, and prevention of Clostridium difficile-associated disease.
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      • Kyne L.
      • et al.
      Prospective derivation and validation of a clinical prediction rule for recurrent Clostridium difficile infection.
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      • Boswell T.
      • Mahida Y.R.
      Recent advances in Clostridium difficile-associated disease.
      These risk factors suggest that the interaction between host immunity and colonic flora disruption plays a crucial role in recurrent CDI.
      The function of the human appendix has long been a matter of debate, but its abundant gut-associated lymphoid tissue (GALT) involved in antigen processing and humoral immune responses suggests an understudied immunomodulatory role in the gut.
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      Recently, this role has been highlighted by epidemiologic studies showing that a history of appendectomy for appendicitis may reduce the risk of developing subsequent ulcerative colitis.
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      Biofilm, adherent colonies of microbes within the extracellular matrix and mucus lining bowel epithelium, is also most abundant in the appendix. This biofilm may enhance the survival of commensal flora and permit their re-inoculation of the gut while excluding pathogens, especially after an episode of intestinal injury.
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      Thus, the appendix could be involved in the complex interplay of host immunity and colonic flora disruption as a result of CDI. The purpose of our study was to determine if there is an association between the presence of an appendix and other clinical variables with C difficile recurrence.

      Methods

       Study Population and Design

      This retrospective study was conducted at Winthrop-University Hospital, a 591-bed, tertiary-care teaching hospital in a suburb of New York City, from January 1, 2005, to January 1, 2007. All patients 18 years of age and older with a positive C difficile toxin assay (Premier Toxins A and B; Meridian Bioscience, Cincinnati, OH) were eligible for inclusion in this study (Figure 1) . CDI recurrence was defined as a patient having diarrhea with a positive C difficile toxin assay with a prior episode of CDI within the past 8 weeks. Among patients with an available record of an abdominal computed tomography (CT) scan, final radiologic reports (including evidence of appendectomy) and medical records were reviewed for determination of the presence or absence of a patient's appendix. All of the CT examinations were performed on 8- or 16-detector CT scanners, with most performed with both oral and intravenous contrast, and an axial slice thickness of 3 mm. Patients without abdominal CT scans were excluded given the general unreliability of retrospective surgical histories unless independent corroborating histories were obtained to enable the confident determination of appendix status. Patients with repeated admissions during the study period for recurrent CDI were counted only once for statistical purposes.
      Figure thumbnail gr1
      Figure 1Flow chart of patient inclusion and exclusion in the study.
      Data were collected on demographic, clinical, and inpatient outcome, and radiologic variables. Demographic data included age, sex, and ethnicity. Clinical data included history of CDI, appendectomy, diabetes mellitus, cancer, or surgery of the bowel; prior use of non–C difficile antibiotics during or after CDI therapy within the previous 3 months before CDI onset; and recent use, defined as 1 week or more during the 6 months before admission of proton pump inhibitors, steroids, or chemotherapy. The Charlson comorbidity index was used to assign patients with a score as an assessment of underlying burden of disease severity.
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      • Ales K.L.
      • et al.
      A new method of classifying prognostic comorbidity in longitudinal studies: development and validation.
      Outcome data included intensive care unit care for CDI, colectomy, and inpatient mortality from CDI and non–CDI-related causes. The medical records of all patients with inpatient mortality during the study period were reviewed independently by 2 authors (G.I. and R.M.) to determine if the primary cause of death was from CDI, with a consensus reached in unclear cases. The study protocol was approved by the institutional review board of Winthrop-University Hospital. The need for informed consent was waived given the retrospective nature of the study.

       Statistical Analysis

      The primary dependent variable for analysis was CDI recurrence. In the initial univariate analysis, the Fisher exact test was used to evaluate differences in recurrence rates across categoric values, and for continuous variables the Wilcoxon rank-sum test was used. Results were considered statistically significant when the P value was less than .05. This was followed by a multivariate analysis to determine if the presence of an appendix still was associated significantly with CDI recurrence after adjusting for other significant variables identified from the univariate analysis. Because the primary dependent variable was not a rare event, a recently developed method of multivariate analysis (in lieu of a multiple logistic regression) was used to adjust relative risks rather than odds ratios, thereby providing a more conservative analysis.
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      All calculations were performed using SAS 9.2 for Windows (SAS Institute, Cary, NC).

