Abstract
Background
The association between bacterial strains and clinical outcomes in Clostridioides difficile infection (CDI) has yielded conflicting results across studies. We conducted a systematic review and meta-analyses to assess the impact of these strains.
Methods
Five electronic databases were used to identify studies reporting CDI severity, complications, recurrence, or mortality according to strain type from inception to June 2022. Random effect meta-analyses were conducted to assess outcome proportions and risk ratios (RRs).
Results
A total of 93 studies were included: 44 reported recurrences, 50 reported severity or complications, and 55 reported deaths. Pooled proportions of complications were statistically comparable between NAP1/BI/R027 and R001, R078, and R106. Pooled attributable mortality was 4.8% with a gradation in patients infected with R014/20 (1.7%), R001 (3.8%), R078 (5.3%), and R027 (10.2%). Higher 30-day all-cause mortality was observed in patients infected with R001, R002, R027, and R106 (range, 20%–25%).
NAP1/BI/R027 was associated with several unfavorable outcomes: recurrence 30 days after the end of treatment (pooled RR, 1.98; 95% CI, 1.02–3.84); admission to intensive care, colectomy, or CDI-associated death (1.88; 1.09–3.25); and 30-day attributable mortality (1.96; 1.23–3.13). The association between harboring the binary toxin gene and 30-day all-cause mortality did not reach significance (RR, 1.6 [0.9–2.9]; 7 studies).
Conclusions
Numerous studies were excluded due to discrepancies in the definition of the outcomes and the lack of reporting of important covariates. NAP1/BI/R027, the most frequently reported and assessed strain, was associated with unfavorable outcomes. However, there were not sufficient data to reach significant conclusions on other strains.
Keywords: Clostridioides difficile, complications, mortality, recurrence, strain
A systematic review (93 studies) and meta-analysis were conducted to assess the association between bacterial strains and complications, recurrence, and mortality in Clostridioides difficile infection. NAP1/BI/R027 was associated with unfavorable outcomes. Data on other strains were insufficient for significant conclusions.
In the early 21st century, an outbreak of Clostridioides difficile infection (CDI) was first reported in Canada and the United States and thereafter in Europe [1]. In addition to the large number of cases, CDI has been associated with severe and recurrent symptoms and high mortality rates [2, 3]. One bacterial strain, NAP1/BI/027, has been frequently detected in complicated cases [4]. This strain has been shown to have high virulence, which is attributed to genetic mutations in the toxin-encoding loci and resistance to fluoroquinolones [1]. The CDI outbreak was successfully managed via sustained infection control and stewardship interventions, and therapeutic options are now available [5, 6]. Several C difficile virulence factors and mechanisms of action have been identified [7]. However, CDI remains the most frequent health care–associated infectious diarrhea, with an important clinical burden, including recurrence of the disease [8], longer hospital stay, and higher costs [9, 10].
Pulsed-field gel electrophoresis is the reference technique for CDI typing in North America, while ribotyping is the reference technique in Europe. More than 200 ribotypes have been identified to date, and some have been systematically associated with the presence of the binary toxin (CDT), such as R027, R078, and R023 [11]. More recent typing methods include multiple-locus variable number tandem repeat analysis, multilocus sequence typing, and amplified fragment-length polymorphism for the flagellin gene (fliC) and surface protein precursor (slpA), as well as whole genome sequencing; all of which are being used to provide a higher level of discrimination than traditional techniques [12, 13].
However, the association between strain type and unfavorable clinical outcomes has been inconsistent across studies. While some authors have asserted that clinical outcomes are related to particular strains [14–18], other large studies have not shown any statistically significant associations [19–21].
To obtain a clear picture of the virulence of C difficile strains and their effects on clinical outcomes, we conducted a systematic review of the literature and meta-analyses.
METHODS
The PRISMA [22] and COSMOS-E [23] guidelines were followed. Electronic databases were searched from inception to 30 June 2022 without language restrictions: PubMed and Ovid MEDLINE, Cochrane Database of Systematic Reviews, Embase, and Web of Sciences. The following keywords with Booleans were used: (“Clostridium difficile” OR “Clostridium difficile–associated diarrhea” OR “Clostridium difficile–associated disease” OR “Clostridioides” OR “colitis” OR “pseudomembranous”) AND (“strain” OR “type” OR “ribotype” OR “typing” OR “binary” OR “toxin”).
Studies were included if they (1) focused on C difficile as the main pathogen, (2) reported the frequency of bacterial strains with at least 1 typing technique, and (3) measured at least 1 relevant clinical outcome: severity, complications, mortality, treatment failure, and/or recurrence of CDI. Data from the clinical trials were analyzed in subgroups when relevant.
Case reports, conference proceedings, surveillance data reports without clinical outcomes or diagnostic techniques, and studies involving <50 patients were excluded (Figure 1).
Figure 1.
Flowchart of inclusion and exclusion.
Data Collection
Two independent reviewers screened the titles and abstracts and assessed full-text eligibility using EndNote software. Data from the studies were extracted in double to a standardized matrix. For studies with missing data, authors were contacted via email (28 publications) and 16 replied.
Detailed descriptions of the studies are provided in Supplementary Tables 2, 3, and 4.
Age distribution, comorbidities indices, and prescribed treatments were extracted according to strains. For recurrent CDI (rCDI), the diagnostic criteria of the initial and recurrent episodes were documented and used as stratification covariates.
The clinical outcomes were extracted as reported and grouped as appropriate. We included 4 CDI complications (cCDIs)—pseudomembranous colitis, intestinal perforation, ileus, and toxic megacolon—all of which are severe events that lead to admission to the intensive care unit (ICU). For recurrence, the definitions were separated according to occurrence after the diagnosis of the initial CDI episode and after the end of treatment for the initial episode. Attributable mortality was considered if reported as such by the authors of the studies.
According to the discrimination levels of the typing techniques [24], R014 and R020, R053 and R163, and R078 and R126 were considered similar and so were grouped.
