2 Year Has Clostridium Difficile.can He Get It Again
Clin Infect Dis. 2012 Aug 1; 55(Suppl 2): S77–S87.
Predictors of Get-go Recurrence of Clostridium difficile Infection: Implications for Initial Management
David W. Eyre
1NIHR Oxford Biomedical Enquiry Heart, John Radcliffe Hospital
A. Sarah Walker
1NIHR Oxford Biomedical Enquiry Eye, John Radcliffe Hospital
twoNuffield Department of Clinical Medicine
David Wyllie
1NIHR Oxford Biomedical Research Heart, John Radcliffe Hospital
Kate Due east. Dingle
1NIHR Oxford Biomedical Research Center, John Radcliffe Hospital
3Department of Clinical Laboratories Sciences, Oxford Academy
David Griffiths
1NIHR Oxford Biomedical Research Middle, John Radcliffe Hospital
2Nuffield Department of Clinical Medicine
John Finney
oneNIHR Oxford Biomedical Research Center, John Radcliffe Hospital
Lily O'Connor
1NIHR Oxford Biomedical Research Centre, John Radcliffe Infirmary
Alison Vaughan
1NIHR Oxford Biomedical Research Centre, John Radcliffe Infirmary
2Nuffield Department of Clinical Medicine
Derrick West. Crook
iNIHR Oxford Biomedical Research Eye, John Radcliffe Hospital
2Nuffield Department of Clinical Medicine
Mark H. Wilcox
4Department of Microbiology, The General Infirmary, Erstwhile Medical School
5Leeds Found of Molecular Medicine, University of Leeds, Great britain
Timothy Due east. A. Peto
1NIHR Oxford Biomedical Inquiry Middle, John Radcliffe Hospital
iiNuffield Department of Clinical Medicine
- Supplementary Materials
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Supplementary Data
GUID: 3F7012AB-4513-4D5B-A403-8FE887A464BE
GUID: 804790DB-FEA9-4FE6-BE88-C7832CF7863B
Abstract
Symptomatic recurrence of Clostridium difficile infection (CDI) occurs in approximately 20% of patients and is challenging to treat. Identifying those at loftier risk could let targeted initial management and improve outcomes. Adult toxin enzyme immunoassay–positive CDI cases in a population of approximately 600 000 persons from September 2006 through December 2010 were combined with epidemiological/clinical data. The cumulative incidence of recurrence ≥14 days after the diagnosis and/or onset of commencement-ever CDI was estimated, treating decease without recurrence as a competing chance, and predictors were identified from cause-specific proportional hazards regression models. A total of 1678 adults alive fourteen days afterwards their showtime CDI were included; median age was 77 years, and 1191 (78%) were inpatients. Of these, 363 (22%) experienced a recurrence ≥fourteen days after their first CDI, and 594 (35%) died without recurrence through March 2011. Recurrence take a chance was independently and significantly college among patients admitted every bit emergencies, with previous gastrointestinal ward admission(southward), terminal discharged 4–12 weeks before offset diagnosis, and with CDI diagnosed at access. Recurrence gamble also increased with increasing historic period, previous full hours admitted, and C-reactive poly peptide level at starting time CDI (all P < .05). The four-month recurrence risk increased by approximately v% (absolute) for every ane-betoken increase in a risk score based on these factors. Risk factors, including increasing age, initial disease severity, and infirmary exposure, predict CDI recurrence and place patients likely to benefit from enhanced initial CDI treatment.
Symptomatic recurrence of Clostridium difficile infection (CDI) causes meaning morbidity and tin prove challenging to treat finer [i]. It also inevitably increases the risk of C. difficile transmission. Reported recurrence rates vary from five% to fifty% and typically are around twenty% [2].
In a meta-analysis, recurrence risk factors included older historic period, utilize of C. difficile–provocative antibiotics after CDI diagnosis, and concomitant receipt of antacids [3]. Other factors identified in private studies include infirmary-acquired affliction [4]; comorbid weather condition, including astringent underlying affliction [5] or poor quality of life scores [6]; and previous recurrent CDI [vii]. However, most existing studies are relatively small and hospital based and predate the polymerase chain reaction (PCR) ribotype 027/sequence type ane (ST1)/North American pulsed-field gel electrophoresis type 1 (NAP-1) epidemic [3], demonstrating a need for contemporaneous big-calibration population-based studies. CDI well-nigh commonly recurs inside a week [8] after treatment abeyance merely can recur upward to 6–viii weeks later [9]. Even so, because well-nigh studies have followed patients for only 1–2 months [3], the pattern of longer-term recurrence is unclear. Up to 50% of apparent relapses have been identified as new infections with a different strain [10–xiii]; uncertainty about which recurrences stand for reinfection hinders the cess of risk factors for true relapse [14].