      Results

       Patient Characteristics

      During the 2-year study period, there were 396 cases of positive C difficile toxin–proven CDI, with 244 patients undergoing abdominal CT scans, enabling radiologic and historical determination of appendix status. Ten of 152 patients without CT had at least 2 separate corroborating histories enabling confident determination of appendix status and also were included in the final study cohort. Patients with repeated admissions for recurrent CDI who were counted only once for statistical purposes led to the exclusion of 12 cases.
      A total of 254 patients with CDI and known appendix status were reviewed: 194 (76%) with first-episode CDI and 60 (24%) with recurrent CDI. Abdominal CT scans were performed in all 60 recurrent CDI cases. Nearly all patients were Caucasian with a slight female predominance and an advanced median age of 79 years (Table 1). A first episode of CDI was recorded for a majority, with most having an appendix. Of note, there was no significant association between age and the presence of an appendix (P = .78).
      Table 1Patient Characteristics
      Variablen (%)
      Age, y
       Median79
       Range19–99
      Sex
       Female132 (52)
       Male122 (48)
      Ethnicity
       Caucasian231 (91)
       African descent13 (5)
       Hispanic6 (2)
       Other4 (2)
      CDI
       First episode194 (76)
       Recurrence60 (24)
      Appendix
       Present203 (80)
       Absent51 (20)

       Patient Outcomes

      When all 396 patients with CDI in the study period were included, the rates of colectomy and inpatient mortality attributable to CDI were 2.5% and 5.6%, respectively. These are consistent with rates reported during CDI outbreaks but higher than nonoutbreak rates reported in the literature.
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      There appeared to be a CDI outbreak at our institution during the study period, given a greater than 5-fold increase in the number of CDI diagnoses from the 2 years before the study. There were no significant associations between the presence of an appendix and CDI-related outcomes (Table 2).
      Table 2Inpatient Outcomes
      OutcomeFirst episode of CDI (n = 194) n (%)Recurrent CDI (n = 60) n (%)P value
      CDI-related ICU care32 (16)9 (15).687
      Colectomy15 (8)1 (2).128
      Death from CDI21 (11)3 (5).215
      Non–CDI-related death35 (18)6 (10).163
      ICU, intensive care unit.

       Clinical Variables and Statistical Analysis

      Eleven clinical variables were evaluated for a possible association with CDI recurrence, with no statistically significant associations found with certain conditions hypothesized to alter bowel flora or suppress immune function (Table 3). All first-episode CDI patients had a history of prior antibiotic use. Fifty-seven of 60 (95%) recurrent CDI patients had a history of non–C difficile antibiotic use during or after C difficile therapy. In a univariate analysis, the presence of an appendix (P < .0002; unadjusted relative risk, 0.404; 95% confidence interval [CI], 0.266–0.615) and age older than 60 years (P = .0328; unadjusted relative risk, 2.37; 95% CI, 1.01–5.58) were associated significantly with CDI recurrence, with a cut-off P value of less than .05. Recent use of chemotherapy and a proton pump inhibitor and a history of bowel cancer approached statistical significance and were included in the multivariate analysis.
      Table 3Univariate Analysis of Variables Associated With C difficile Recurrence
      VariableFirst episode of CDI (n = 194) n (%)Recurrent CDI (n = 60) n (%)P value
      Age, >60 y154 (79)55 (92).033
      Female sex104 (54)28 (47).380
      History of diabetes mellitus44 (23)15 (25).728
      History of bowel cancer8 (4)3 (5).104
      History of bowel surgery16 (8)6 (10).310
      Appendix present166 (86)37 (62)<.001
      Non–C difficile antibiotics during or after CDI therapy
      Within previous 3 months before CDI onset.
      NA57 (95)NA
      Recent proton pump inhibitor
      Defined as 1 week of use or more during the 6 months before admission.
      95 (49)33 (55).104
      Recent steroids
      Defined as 1 week of use or more during the 6 months before admission.
      28 (14)11 (18).230
      Recent chemotherapy
      Defined as 1 week of use or more during the 6 months before admission.
      8 (4)3 (5).104
      Charlson Index Score, median66.5.180
      NA, not applicable.
      a Within previous 3 months before CDI onset.
      b Defined as 1 week of use or more during the 6 months before admission.
      Multivariate analysis determined that the presence of an appendix (P < .0001; adjusted relative risk, 0.398; 95% CI, 0.262–0.605] and age older than 60 years (P = .0280; adjusted relative risk, 2.44; 95% CI, 1.10–5.41) were associated significantly with CDI recurrence (Table 4). These findings suggest that the presence of an appendix may be protective against CDI recurrence. The CDI recurrence rate for patients with an appendix was 18%, compared with 45% in those without an appendix. Furthermore, the observation that the adjusted relative risk (0.398) was virtually unchanged from the unadjusted relative risk (0.404) for the presence of an appendix indicates that it has a strong and independent inverse association with CDI recurrence. Age older than 60 years had a strongly direct association with CDI recurrence. The CDI recurrence rate for patients younger than 60 years was 11% compared with 26% in those older than 60 years of age.
      Table 4Multivariate Analysis of Variables Associated With C difficile Recurrence
      VariableAdjusted relative risk95% CIP value
      Appendix present0.3980.262–0.605<.0001
      Age, >60 y2.441.10–5.41.0280