Meta-analyses
Raw data were extracted based on the assumption that each patient was infected by 1 strain. For each outcome and strain, we assessed the pooled proportion (number of patients with outcome/number of strains) with a 95% CI and crude risk ratio (RR). For the RR, each strain was compared with all other strains in the same study.
All analyses were conducted with the meta package in R software (R Core Team) and the functions metaprop for meta-analysis of single proportions and metabin for that of binary outcome data. The codes are shown in the Supplementary material.
Random effects and inverse variance weighting were considered for pooling the studies in all analyses. To take account of the distribution of proportions, Freeman-Tuckey double-arcsine, logit, or logarithmic transformations were used as appropriate, and the results are shown after back-transformation. An increment of 0.001 was used in case of 0 events. For estimation of pooled RRs, a mixed-effects logistic regression model with random study effects was used.
A DerSimonian and Laird, maximum likelihood, or Sidik-Jonkman estimator was used to estimate the between-study variance (τ). Heterogeneity within the studies was estimated with Cochran Q and I2 statistics. The analyses were stratified according to available data.
RESULTS
Characteristics of Studies
A total of 93 studies were included in the review: 48 reported recurrence according to strain type, 52 reported CDI severity or complications, and 55 reported mortality (Figure 1). Four studies assessed recurrence in the pediatric population [25–28], and 2 assessed severity and complications [25, 27]. These studies did not assess the effects of common strains and were therefore not in the meta-analysis.
A summary of the study characteristics is presented in Table 1. The reported outcomes are summarized in Supplementary Table 1.
Table 1.
Characteristics of Studies According to Clinical Outcomes, Excluding Studies in Pediatric Patients Only
| Studies, No. (%) | |||
|---|---|---|---|
| Characteristic | Severity/cCDI (n = 50) | Recurrence (n = 44) | Mortality (n = 55) |
| Region of studies | |||
| Europe | 23 (46.0) | 21 (47.73) | 32 (58.18) |
| UK | 4 (8.0) | 4 (9.09) | 9 (16.36) |
| America | 20 (40.0) | 14 (31.82) | 18 (32.73) |
| Canada | 6 (12.0) | 2 (4.55) | 5 (9.09) |
| US | 11 (22.0) | 7 (15.91) | 10 (18.18) |
| Latin America | 3 (6.0) | 5 (11.36) | 3 (5.45) |
| Asia/Australia/New Zealand | 6 (12.0) | 5 (11.36) | 4 (7.27) |
| Multiple | 1 (2.0) | 4 (9.09) | 1 (1.82) |
| Study design | |||
| Prospective cohort | 25 (50.0) | 16 (36.36) | 24 (43.64) |
| Surveillance data | 13 (26.0) | 5 (11.36) | 14 (25.45) |
| Retrospective cohort | 20 (40.0) | 23 (52.27) | 26 (47.27) |
| Case-control | 3 (6.0) | 2 (4.55) | 4 (7.27) |
| Cross-sectional | 1 (2.0) | … | … |
| Randomized controlled trial | 1 (2.0) | 3 (6.82) | 1 (1.82) |
| No. of settings/centers | |||
| 1 | 24 (48.0) | 28 (63.64) | 27 (49.09) |
| 2 or 3 | 2 (4.0) | 3 (6.82) | 4 (7.27) |
| ≥4 (up to 322) | 23 (46.0) | 13 (29.55) | 23 (41.82) |
| Not reported | 1 (2.0) | … | 1 (1.82) |
| Study population | |||
| All CDI cases | 27 (54.0) | 35 (79.55) | 27 (49.10) |
| Hospitalized CDI | 23 (46.0) | 9 (23.45) | 17 (30.91) |
| HCFA | 4 (8.0) | 8 (18.18) | 8 (14.55) |
| Inpatients only | 12 (24.0) | … | 9 (16.36) |
| CDI episodes | |||
| Primary | 4 (8.0) | 5 (11.36) | 6 (10.91) |
| Recurrent | … | 3 (6.82) | … |
| Study population's age group | |||
| All ages | 27 (54.0) | 18 (40.91) | 34 (61.82) |
| Adults only | 17 (34.0) | 20 (45.45) | 18 (32.73) |
| Elderly | 2 (4.0) | 3 (6.82) | 1 (1.82) |
| Not reported | 4 (8.0) | 3 (6.82) | 2 (3.64) |
| Typing technique | |||
| Ribotyping | 33 (66.0) | 34 (77.27) | 34 (61.82) |
| Gene detection or deletion | 9 (18.0) | 3 (6.82) | 13 (23.64) |
| PFGE | 5 (10.0) | 1 (2.27) | 3 (5.45) |
| EIA/REA | 2 (4.0) | 5 (11.36) | 4 (7.27) |
| MLST | 1 (2.0) | 1 (2.27) | 1 (1.82) |
Abbreviations: cCDI, C difficile infection complication; CDI, Clostridioides difficile infection; EIA, enzyme immunoassay; HCFA, health care facility acquired; MLST, multilocus sequencing typing; PFGE, pulsed-field gel electrophoresis; REA, restriction endonuclease analysis.
Data were collected during overlapping periods (Supplementary Figure 1). In most studies (54% reporting severity or complications, 44% recurrence, and 62% mortality), patients were of any age, including pediatrics and elderly, and no data were reported about patients’ age in 8%, 7%, and 4% of studies, respectively. Ribotyping was the most frequently used technique, followed by CDT gene detection or deletion techniques to identify the strains, mainly with Cepheid Xpert C difficile Epi assay.
Many discrepancies were noted in the definitions of the outcomes (Supplementary Table 1): cCDI, including ICU admission, surgery, or all-cause 30-day death, was the most frequently retrieved outcome (13 studies), followed by severe CDI criteria per the Infectious Diseases Society of America (11 studies) and cCDI including CDI-associated death (8 studies; Supplementary Table 2). The definition of rCDI was not consistent (Supplementary Table 3), with the most frequent one being recurrence 60 days after diagnosis and 30 days after the end of treatment for the previous episode. Multiple recurrences with different delays were assessed in 4 studies [19, 29–31] and could not be included in the meta-analysis. All-cause 30-day mortality was assessed in 41 studies (Supplementary Table 4), while attributable 30-day mortality was assessed in only 14. The time of occurrence of mortality was not reported in 6 studies, and they had to be precluded.