Recent guidelines [15] outline strategies for treating recurrent CDI. However, if patients at loftier adventure could be identified earlier, relapse might exist prevented by using novel therapies [1, 16]. Therefore, the objectives of this long-term population-based study were to place independent predictors of CDI recurrence in Oxfordshire during 2006–2010 and to confirm which predictors were related to relapses acquired past the same strain by using genotyping.
METHODS
Oxford Radcliffe Hospitals (ORH) NHS Trust provides >90% of hospital care in Oxfordshire (population, approximately 600 000) and all acute services. The ORH Microbiology Laboratory tests all stool samples from the canton, including those from other healthcare facilities and general practitioners (primary intendance). From September 2006, all unformed stools (taking the shape of the container) positive by enzyme immunoassay (EIA) for C. difficile toxins A and B (Meridian Bioscience, Cincinnati, Ohio) and with sufficient sample remaining were routinely cultured. Clostridium difficile isolates were genotyped by multilocus sequence typing (MLST) [17], typing morphologically distinct colonies separately. Infection control policy required samples from any admitted patient with diarrhea (locally divers every bit ≥three unformed stools inside 24 hours) to be tested for C. difficile and vancomycin treatment to be initiated empirically, standing for 14 days if CDI is confirmed. From May 2007, all unformed stool samples from patients aged ≥65 years were routinely tested for C. difficile according to UK Section of Health policy (a mandatory examination, typically not meeting the previous diarrhea definition).
Clostridium difficile MLST data were anonymously linked to data for ORH hospital admissions and discharges from Apr 1997 and mortality from the Infections in Oxfordshire Research Database (IORD) [xviii]. Admissions to other smaller hospitals in the area (including a specialist orthopedic, a psychiatric, and several community hospitals) were not included, although samples taken at these locations were identifiable. The IORD has Inquiry Ethics Committee and Britain National Information Governance Board approval.
We included the get-go CDI for each adult (aged ≥18 years) from September 2006 through December 2010 (when >99% of samples had been typed), if the patient had no previous CDI recorded since Apr 1997. Included cases therefore had ≥3 months of potential follow-up to the 1 Apr 2011 data cutoff. Neither symptom resolution nor antibiotic apply is routinely recorded electronically and, therefore, was not available for analysis. Because (1) patients received 14 days of vancomycin handling, (2) near symptoms resolve before 14 days in successfully treated patients, and (3) United kingdom Section of Wellness guidance was non to retest patients with ongoing diarrhea (ie, without resolution) for 28 days, the primary upshot was time from first-always CDI to the first new EIA-positive sample ≥14 days later on. Analyses therefore were restricted to patients known to be alive 14 days afterward the get-go CDI. The cumulative incidence of recurrence over time was estimated using competing risks methods to account for death before recurrence. Flexible parametric models were used to estimate precisely how the unadjusted daily recurrence risk varied with fourth dimension from first CDI [19]. Cause-specific proportional hazards (Cox) models were used to estimate effects of factors theoretically available at treatment initiation (demographic characteristics, sample characteristics, previous ORH hospital exposure, and previous healthcare-associated infections; details in Table1) on recurrence gamble. Independent predictors were identified using backward selection with the Akaike data criterion [20], including pairwise interactions and allowing nonlinear effects of continuous factors through partial polynomials. Categorical effects are presented for factors with significant evidence of nonlinearity. Results from regression models for the cumulative incidence subhazard for recurrence [21] (rather than the cause-specific hazard) were similar (information not shown). In all analyses, patients not known to have died were censored at their last hospital or laboratory contact.
Table 1.