      Discussion

      In our retrospective analysis of possible predictors of recurrent CDI, we provided evidence that the appendix may protect against CDI recurrence. Multivariate analysis established the presence of an appendix and age older than 60 years as highly significant and independent variables associated with CDI recurrence.
      The use of CT to visualize and assess the appearance of the appendix to verify or exclude disease is common.
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      • Kyne L.
      • et al.
      Prospective derivation and validation of a clinical prediction rule for recurrent Clostridium difficile infection.
      • Kyne L.
      • Warny M.
      • Qamar A.
      • et al.
      Association between antibody response to toxin A and protection against recurrent Clostridium difficile diarrhoea.
      Nearly all (95%) of the CDI recurrence patients in our study had a history of such antibiotic use, with the retrospective nature of the study limiting further statistical analysis.
      There has been considerable interest in defining the systemic and mucosal antibody responses to CDI, including toxins A and B and other nontoxic proteins.
      • Johnson S.
      Antibody responses to clostridial infection in humans.
      Humoral immune responses to C difficile toxin A play a central role in the pathogenesis of recurrent CDI.
      • Katchar K.
      • Taylor C.P.
      • Tummala S.
      • et al.
      Association between IgG2 and IgG3 subclass responses to toxin A and recurrent Clostridium difficile-associated disease.
      • Lowy I.
      • Molrine D.C.
      • Leav B.A.
      • et al.
      Treatment with monoclonal antibodies against Clostridium difficile toxins.
      This appears to be mediated largely by serum IgG against toxin A, particularly IgG2 and IgG3 subclasses: this IgG is common in healthy individuals, with high levels seen in asymptomatic carriers of C difficile whereas significantly lower IgG levels have been shown in children and adults with recurrent CDI versus controls.
      • Katchar K.
      • Taylor C.P.
      • Tummala S.
      • et al.
      Association between IgG2 and IgG3 subclass responses to toxin A and recurrent Clostridium difficile-associated disease.
      • Kelly C.P.
      • Pothoulakis C.
      • Orellana J.
      • et al.
      Human colonic aspirates containing immunoglobulin A antibody to Clostridium difficile toxin A inhibit toxin A-receptor binding.
      • Leung D.Y.
      • Kelly C.P.
      • Boguniewicz M.
      • et al.
      Treatment with intravenously administered gamma globulin of chronic relapsing colitis induced by Clostridium difficile toxin.
      • Kyne L.
      • Warny M.
      • Qamar A.
      • et al.
      Asymptomatic carriage of Clostridium difficile and serum levels of IgG antibody against toxin A.
      In addition, recurrent CDI patients with low serum IgG against toxin A treated with pooled intravenous IG (known to have high levels of antibodies against toxin A and B) had increased median serum IgG levels against toxin A coinciding with clinical recovery.
      • Leung D.Y.
      • Kelly C.P.
      • Boguniewicz M.
      • et al.
      Treatment with intravenously administered gamma globulin of chronic relapsing colitis induced by Clostridium difficile toxin.
      • Kyne L.
      • Warny M.
      • Qamar A.
      • et al.
      Asymptomatic carriage of Clostridium difficile and serum levels of IgG antibody against toxin A.
      • Warny M.
      • Denie C.
      • Delmée M.
      • et al.
      Gamma globulin administration in relapsing Clostridium difficile-induced pseudomembranous colitis with a defective antibody response to toxin A.
      • Hassett J.
      • Meyers S.
      • McFarland L.
      • et al.
      Recurrent Clostridium difficile infection in a patient with selective IgG1 deficiency treated with intravenous immune globulin and Saccharomyces boulardii.
      The key roles of host immunity and the disruption of colonic flora in CDI shown in prior studies suggested a possible functional role of the appendix in recovering from first-episode CDI and protecting against recurrent CDI.
      • Garey K.W.
      • Sethi S.
      • Yadav Y.
      • et al.
      Meta-analysis to assess risk factors for recurrent Clostridium difficile infection.
      The GALT of the human appendix contains helper T cells and B cells producing 87.3% IgA, 5.6% IgM, 7.0% IgG, and 0.1% IgD.
      • Bjerke K.