Meta-analysis
Severity and Complications
Five strains (R001, R002, R014/020, NAP1/R027, R078/126) were frequently reported across studies assessing severity [32], CDI-associated ICU admission, and cCDI, including colectomy or associated/all-cause death (Table 2). The pooled proportions of severity in patients infected with R001, R014, and NAP1/R027 overlapped (Supplementary Figure 2). However, only NAP1/R027 was associated with a higher risk of severity (RR, 1.6; 95% CI, 1.2–2.1): 9% of patients infected with this strain required ICU admission vs 4% for other strains (Supplementary Figure 3), and the risk was 2-fold higher (2.0; 0.99–4.1).
Table 2.
Meta-analysis of Proportion and Risk Ratio of Severity and Complications by Strain Types and Subgroups
| Outcome: Strain and Subgroup | No. of Studies | Sample Size, Range | Total Typed Isolates | Strain, % | Events/Strain, No. | Outcome, % (95% CI) | Risk Ratio (95% CI) | Heterogeneity I2, % (95% CI) |
|---|---|---|---|---|---|---|---|---|
| Severitya | ||||||||
| R001 | 3 | 254–1357 | 1626 | 7.81 | 45/127 | 36.05 (28.05–44.90) | 1.00 (.79–1.28) | 96.95 (93.83–98.49) |
| R014/020 | 4 | 150–1357 | 1936 | 8.68 | 62/168 | 37.43 (30.36–45.07) | 0.84 (.20–3.56) | 97.47 (95.62–98.54) |
| R027 or NAP1 | 6 | 57–1357 | 2367 | 36.97 | 405/875 | 50.68 (36.04–65.20) | 1.55 (1.17–2.06) | 92.62 (86.68–95.92) |
| CDI-associated ICU admissionb | ||||||||
| R027 or NAP1 | 4 | 150–17202 | 3998 | 39.87 | 73/1594 | 9.26 (3.27–23.53) | 2.00 (.99–4.06) | 74.13 (27.73–90.74) |
| ICU admission, colectomy, or associated deathb | ||||||||
| R014 | 3 | 133–1357 | 2097 | 12.30 | 14/258 | 3.13 (.87–6.27) | 0.62 (.06–6.43) | 93.37 (84.00–97.25) |
| R027 or NAP1 | 6 | 133–3084 | 5516 | 21.16 | 143/1167 | 12.41 (8.94–16.30) | 1.50 (.80–2.81) | 82.06 (58.63–92.22) |
| R027 | 5 | 133–3084 | 5280 | 20.98 | 129/1108 | 10.57 (8.10–13.28) | 1.72 (.97–3.04) | 70.11 (14.19–89.59) |
| N ≥ 1000 patients | 4 | 1144–3084 | 5204 | 21.19 | 128/1103 | 11.86 (9.49–14.45) | 1.88 (1.09–3.25) | 72.93 (8.97–91.95) |
| Prospective design | 4 | 133–1357 | 2333 | 30.56 | 85/713 | 12.45 (7.32–18.49) | 1.43 (.65–3.18) | 83.05 (56.74–93.36) |
| Canada and USA | 4 | 272–3084 | 4763 | 21.79 | 120/1038 | 12.13 (9.22–15.37) | 1.62 (.70–3.70) | 86.71 (61.87–95.37) |
| R078/126 | 3 | 1144–1687 | 2698 | 4.11 | 7/111 | 4.69 (.40–11.96) | 0.59 (.06–5.49) | 85.54 (57.66–95.06) |
| ICU admission, colectomy, or 30-d all-cause deathb | ||||||||
| R001 | 3 | 112–4387 | 5887 | 14.76 | 140/869 | 18.86 (11.70–28.97) | 1.36 (.44–4.22) | 95.18 (89.23–97.85) |
| R002 | 3 | 112–3333 | 2719 | 7.54 | 18/205 | 8.91 (5.50–14.13) | 0.84 (.08–8.59) | 87.45 (64.53–95.56) |
| R014/020 | 5 | 171–4387 | 8840 | 18.30 | 140/1618 | 10.71 (7.40–15.26) | 0.95 (.27–3.31) | 97.37 (95.75–98.38) |
| Europe | 4 | 171–4387 | 8530 | 18.36 | 133/1566 | 10.49 (6.71–16.05) | 0.88 (.20–3.81) | 97.98 (96.64–98.79) |
| R027 or NAP1 | 5 | 171–4387 | 9358 | 6.57 | 86/615 | 14.65 (10.55–19.99) | 1.73 (1.05–2.87) | 75.28 (39.19–89.95) |
| R027 or data ≥2010 | 4 | 171–4387 | 8350 | 3.64 | 47/304 | 15.58 (10.22–23.04) | 1.85 (1.40–2.45) | 60.86 (0–86.90) |
| N ≥ 1000 patients | 3 | 1150–4387 | 8877 | 6.05 | 73/537 | 13.90 (10.39–18.34) | 1.99 (1.30–3.08) | 63.71 (0–89.62) |
| Europe | 3 | 171–4387 | 8040 | 3.23 | 37/260 | 13.94 (9.04–20.91) | 1.73 (1.27–2.36) | 69.97 (0–91.22) |
| R078/126 | 5 | 112–4387 | 8388 | 11.08 | 127/930 | 13.19 (9.53–17.98) | 1.24 (.48–3.16) | 87.88 (74.21–94.30) |
| Prospective design | 4 | 112–4387 | 8078 | 11.34 | 126/916 | 13.79 [11.71–16.19) | 1.37 (.49–3.76) | 90.26 (78.04–95.68) |
| Europe | 3 | 171–4387 | 8040 | 11.34 | 125/912 | 13.73 (11.65–16.13) | 1.35 (.43–4.22) | 93.41 (84.11–97.26) |
| Data ≥2010 | 4 | 171–4387 | 8350 | 11.09 | 126/926 | 13.47 (11.27–15.67) | 1.20 (.42–3.39) | 90.77 (79.44–95.86) |
Abbreviations: CDI, Clostridioides difficile infection; EIA, enzyme immunoassay; ICU, intensive care unit; RR, risk ratio.