Characteristics of First Clostridium difficile Infection, September 2006–Dec 2010
| Levels (for Continuous Factors, Unit Increase Respective to the RR in the Regression Model) | No. (%) or Median (IQR) | Unadjusted Univariable Cause-Specific Hazard Model | ||||
|---|---|---|---|---|---|---|
| Cistron | Overall | With Recurrence | RR | 95% CI | Global P Value | |
| CDI, No. (%) | 1678 (100) | 393 (22) | ||||
| Demographics | ||||||
| Sexual activity, No. (%) | Male person | 711 (42) | 146 (21) | 1.00 | .36 | |
| Female | 967 (58) | 217 (22) | 1.x | .90–1.36 | ||
| Age (y) | (/x-y older) | 77 (64–85) | 79 (71–86) | 1.23 | 1.14–1.32 | <.0001 |
| Previous infirmary exposure | ||||||
| Ever previously admitted to ORH, No. (%)a | No | 230 (14) | 34 (15) | ane.00 | .11 | |
| Yes, <viii-h admissions only | 108 (half dozen) | 22 (twenty) | i.xiii | .74–i.75 | ||
| Aye, ≥1 admission for >8 h | 1340 (80) | 307 (23) | 1.45 | ane.02–ii.07 | ||
| Last ORH admission, No. (%) | >ane y ago/never | 568 (34) | 103 (18) | 1.00 | .01 | |
| Within the last y | 1110 (66) | 260 (23) | one.33 | 1.06–1.67 | ||
| Previous dialysis/ chemotherapy at ORH, No. (%) | No | 1486 (89) | 323 (22) | 1.00 | .97 | |
| Yeah | 192 (eleven) | 40 (21) | i.01 | .73–1.forty | ||
| Previously admitted to ORH GI ward, No. (%) | No | 1090 (65) | 241 (22) | 1.00 | .33 | |
| Yes | 588 (35) | 122 (21) | 0.90 | .72–i.12 | ||
| No. of previous admissions >8 h | (/5 additional >8-h admissions) | 2 (1–v) | 3 (1–5) | 1.eighteenb | 1.03–1.36 | .02 |
| Full previous h in hospital (ORH) in admissions >viii h (h) | (/doubling of total previous h in hospital) | 366 (44–909) | 528 (122–1180) | 1.xvib | 1.09–1.24 | <.0001 |
| Days since final discharged | (/additional six mo since last ORH discharge) | 96 (23–870) | 77 (22–472) | 0.96 | .90–1.01 | .14 |
| Discharged in final 7 d, No. (%) | No | 1567 (93) | 331 (21) | 1.00 | .07 | |
| Yep | 111 (7) | 32 (29) | 1.41 | .98–ii.02 | ||
| Likely source of outset infection (IDSA/SHEA), No. (%) [15] | Infirmary onset, healthcare-associated | 880 (52) | 185 (21) | 1.00 | <.001 | |
| Customs onset, healthcare-associated | 334 (xx) | 80 (24) | 1.07 | .82–ane.39 | ||
| Indeterminate | 127 (eight) | 45 (35) | 1.77 | i.27–2.45 | ||
| Community-associated | 337 (20) | 53 (sixteen) | 0.64 | .47–.86 | ||
| Previous MRSA, No. (%) | No | 1503 (90) | 312 (21) | i.00 | .01 | |
| Yes | 175 (10) | 51 (29) | 1.45c | 1.08–1.95 | ||
| Sample characteristics | ||||||
| Season, No. (%) | Winter (Dec/Jan/Feb) | 424 (25) | 81 (nineteen) | 1.00 | .35 | |
| Spring (Mar/April/May) | 388 (23) | 86 (22) | 1.xviii | .87–1.60 | ||
| Summer (Jun/Jul/Aug) | 431 (26) | 98 (23) | 1.31 | .97–1.76 | ||
| Autumn (Sep/Oct/November) | 435 (26) | 98 (23) | i.20 | .89–1.61 | ||
| Calendar year | (/additional y) | 2008 (2007–2009) | 2008 (2007–2009) | 0.93 | .85–1.02 | .11 |
| Mandatory EIA test (mild diarrhea), No. (%) | No (requested by clinician) | 1404 (84) | 316 (23) | ane.00 | .01 | |
| Yes (not requested) | 274 (16) | 47 (17) | 0.68 | .l–.92 | ||
| Previous negative Environmental impact assessment examination | Ever | 714 (43) | 187 (26) | ane.49 | one.21–1.83 | |
| Never | 964 (57) | 176 (18) | one.00 | <.0001 | ||
| Previous negative EIA test | In last 14 d | 452 (27) | 261 (21) | 1.11 | .88–i.40 | |
| Not in last fourteen d | 1226 (73) | 102 (23) | 1.00 | .37 | ||
| Location where beginning sample taken | Inpatient (overnight) | 1191 (71) | 260 (21) | 1.00 | .58 | |