      • Brandtzaeg P.
      • Rognum T.O.
      Distribution of immunoglobulin producing cells is different in normal human appendix and colon mucosa.
      There are significantly more IgG-producing B cells in the human appendix than the colon.
      • Bjerke K.
      • Brandtzaeg P.
      • Rognum T.O.
      Distribution of immunoglobulin producing cells is different in normal human appendix and colon mucosa.
      Animal model experiments have shown that the excision of the appendix results in decreased immunoglobulin production.
      • Zahid A.
      The vermiform appendix: not a useless organ.
      The human appendix has a GALT similar to Peyer's patches of the small intestine with a significantly higher proportion of IgG-producing B cells of mature clones than proximal gut lamina propria.
      • Bjerke K.
      • Brandtzaeg P.
      Immunoglobulin- and J chain-producing cells associated with lymphoid follicles in the human appendix, colon and ileum, including Peyer's patches.
      In addition, the appendix is a B-cell–mediated IgA inductive site responding to interleukin-6, whereby precursors of less mature memory clones migrate to distant gut sites and undergo isotype switching to IgA-producing B cells in response to viral and bacterial antigens, such as C difficile toxin A.
      • Fujihashi K.
      • McGhee J.R.
      • Lue C.
      • et al.
      Human appendix B cells naturally express receptors for and respond to interleukin 6 with selective IgA1 and IgA2 synthesis.
      • Bjerke K.
      • Brandtzaeg P.
      • Rognum T.O.
      Distribution of immunoglobulin producing cells is different in normal human appendix and colon mucosa.
      • Bjerke K.
      • Brandtzaeg P.
      Immunoglobulin- and J chain-producing cells associated with lymphoid follicles in the human appendix, colon and ileum, including Peyer's patches.
      Serum IgA, but not IgG, against toxin A is expressed at high levels in the convalescent phase after CDI, but at varying levels and in only about one third of patients.
      • Johnson S.
      • Gerding D.N.
      • Janoff E.N.
      Systemic and mucosal antibody responses to toxin A in patients infected with Clostridium difficile.
      • Johnson S.
      • Sypura W.D.
      • Gerding D.N.
      • et al.
      Selective neutralization of a bacterial enterotoxin by serum immunoglobulin A in response to mucosal disease.
      In addition, lower levels of fecal IgA against toxin A have been shown in recurrent CDI patients versus single-episode CDI.
      • Johnson S.
      • Sypura W.D.
      • Gerding D.N.
      • et al.
      Selective neutralization of a bacterial enterotoxin by serum immunoglobulin A in response to mucosal disease.
      • Warny M.
      • Vaerman J.P.
      • Avesani V.
      • et al.
      Human antibody response to Clostridium difficile toxin A in relation to clinical course of infection.
      Thus, it is plausible that toxin A from CDI induces stimulation of B cells in the appendix that migrate, mature, and cause measurable increases in toxin A–specific IgG and IgA production in the blood that confers protection against recurrent CDI.
      Secretory IgA, a key factor in preventing bacterial translocation in the gut, may contribute to biofilm formation, which has its highest prominence in the human appendix.
      • Bollinger R.
      • Barbas A.S.
      • Bush E.L.
      • et al.
      Biofilms in the large bowel suggest an apparent function of the human vermiform appendix.
      The appendix has been proposed to be a “safe house”
      • Bollinger R.
      • Barbas A.S.
      • Bush E.L.
      • et al.
      Biofilms in the large bowel suggest an apparent function of the human vermiform appendix.
      for commensal bacteria by aiding in biofilm formation via mucin and secretory IgA production that enhances survival of commensal bacteria within the gut while excluding pathogens.
      • Zahid A.
      The vermiform appendix: not a useless organ.
      • Bollinger R.
      • Barbas A.S.
      • Bush E.L.
      • et al.
      Biofilms in the large bowel suggest an apparent function of the human vermiform appendix.
      Regular shedding and regeneration of biofilms within the appendix potentially re-inoculates the colon with commensal bacteria in the event of CDI.
      • Bollinger R.
      • Barbas A.S.
      • Bush E.L.
      • et al.
      Biofilms in the large bowel suggest an apparent function of the human vermiform appendix.