aWhite blood cell count ≥ 15 × 109 C/L or creatinine ≥1.5× baseline, as defined by the guidelines of the Infectious Diseases Society of America [32].
bIncluding pseudomembranous colitis, intestinal perforation, ileus, and toxic megacolon in some studies, which are considered rare events that lead to ICU admission.
cCDI including associated 30-day death was more frequent in patients infected with NAP1/027: 12% vs 3% and 5% in patients infected with R014 and R078, respectively (Supplementary Figure 4). The overall observed risk was higher in large studies (RR, 1.9; 95% CI, 1.1–3.2) but not according to design or country (Table 2). For cCDI including all-cause 30-day death, NAP1/R027 was less frequently found among typed strains (6%) than other strains: R014 (18%), R001 (15%), and R078 (11%). The pooled proportions of outcomes were comparable across all strains with overlapping 95% CIs (9%–19%; Supplementary Figure 5). However, only NAP1/R027 was significantly associated with a higher risk, mainly in large and recent studies (RR, 2.0 [95% CI, 1.3–3.1] and 1.8 [1.4–2.4], respectively).
Eight studies assessed the effect of tcdC/Δ117 gene deletion or harboring the CDT gene but without a common outcome for the meta-analysis [15, 33–39].
Recurrence
Regardless of the study design, period of data collection, region, types of patients, and sample size, rCDI occurred 30 days after the end of treatment in 1 out of every 4 cases of NAP1/R027 infection (overall, 24.3%; 95% CI, 16.5%–32.9%; Table 3, Supplementary Figure 6). This strain represented 45% of total typed strains, and R027 represented 50% in 5 studies. Although the proportion of rCDI seemed lower after 2010 (17% vs 30%), the studies had smaller sample sizes (135–288 patients) and 364 total typed isolates. R027 was significantly associated with a 2-fold higher risk of rCDI (RR, 1.98) in only 4 studies conducted in adult patients [19, 40–42].
Table 3.
Meta-analysis of Proportion and Risk Ratio of CDI Recurrence by Strain Types and Subgroups
| Outcome: Strain and Subgroup | No. of Studies | Sample Size, Range | Total Typed Isolates | Strain, % | Events/Strain, No. | Outcome, % (95% CI) | Risk Ratio (95% CI) | Heterogeneity I2, % (95% CI) |
|---|---|---|---|---|---|---|---|---|
| 30 d after end of treatment | ||||||||
| R027 or NAP1 | 7 | 128–1380 | 2170 | 45.02 | 278/977 | 24.26 (16.55–32.91) | 1.65 (.98–2.77) | 82.36 (65.85–91.15) |
| R027 | 5 | 133–1380 | 1372 | 50.94 | 204/699 | 25.10 (9.33–40.87) | 1.78 (.92 3.47) | 80.55 (54.40–91.70) |
| Adult patients onlya | 4 | 133–1380 | 1757 | 46.61 | 244/819 | 29.57 (26.46–32.69) | 1.98 (1.02–3.84) | 86.59 (67.53–94.46) |
| All patients with CDIb | 6 | 128–1380 | 2091 | 45.24 | 272/946 | 25.14 (16.42–33.87) | 1.52 (.88–2.62) | 85.09 (69.42–92.74) |
| Diarrhea for diagnosis of recurrencec | 4 | 128–1380 | 1752 | 42.35 | 214/742 | 28.47 (24.98–31.96) | 1.86 (.96–3.62) | 87.76 (70.96–94.84) |
| Prospective designd | 4 | 128–1380 | 1752 | 42.35 | 214/742 | 28.47 (24.98–31.96) | 1.86 (.96–3.62) | 87.76 (70.96–94.84) |
| Excluding clinical trial | 3 | 128–1380 | 1033 | 47.92 | 146/495 | 27.26 (20.40–34.11) | 2.06 (.68–6.29) | 84.95 (55.48–94.90) |
| Retrospective design | 3 | 133–150 | 418 | 56.22 | 64/235 | 23.26 (1.22–45.31) | 1.32 (.40–4.37) | 78.97 (32.75–93.42) |
| Data <2010 | 4 | 128–1380 | 1806 | 45.51 | 246/822 | 30.12 (27.13–33.43) | 1.68 (.90–3.15) | 87.83 (71.16–94.86) |
| Data ≥2010 | 3 | 135–288 | 364 | 42.58 | 32/155 | 16.88 (5.10–33.66) | 1.66 (.36–7.57) | 78.65 (31.52–93.34) |
| Isolates typed ≥50% of sample | 6 | 128–1380 | 2091 | 45.24 | 272/946 | 25.23 (14.66–35.80) | 1.52 (.88–2.62) | 85.09 (69.42–92.74) |
| 60 d after index episode | ||||||||
| R014/R020 (all data ≥2010) | 3 | 600–3333 | 4544 | 15.93 | 68/724 | 9.37 (7.35–11.59) | 0.92 (.72–1.18) | 97.29 (94.66–98.63) |
| R027 | 5 | 111–3333 e | 5673 | 10.06 | 124/571 | 21.62 (18.35–25.09) | 1.82 (1.12–2.96) | 84.06 (64.14–92.92) |
| R078 | 3 | 899–3333 | 4699 | 5.19 | 22/244 | 9.68 (5.37–15.08) | 0.82 (.50–1.36) | 94.63 (87.66–97.66) |
| R053/163f | 3 | 50–899 | 1261 | 5.23 | 5/66 | … | … | … |
| 60 d after end of treatment | ||||||||
| R014/R020 | 4 | 60–490 | 744 | 9.41 | 9/70 | 12.16 (5.61–20.78) | 1.06 (.30–3.70) | 63.36 (0–87.64) |
| R027 or NAP1 | 4 | 60–324 | 583 | 42.19 | 73/246 | 31.51 (14.21–51.99) | 2.04 (.79–5.22) | 79.80 (46.42–92.38) |
Abbreviations: CDI, Clostridioides difficile infection; RR, risk ratio.
aOverall analyses included 1 study in an elderly population [40].
bExcluding 1 study in primary CDI cases only [42].
cDefined as ≥3 loose stools/d for >24 hours as the main diagnostic criterion for the initial CDI episode. In most studies, these criteria defined recurrent episodes.
dA randomized clinical trial was considered a prospective design [41]. As the patients were enrolled in the same clinical trial, the study by Louie et al [41], with the largest sample size, was considered in the analyses and not the study by Petrella et al [21].
eFor Neely et al [43], follow-up data were reported for 2698 of the 3333 patients included and typed. In this study, data on R014 and R020 were considered together for the assessment of the RR.