| Main intendance | 294 (18) | 63 (22) | 0.83 | .63–1.09 | ||
| Outpatient/ED/day instance | 87 (5) | 20 (23) | 0.91 | .58–1.44 | ||
| Other hospital | 106 (6) | 20 (19) | 0.88 | .56–ane.39 | ||
| If inpatient at first CDI, access specialty | Surgical | 376 (32) | 65 (17) | 1.00 | .03 | |
| Medical | 815 (68) | 195 (24) | ane.37 | ane.11–1.68 | ||
| If inpatient at first CDI, method of admission | Elective | 237 (20) | 34 (14) | 1.00 | <.0001 | |
| Emergency | 954 (80) | 226 (24) | 1.58 | 1.x–2.27 | ||
| If inpatient at first CDI, d since admitted | Within 2 d of access | 311 (26) | 75 (24) | i.00 | .50 | |
| >ii d afterward admission | 880 (74) | 185 (21) | 1.ten | .84–1.43 | ||
| If inpatient at first CDI, d since admitted | Nonlinear issued | 8 (2–twenty) | 10 (2–22) | |||
| On d of admission | 128 (11) | 35 (27) | i.51d | .99–2.30 | ||
| 1–v d later on admission | 351 (29) | 67 (nineteen) | 1.03d | .72–1.47 | ||
| 6–14 d subsequently admission | 311 (26) | 56 (eighteen) | 1.00 | .03 | ||
| ≥fifteen d afterward admission | 401 (34) | 102 (25) | one.46d | i.06–two.03 | ||
| Biomarkerseast | ||||||
| C-reactive poly peptide (mg/L) | (/120 mg/Fifty)f | 84 (33–156) | 97 (44–>160) | 1.69 | ane.31–2.xviii | <.0001 |
| White blood cell count (×109/L) | (/ten × ten9/L)f | 11.2 (7.eight–sixteen.1) | 12.2 (7.9–xviii.3) | 1.34 | ane.15–one.36 | <.0001 |
| Neutrophils (×x9/Fifty) | (/10 × 109/Fifty)f | viii.ix (5.6–thirteen.4) | 9.7 (5.seven–15.four) | 1.42 | 1.xx–1.69 | <.0001 |
| Lymphocytes (×10nine/L) | (/ten × ten9/L)f | 11.0 (7.0–16.0) | 10.0 (vii.0–15.0) | 0.84 | .73–.97 | .02 |
| Albumin (g/L) | (/x chiliad/L) | 34 (30–38) | 34 (30–37) | 0.82 | .68–i.00 | .05 |
| Urea (mmol/L) | (/5 mmol/50)f | 6.seven (iv.v–11.0) | 7.iii (5.1–12.1) | i.09 | ane.01–i.17 | .02 |
Baseline biomarker values were defined every bit the closest measurement within (−3, +one) days of the stool sample. Fourteen biomarkers available for >50% of CDI cases were considered (white blood jail cell count, neutrophil count, lymphocyte count, C-reactive protein level, hemoglobin level, platelet count, and sodium, potassium, creatinine, urea, albumin, alanine aminotransferase, element of group i phosphatase, and bilirubin levels). To avoid bias and/or loss of ability from restricting to complete cases with all biomarkers measured, associations betwixt biomarkers and recurrence were estimated, imputing missing values in the subset of patients with at to the lowest degree 1 observed baseline biomarker. As recommended, chained estimating equations [22, 23] were used to create 20 imputations on BoxCox transformed variables [24], including all cofactors listed in Table1, allowing nonlinearity in all continuous factors with natural cubic splines (knots at tenth, 50th, and 90th percentiles [25]) and including log(recurrence time) and the censoring indicator. Standard errors were estimated beyond imputations using Rubin'south rules.
Stata software, version eleven.2 (StataCorp, College Station, Texas), was used for all analyses, which were conducted past 1 of the authors (A. S. W.).
RESULTS
From September 2006 through December 2010, a total of 2043 adults had their start CDI (toxin EIA-positive stool sample with no previous positive). A total of 271 (13%) patients died within 0–xiii days after the Environmental impact assessment-positive sample, and 94 (5%) had no follow-up after xiii days, leaving 1678 (82%) alive 14 days after the commencement CDI for analysis of recurrence.