      A significant decrease in overall diversity of gut flora in patients with recurrent CDI has been described compared with first-episode CDI patients and healthy controls.
      • Chang J.Y.
      • Antonopoulos D.A.
      • Kalra A.
      • et al.
      Decreased diversity of the fecal microbiome in recurrent Clostridium difficile-associated diarrhea.
      In addition, Randall et al
      • Randall J.K.
      • Young B.C.
      • Patel G.
      • et al.
      Is Clostridium difficile infection a particular problem after reversal of ileostomy?.
      showed a higher rate of recurrent CDI among patients undergoing surgeries in which the appendix was removed (reversal of ileostomy, right hemicolectomy, appendectomy) compared with surgeries in which the appendix remained intact (small-bowel resection, low anterior resection) and controls.
      This study has provided novel evidence that the presence of an appendix has a highly significant and independent, inverse association with CDI recurrence. The study, however, had several limitations. First, it was a retrospective study without standardized CDI therapy, although collected patient characteristics and treatments were statistically well distributed between patients with an appendix compared with those without (data not shown). Second, the study was subject to selection bias given the reliance on chart review and abdominal CT findings to establish appendix status reliably, leading to the exclusion of 142 patients. As a result, statistically significant associations found in the study should not be considered as causative until validated by a prospective study. Third, our study population only included inpatients with a lack of reliable longitudinal follow-up and outpatient data regarding CDI recurrence. This was mitigated by the high prevalence of elderly patients, local preferences for inpatient medical care, and those admitted from a health care facility (27%) in our study, increasing the likelihood that clinically significant CDI recurrence within the first CDI episode cohort would have prompted re-admission to our institution. Finally, the effects of the likely CDI outbreak in our institution during the study period and the sensitivity and specificity of the C difficile toxin assay used during the study period compared with newer polymerase chain reaction techniques are unknown.
      The findings of this study suggest a possible protective mechanism of the appendix against CDI recurrence that could enhance, in simple fashion, existing clinical prediction rules for recurrent CDI.
      • Hu M.Y.
      • Katchar K.
      • Kyne L.
      • et al.
      Prospective derivation and validation of a clinical prediction rule for recurrent Clostridium difficile infection.
      Another implication of this finding is the need to re-assess the practice of incidental appendectomies being performed during abdominal and gynecologic surgeries. It is estimated that 1000 such procedures are required to prevent 13 future cases of appendicitis and may subject the patient to an increased risk of recurrent CDI.
      • Sugimoto T.
      • Edwards D.
      Incidence and costs of incidental appendectomy as a preventive measure.
      • Albright J.B.
      • Fakhre G.P.
      • Nields W.W.
      • et al.
      Incidental appendectomy: 18-year pathologic survey and cost effectiveness in the nonmanaged-care setting.
      • Fisher K.S.
      • Ross D.S.
      Guidelines for therapeutic decision in incidental appendectomy.
      • Snyder T.E.
      • Selanders J.R.
      Incidental appendectomy—yes or no? A retrospective case study and review of the literature.
      • Salom E.M.
      • Schey D.
      • Peñalver M.
      • et al.
      The safety of incidental appendectomy at the time of abdominal hysterectomy.
      • Strom P.R.
      • Turkleson M.L.
      • Stone H.H.
      Safety of incidental appendectomy.
      • Kelly C.P.
      A 76-year-old man with recurrent Clostridium difficile-associated diarrhea: review of C. difficile infection.
      • Mayer L.
      • Eisenhardt D.
      Lack of induction of suppressor T cells by intestinal epithelial cells from patients with inflammatory bowel disease.
      Given the limitations of our retrospective study, further epidemiologic and prospective studies are necessary to better define the relationship between the appendix and recurrent CDI.

      Video Abstract

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