When defined within 60 days of the index episode, the proportion of rCDI was assessed in patients infected with NAP1/R027, R014, R078, and R053 strains. The studies had larger sample sizes and more typed strains than those assessing recurrence within 60 days after the end of treatment (total typed isolates: 60 days after index episode, n = 5673 for R027; 60 days after end of treatment, n = 583 for R027/NAP1). The pooled proportion of rCDI was higher in patients infected with R027/NAP1 (21.6%) than in those infected with R014 and R078 (9.3% and 9.7%, respectively; Supplementary Figure 7). Only NAP1/R027 was significantly associated with a higher risk (RR, 1.82; 95% CI, 1.12–2.96), although this strain represented 10% of typed strains and R014 represented 16%.
Within 60 days after the end of treatment, the proportion of rCDI was significantly higher in patients infected with NAP1/R027 than in those infected with R014 (32% vs 12%; Supplementary Figure 8). NAP1/R027 presented 42% of typed strains. However, the risk of recurrence was not associated with any of the tested strains.
Four studies assessed the effect of tcdC/Δ117 gene deletion or harboring the CDT gene, but without a common outcome for the meta-analysis [33, 34, 46, 47].
Mortality
Short-term Mortality
The pooled proportion of short-term mortality was similar (11%) in patients infected by NAP1/R027 and R078 strains (Table 4, Supplementary Figure 9; 5 studies) despite the 10-fold lower frequency of R078 vs R027 (34% vs 3.2%). Furthermore, only the NAP1/R027 strain showed a significant association with mortality (RR, 1.6; 95% CI, 1.0–2.5) in 3 large studies including 4821 typed isolates.
Table 4.
Meta-analysis of Proportion and Risk Ratio of Mortality Alone by Strain Types and Subgroups
| Outcome: Strain and Subgroup | No. of Studies | Sample Size, Range | Total Typed Isolates | Strain, % | Events/Strain, No. | Outcome, % (95% CI) | Risk Ratio (95% CI) | Heterogeneity I2, % (95% CI) |
|---|---|---|---|---|---|---|---|---|
| 14-d all-cause mortality | ||||||||
| R027 or NAP1 | 5 | 319–2222 | 5405 | 34.43 | 206/1861 | 10.14 (5.94–15.30) | 2.01 (.84–4.83) | 93.06 (86.75–96.36) |
| Isolates typed ≥50% and N ≥ 1000 patients | 3 | 1380–2222 | 4821 | 33.02 | 183/1592 | 10.78 (4.87–18.64) | 1.58 (1.00–2.50) | 72.02 (5.40–91.73) |
| R078 | 3 | 1380–2222 | 4821 | 3.22 | 20/155 | 11.99 (.18–23.81) | 1.19 (.30–4.63) | 79.99 (36.75–93.67) |
| 30-d attributable mortality | ||||||||
| R001 | 4 | 230–4387 | 6814 | 13.15 | 34/896 | 3.81 (2.73–5.28) | 0.80 (.13–4.91) | 91.67 (81.85–96.18) |
| R014/020 | 3 | 335–4387 | 6584 | 16.16 | 18/1064 | 1.71 (1.08–2.71) | 0.46 (.29–.75) | 0 (0–89.60) |
| R027 or NAP1 | 8 | 57–17 202 | 11 997 | 17.87 | 165/2144 | 10.17 (6.51–15.55) | 1.96 (1.23–3.13)a | 57.45 (0–82.81) |
| R027 | 5 | 137–4387 | 9143 | 11.95 | 90/1093 | 9.18 (5.43–15.09) | 1.89 (.86–4.14) | 70.83 (16.63–89.79) |
| N ≥ 1000 patients | 4 | 1380–17 202 | 11 477 | 16.81 | 124/1929 | 6.48 (5.46–7.68) | 2.05 (1.24–3.39) | 57.51 (0–87.89) |
| Data ≥2008 | 4 | 57–17 202 | 10 719 | 13.96 | 102/1497 | 8.21 (4.18–15.50) | 1.67 (.77–3.63) | 62.90 (0–89.40) |
| R078 | 4 | 1037–4691 | 11 073 | 13.65 | 77/1512 | 5.26 (4.08–6.75) | 1.31 (.53–3.25) | 90.65 (79.13–95.82) |
| Europe and data ≥2008 | 3 | 1037–4691 | 10 151 | 14.65 | 76/1487 | 5.27 (3.71–7.09) | 1.36 (.51–3.66) | 93.57 (84.58–97.31) |
| 30-d all-cause mortality | ||||||||
| R001 | 7 | 114–11 571 | 11 421 | 11.50 | 228/1313 | 20.15 (14.61–27.11) | 1.27 (.57–2.82) | 97.02 ([95.1–98.03) |
| N ≥ 1000 patients | 5 | 1350–11 571 | 11 004 | 11.28 | 208/1241 | 18.43 (12.75–25.88) | 1.23 (.46–3.26) | 97.93 (96.77–98.68) |
| Europe | 6 | 114–11 571 | 10 499 | 11.72 | 214/1231 | 20.70 (14.37–28.88) | 1.24 (.50–3.03) | 97.45 (96.08–98.34) |
| UK and Scotland | 4 | 114–11 571 | 4454 | 10.66 | 119/475 | 25.01 (21.22–29.0) | 1.31 (.44–3.87) | 96.70 (93.98–98.17) |
| Data ≥2008 | 5 | 114–11 571 | 9813 | 11.96 | 191/1174 | 21.42 (15.36–28.18) | 1.22 (.44–3.33) | 97.91 (96.72–98.66) |
| R002 (data ≥2009) | 5 | 139–11 571 | 4750 | 9.77 | 82/464 | 22.66 (13.42–35.63) | 1.25 (.79–1.98) | 71.60 (28.25–88.76) |