Recurrence Rates
Overall, 363 of 1678 (22%) patients experienced a recurrence (new EIA-positive sample) ≥14 days after their first CDI, and 594 (35%) died without recurrence through March 2011. Median follow-upward in those without recurrence was eleven months (interquartile range [IQR], 2–28 months). Cumulative incidences of recurrence increased to 7% and 16% by one and two months afterwards, respectively (Figure1 A), corresponding to rates of 7.4 cases per 100 person-months at risk and xi.3 cases per 100 person-months at take a chance, respectively. Thereafter, the incidence increased more slowly to eighteen% and 20% by 3 and 4 months and to 22% and 23% at i and ii years, respectively. The risk for recurrence was greatest 24 days later on the first CDI, 10 days after cessation of handling (Figure1 B). Of the 363 recurrences, 94 patients (26%) experienced a third CDI episode (≥14 days after the recurrence), of whom 24 had further episodes (maximum, 6) through March 2011.
Time to recurrence. A, Months to new enzyme immunoassay (Eia)–positive sample or death ≥fourteen days after offset-ever EIA-positive sample. B, Daily risk of post–14-day new Eia-positive sample. Abbreviations: AIC, Akaike data criterion; EIA, enzyme immunoassay.
Adventure Factors for Recurrence
As expected, the population was predominantly older (median age, 77 years), although 302 (18%) were <60 years of historic period at first CDI (Tabular array1). A total of 1191 (71%) were inpatients (admitted a median of viii [IQR, 2–20] days), and most (1448; 86%) had previously been admitted to ORH facilities (66% in the by year). In a multivariable model (Tabletwo), recurrence risk independently was significantly college among patients admitted every bit emergencies, those with previous gastroenterology ward admission(s), and after diagnosis on day of admission or ≥xv days afterward admission and too increased with age and increasing previous total hours in the hospital (all P < .05). Risks also were college among those for whom the concluding inpatient stay was 4–12 weeks earlier diagnosis (P = .006). Recurrence run a risk was independently lower among those with CDI diagnosed using a examination that had not been clinically requested (a mandatory test, often for balmy diarrhea; P = .07). Patients without previous hospital admissions by and large had fewer other hazard factors, but after adjusting for these, they had higher recurrence risks. One potential explanation, non assessable in our data, would exist if such patients were more likely to be 3rd referrals with other not-ORH hospital exposure. Other factors (in particular, medical specialty, previous Eia-negative test effect, number of previous admissions, and discharged in the previous 7 days) were meaning in only univariable and non multivariable models (ie, were confounded with other factors).
Tabular array two.
Predictors of Recurrence ≥14 Days After First Clostridium difficile Infection
| All Recurrences Multivariable Cause-Specific Take chances Modela | Shared STs Multivariable Cause-Specific Hazard Modela | ||||||
|---|---|---|---|---|---|---|---|
| Factor | Levels (Effect in Regression Model) | RR | 95% CI | Global P Value | RR | 95% CI | Global P Value |
| No. of CDI recurrences | 363 | 169 | |||||
| Historic period (y) | (/ten-y older) | 1.xvi i.57 (if previous dialysis/chemotherapy [interaction P = .02]) | 1.07 – one.26 one.23 – 2.00 | .0004 .0003 | 1.29 ane.71 (if previous dialysis/chemotherapy) | i.xiii – i.48 1.19 – 2.47 | .0001 .004 |
| Total previous h in hospital (ORH) in admissions >8 h (h) | (/doubling of full previous h in hospital) | i.29 1.12 (if emergency admission [interaction P = .002]) one.fifteen (if previous GI admission [interaction P = .007]) | ane.17 – 1.42 1.03 – one.22 i.04 – 1.28 | <.0001 .008 .008 | 1.38 one.15 (if emergency admission) one.24 (if previous GI admission) | 1.19 – ane.threescore one.01 – 1.xxx 1.05 – 1.46 | <.0001 .03 .009 |
| Always previously admitted to ORH | No or <8-h admissions (vs yes for >viii-h access) | ane.99 | i.20 – iii.31 | .008 | two.57 | one.xviii – 5.62 | .02 |
| Mandatory EIA test (balmy diarrhea) | Yep (vs no) | 0.74 | .53 – 1.03 | .07 | 0.67 | .41 – 1.09 | .11 |
| If inpatient at first CDI, admission method | Elective emergency | i.00 2.79 v.10 (if previous MRSA [interaction P = .0003]) 4.74 (if previous dialysis/chemotherapy [interaction P = .04]) | one.29 – vi.04 2.12 – 12.2 1.96 – 11.four | .006 .0003 .0005 | 1.00 4.85 9.52 eight.79 (if previous dialysis/chemotherapy) | 1.42 – xvi.6 ii.42 – 37.5 2.23 – 34.half dozen | .01 .001 .002 |