| Isolates typed ≥50% of patients | 4 | 139–1426 | 2139 | 8.79 | 48/188 | 26.26 (16.31–37.46) | 1.49 (.88–2.52) | 66.44 (1.76–88.53) |
| Europe | 4 | 171–11 571 | 4658 | 9.51 | 72/443 | 17.62 (10.16–26.40) | 1.05 (.27–4.08) | 96.58 (93.76–98.12) |
| R014/020 | 8 | 142–11 571 | 11 140 | 15.94 | 165/1776 | 9.83 (7.02–13.61) | 0.78 (.59–1.03) | 66.28 (28.56–84.08) |
| Isolates typed ≥50% of patients | 7 | 142–4387 | 8529 | 16.72 | 110/1426 | 8.18 (6.53–10.25) | 0.67 (.51–.87) | 37.62 (0–73.73) |
| Strains ≥500 and N ≥ 1000 patients | 5 | 1350–11 571 | 10 677 | 15.69 | 154/1675 | 9.62 (6.95–13.32) | 0.76 (.56–1.03) | 66.28 (28.56–84.08) |
| Canada and US | 3 | 150–1380 | 2171 | 13.91 | 25/302 | 8.47 (5.83–12.32) | 0.83 (.15–4.57) | 93.68 (84.93–97.35) |
| Europe | 5 | 142–11 571 | 8969 | 16.43 | 140/1474 | 10.47 (7.31–14.99) | 0.76 (.52–1.10) | 79.67 (51.92–91.40) |
| Data ≥2008 | 5 | 150–11 571 | 9390 | 16.69 | 145/1567 | 10.01 (7.03–14.25) | 0.80 (.56 1.15) | 79.92 (52.63–91.49) |
| R023 | 3 | 1426–11 571 | 9396 | 3.07 | 31/289 | 11.71 (6.75–19.54) | 0.72 (.52–1.01) | 96.77 (93.40–98.42) |
| R027 or NAP1 | 21 | 57–17 202 | 17 187 | 18.04 | 604/3101 | 22.34 (18.24–27.06) | 1.57 (1.15–2.16) | 88.23 (83.40–91.66) |
| R027 | 17 | 86–11 571 | 14 186 | 21.88 | 421/1924 | 23.09 (18.43–28.11 | 1.63 (1.15–2.31) | 87.52 (81.56–91.55) |
| NAP1 or BI | 4 | 57–17 202 | 3087 | 16.15 | 194/1201 | 15.49 (13.49–17.62) | 1.32 (.33–5.23) | 92.81 (84.82–96.60) |
| Isolates typed ≥50% and N ≥ 100 patients | 16 | 111–4387 | 11 381 | 20.0 | 345/1746 | 20.78 (16.56–25.35) | 1.65 (1.14–2.39) | 85.67 (78.21–90.57) |
| R027 only | 14 | 111–4387 | 11 321 | 20.16 | 325/1606 | 21.71 (17.0426.78) | 1.62 (1.31–2.01) | 57.15 (22.27–76.37) |
| N ≥ 1000 patients/500 strains | 5 | 1114–4387 | 9492 | 10.22 | 177/971 | 20.24 (12.36–29.49) | 1.55 (1.22–1.96) | 63.28 (3.03–86.09) |
| All patients with CDI | 10 | 111–4387 | 8579 | 12.36 | 208/1060 | 20.95 (15.07–27.51) | 1.34 (.77–2.31) | 90.58 (84.83–94.16) |
| HCFA CDI/inpatients | 6 | 111–1350 | 2802 | 25.05 | 147/702 | 20.75 (15.68–26.33) | 2.35 (1.65–3.34) | 45.08 (0–78.27) |
| Canada and US | 6 | 111–1380 | 2655 | 37.06 | 156/984 | 16.71 (12.34–21.61) | 1.55 (.78–3.09) | 88.21 (76.85–93.99) |
| Europe | 10 | 111–4387 | 8726 | 8.73 | 216/762 | 23.89 (17.99–30.33) | 1.72 (1.06–2.79) | 85.55 (75.23–91.57) |
| Data<2008 | 7 | 97–1380 | 2306 | 37.20 | 160/858 | 21.29 (15.11–28.21) | 1.59 (.81–3.12) | 88.15 (77.99–93.62) |
| Data ≥2008 | 9 | 111–4387 | 9172 | 10.16 | 208/1932 | 20.33 (14.74–26.57 | 1.71 (1.05–2.78) | 85.19 (73.72–91.66) |
| Prospective design | 9 | 124–4387 | 8821 | 12.20 | 184/1076 | 19.25 (14.28–24.76) | 1.53 (.89–2.60) | 88.20 (79.78–93.11) |
| Retrospective design | 7 | 111–1426 | 2560 | 26.80 | 171/686 | 22.51 (15.95–29.83) | 1.85 (.99–3.44) | 83.73 (68.04–91.72) |
| R053/163 | 3 | 142–1114 | 1412 | 8.07 | 12/114 | 11.66 (5.26–23.89) | 1.39 (.39–4.97) | 72.83 (8.57–91.92) |
| R078/126 | 11 | 114–11 571 | 16 711 | 10.84 | 280/1812 | 16.20 (14.31–18.29) | 0.94 (.47–1.85) | 96.00 (94.33–97.18) |
| Isolates typed ≥50% of patients | 9 | 114–4691 | 13 835 | 10.85 | 229/1501 | 10.35 (7.03–13.67) | 0.91 (.41–2.02) | 98.13 (95.69–99.19) |
| N ≥ 1000 patients | 8 | 1114–11 571 | 16 123 | 10.84 | 270/1747 | 15.17 (7.04–23.30) | 1.01 (.46–2.19) | 96.99 (95.59–97.95) |
| R106 | 4 | 97–11 571 | 4260 | 9.08 | 86/387 | 24.56 (16.66–34.63) | 1.02 (.64–1.62) | 76.41 (35.34–91.39) |
| Binary toxin gene | ||||||||
| Yes | 7 | 66–2299 | 1965 | 28.70 | 128/564 | 17.63 (11.41–24.76) | 1.64 (.92–2.92)b | 71.45 (33.74–87.69) |
| No | 6 | 1879 | 71.05 | 163/1335 | 10.72 (7.61–14.27) | |||
| N ≥ 100 patients | 5 | 107–2299 | 1813 | 27.74 | 122/503 | 12.25 (9.32–15.48) | 1.75 (.91–3.36) | 80.82 (49.69–92.68) |
| Isolates typed ≥50% patients | 5 | 66–880 | 1488 | 20.09 | 54/299 | 10.41 (7.87–13.22) | 1.63 (.80–3.35) | 59.23 (0–84.78) |
| Data ≥2008 | 5 | 66–2299 | 1883 | 28.84 | 125/543 | 11.27 (7.82–15.18) | 1.70 (.91–3.18) | 75.24 (39.07–89.93) |
Abbreviations: CDI, Clostridioides difficile infection; HCFA, health care facility acquired; ICU, intensive care unit.
aRisk ratio was assessed in 7 studies, as data on other strains were scarcely reported [48].
bRisk ratio was assessed in 6 studies, as data on the absence of the binary toxin gene were not reported [49].
Attributable Mortality
Associations with 30-day attributable mortality could be assessed for R001, R014, NAP1/R027, and R078. These strains were reported at similar frequencies (13%–19%), but the proportion of the outcome was much lower in patients infected with R014 (1.7%, n = 18 events) and R001 (3.8%, 34 events), whereas attributable mortality rates were higher in patients infected with NAP1/R027 (10.2%; 95% CI, 6.5–15.5) and R078 (5.3%; 4.1–6.7; Supplementary Figure 10). However, the risk of attributable mortality was 2-fold higher in patients infected with NAP1/R027 and 2-fold lower in patients infected with R014 (Table 4), with the proportion of deaths decreasing from 12% to 8% after 2008.
All-cause Mortality
The pooled proportion of 30-day all-cause mortality ranged between 20% and 25% in patients infected with R001, R002, R027, and R106 (Supplementary Figure 11) and between 10% and 16% in those infected with R014, R023, R053, and R078. With overlaps in 95% CIs, the proportion of mortality was lower in patients infected with R014, R023, R053, and R078 and higher and similar in patients infected with R001, R002, R027, and R106. NAP1/R027 was the most frequently reported strain (21 studies), with a median frequency of 37% in small studies and only 8% in large studies (n ≥ 500 patients, 9 studies). R078 was less frequently retrieved (median, 10% of typed strains) and mainly in large studies (n ≥ 1000 patients, 8 studies), with a maximum of 13%.
Only NAP1/R027 showed a higher risk of 30-day all-cause mortality (RR, 1.6; Table 4). However, when stratified by typing technique, NAP1 strains were not associated with mortality risk (RR, 1.3; 95% CI, 0.3–5.2). The risk remained higher (1.6; 1.2–1.96) in large studies and those that had typed more than half of patients, with lower heterogeneity across studies (63%). The risk of mortality increased in studies conducted on inpatients and health care facility–acquired CDI (RR, 2.3), European studies, and more recently collected data (≥2008).
The effects of harboring the CDT gene were reported in 9 studies [33, 35, 37, 38, 46, 47, 49–51]. Among the 1965 typed isolates, 29% harbored the CDT gene (Table 4). Although pooled 30-day all-cause mortality was higher in patients infected by these strains as compared with those who were not (18% vs 11%; Supplementary Figure 12), the pooled RR was not statistically significant (1.6; 95% CI, 0.9–2.9) overall or across possible stratifications.
DISCUSSION
This is the first review to assess the association between C difficile strains, disease severity, and unfavorable clinical outcomes via a meta-analysis. In contrast, previous reviews employed narrative approaches [52–54]. Our review included a large number of studies (n = 93) overall and for each outcome. The studies were published between 2004 and 2022 and encompass data spanning 1999 to 2019.
However, we faced substantial discrepancies that reduced the number of studies in the meta-analyses. Major limitations include the lack of a standard definition for the severity of CDI disease, the associated events that were considered complications, and the delay of occurrence of mortality. Studies that assessed all-cause mortality with a delay >30 days were also excluded due to the reduced possibility of attributing mortality to CDI. Studies on recurrence also had discrepancies in the index date, as well as in the criteria to consider a separate recurrent episode vs persistence of previous symptoms. The data were collected during various and overlapping periods, making it challenging to establish clear cutoffs for the eventual evolution of the strains. We could not conduct meta-regressions because several important factors were scarcely reported, such as follow-up duration for prospective studies, delay in the occurrence of outcomes, patient age, underlying diseases, and treatments. Stratifying the analyses by typing techniques is challenging. Most techniques were grouped under polymerase chain reaction, and only a few studies used advanced techniques. The definition of patients with CDI and the distinction between health care facility–acquired CDI and other conditions were not clearly stated across studies (eg, inpatients vs inpatients and outpatients admitted upon diagnosis).
NAP1/BI/R027 was the most frequently reported strain and is associated with almost all unfavorable outcomes. We showed that the proportions of outcomes were statistically comparable between this strain and other strains, such as R001, R078, and R106. However, few studies were included in the meta-analysis of other strains, and many studies grouped ribotypes without providing further details. The focus on a specific strain may have led to the oversight of other strains and contributed to the nonsignificant findings in RR. In this context, drawing definitive conclusions regarding the absence of association between other strains and the risk of unfavorable outcomes becomes challenging. NAP1/BI/R027 was associated with an 88% increased risk of cCDI, including the need for ICU admission, colectomy, and CDI-associated death in studies of ≥1000 patients. It was also associated with less specific outcomes, such as severity according to Infectious Diseases Society of America criteria [32] and cCDI including all-cause death. Only 3 studies [39, 55, 56] assessed the severity criteria of the European Society of Clinical Microbiology and Infectious Diseases [57] without common strains for meta-analysis. As highlighted by another review [58, 59], many other definitions used for severity are heterogenous and infrequent and include patient age (Supplementary Table 1).
Except for R002, the same patterns of results were observed for cCDI and across studies assessing 30-day all-cause death alone. All-cause death probably increased the frequency of the outcomes and led to misclassification bias. This is supported by lower frequencies retrieved in studies reporting early death, within 10 to 14 days after diagnosis.
Thirty days after the end of treatment, rCDI was estimated in 24% of patients infected with the NAP1/BI/R027 strain, which was significantly associated with a 2-fold higher risk (RR, 1.98) in adult patients. The proportion of patients with rCDI decreased by 40% after 2010 (from 30% to 16.8%). Across the studies [19, 40–42, 60–62], the NAP1/R027 strain represented 45% of all strains, and only 10% of the studies assessed recurrence within 60 days after the index CDI episode [29, 31, 34, 36, 43–45, 55, 63–65]. Nonetheless, this was associated with an increased risk of occurrence (RR, 1.8). Within 60 days of the index episode, rCDI occurred in 9% of patients initially infected with R014 (3 studies) and 10% of patients infected with R078. None of the strains were significantly associated with this outcome.
CDI-attributable mortality was less frequently reported, showing a lower overall frequency of 5% with an increase from 2% in patients infected with R014/20 to 4% in those infected with R001, 5% in R078, and 10% in NAP1/R027. The risk of mortality was 2-fold higher in patients infected with R027/NAP1 vs other strains overall and in large studies. A high and similar frequency (23%) of 30-day all-cause mortality was observed in patients infected with R001, R002, R027, or R106. Lower frequencies were observed in R014, R053, and R078.
We were able to quantify only the association between strains harboring the CDT gene and 30-day all-cause mortality (RR, 1.6; 95% CI, 0.9–2.9) in 7 studies. A recent review highlighted the emerging epidemiology of CDT-producing strains [66]. Our findings showed that this gene is present in 35% of strains. While CDT is thought to be an additional virulence factor [11], it is not possible to link the higher risk of mortality to the actual production of the binary toxin.
Available data did not allow us to demonstrate whether more or less virulent strains have been circulating in recent years. A study analyzing a sample of 939 isolates in the United States between 2011 and 2016 showed a decline in R027 (35% to 13%), with R106 becoming the most common strain in 2016 [67]. The European Healthcare-Associated Infections Surveillance Network showed that, in 2016, R027 remained the most frequent strain (23%) in 20 countries [68]. R001 and R014 accounted for 7% each. Similar to R027, R002 strains showed higher in vitro sporulation rates and levels of produced toxins [69]. Although mostly induced by the action of toxins, other virulence factors have been discovered and associated with rCDI [7, 70]. The virulence of strains, mostly measured in vitro, could not be considered independently from host factors and risk factors for acquisition. The recent guidelines suggested fidaxomicin or vancomycin as first-line treatment regardless of CDI severity [6, 32], and there are no specific treatment recommendations based on C difficile strains. This is partly explained by limited real-time typing capacities in clinical settings. Overall, this review demonstrates the need for close surveillance of other emergent ribotypes.
CONCLUSION
The definitions of CDI clinical outcomes were heterogeneous, and important factors were scarcely reported, leading to the exclusion of many studies from meta-analysis. Thus, conducting meta-regressions was not possible. NAP1/BI/R027 was the most frequently reported and assessed strain, and it was associated with a higher proportion of unfavorable clinical outcomes. Data on other strains were lacking, precluding a comprehensive assessment of other strains.
Supplementary Material
Contributor Information
Claire Nour Abou Chakra, Department of Microbiology and Infectious Diseases, Université de Sherbrooke, Sherbrooke, Quebec, Canada.
Anthony Gagnon, Department of Microbiology and Infectious Diseases, Université de Sherbrooke, Sherbrooke, Quebec, Canada.
Simon Lapointe, Department of Microbiology and Infectious Diseases, Université de Sherbrooke, Sherbrooke, Quebec, Canada.
Marie-Félixe Granger, Department of Microbiology and Infectious Diseases, Université de Sherbrooke, Sherbrooke, Quebec, Canada.
Simon Lévesque, Department of Microbiology and Infectious Diseases, Université de Sherbrooke, Sherbrooke, Quebec, Canada; Laboratoire de Microbiologie, CIUSSS de l’Estrie-CHUS, Sherbrooke, Quebec, Canada.
Louis Valiquette, Department of Microbiology and Infectious Diseases, Université de Sherbrooke, Sherbrooke, Quebec, Canada.
Supplementary Data
Supplementary materials are available at Open Forum Infectious Diseases online. Consisting of data provided by the authors to benefit the reader, the posted materials are not copyedited and are the sole responsibility of the authors, so questions or comments should be addressed to the corresponding author.
Notes
Acknowledgments . The research protocol was registered in PROSPERO (CRD42018073826). We are thankful to authors who were contacted for clarifications or missing data and agreed to share the data: David Aronoff, A-Lan Banks, Martijn Bauer, Kerrie Davies, Esteban Chaves Olarte, Jieun Kim, Marcela Krutova, Annie-Claude Labbé, Torbjörn Norèn, Krishna Rao, Thomas Riley, José Sifuentes Osornio, Karla Tamez, Surabhi Taori, Carlos Quesada-Gómez, Seth Walk, Sarah Walker, J. Scott Weese, and Sunny H. Wong.
Author contributions. C. N. A C. designed the study, contributed to the selection of studies and data extraction, conducted the analyses, and drafted the manuscript. A. G., S. L., and M.-F. G. contributed to the selection of studies and to data extraction and analyses and reviewed the manuscript. S. L. contributed to the data overview and to revision of the manuscript. L. V. supervised the team and reviewed the manuscript.
Patient consent statement. This study was conducted on aggregated published data and does not include factors necessitating patient consent.
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