| Previous MRSA | Yes (vs no) | 0.45 (if not emergency) | .23 – .88 | .02 | 0.70 (if not emergency) | .31 – ane.59 | .39 |
| Previous dialysis/chemotherapy at ORH | Yes (vs no) | 0.77a (if not emergency) | .39 – ane.52 | .45 | 1.15a (if not emergency) | .46 – 2.82 | .77 |
| Previously admitted to ORH GI ward | Yes (vs no) | two.33 | 1.xiii – iv.78 | .02 | ii.ten | .71 – 6.23 | .18 |
| If inpatient at first CDI, d since admitted | On d of admission | i.73b | .52 – 5.73 | 1.15 | .21 – six.31 | ||
| 1 – five d after access | 0.50b | .21 – one.19 | 0.54 | .18 – one.65 | |||
| half dozen – 14 d after access | 1.00 | .006 | one.00 | .38 | |||
| ≥15 d later on access | one.84b | ane.05 – 3.23 | i.37 | .62 – three.04 | |||
| If inpatient at first CDI, access specialty | Medical (vs surgical) | 0.98b | .34 – 2.79 | .97 | 0.ninety | .fourscore – i.01 | .08 |
| Location where first CDI sample taken | Non inpatient (vs inpatient overnight) | 0.58c | .20 – 1.73 | .33 | 0.fifty | .11 – 2.39 | .39 |
| Probable source of commencement infection (IDSA/SHEA) [xv] | Hospital onset, healthcare-associated | 1.00 | .006 | ane.00 | .07 | ||
| Customs onset, healthcare-associated | 1.xix | .71 – 2.00 | 1.71 | .77 – 3.79 | |||
| Indeterminate | 2.03 | i.16 – 3.57 | 2.89 | 1.24 – 6.76 | |||
| Community-associated | 1.03 | .60 – i.78 | 1.72 | .76 – 3.89 | |||
In this multivariable model, 5 major effect modifications (interactions) were identified (Table2): (1) increased hazard at older ages was augmented in those with previous dialysis/chemotherapy, (2) increased risks associated with emergency admissions were augmented in those with previous methicillin-resistant Staphylococcus aureus (MRSA) infection or dialysis/chemotherapy, (3) recurrence gamble increased less strongly with increasing previous total hours in the hospital in those admitted every bit emergencies and/or with previous gastroenterology ward admissions, (4) risk was significantly lower in those with previous MRSA infection and CDI in an constituent access (mostly surgical specialties; such patients received vancomycin and gentamicin perioperatively in place of broad-spectrum penicillin-based prophylaxis), and (5) recurrence risks varied less over days from admission to the first CDI diagnosis in medical than in nonmedical inpatients. No other factor listed in Tabular array1 had an boosted effect in this multivariable model (P > .2). In that location too was no evidence of a trend over agenda year (P = .37) or season (P = .24).
The multivariable model in Table2 included factors theoretically available to clinicians at treatment initiation. Of importance, after adjusting for these, higher EIA optical density of the commencement C. difficile test was associated with a higher risk for recurrence, comparing beyond absolute values (relative chance [RR], 1.twenty per unit college [95% conviction interval {CI}, 1.06–one.35]; P = .003; median, one.6 [IQR, 0.5–>2.5]) or comparing the 37% with optical density exceeding the analysis maximum (two.five) with other cases (RR, one.33; 95% CI, 1.08–one.65; P= .008).
Biomarkers
One or more of the fourteen potential biomarkers was available in 1295 patients (77%), imputing missing data in this subgroup. But higher C-reactive poly peptide level and higher neutrophil count at first CDI independently increased recurrence risk, but the upshot was much larger for C-reactive protein level (RR, one.45 per 120 mg/L [the IQR] college [95% CI, 1.09–1.93]; P = .01) than for neutrophil count (RR, i.xix per 10 × 10ix/L higher [95% CI, .97–1.45]; P= .09). Effects of other factors listed in Tabular arraytwo were similar after adjusting for these baseline biomarkers.
Strain-Specific Recurrence Risks
MLST was obtained for 1076 of 1678 (64%) first CDI cases: 418 (25%) samples did not yield C. difficile on culture (EIA-positive culture-negative samples), and 184 (11%) were non available for civilization (28% pre– vs 4% post–September 2007 when staff cover increased). A full of 685 (64%) typed isolates belonged to phylogenetic clade one, from 56 STs, including those corresponding to PCR ribotypes 001, 002, 005, 014, 015, 020, 072, and 106 [26]. A full of 300 typed isolates (28%) belonged to clade 2 (295 of 300 PCR ribotype 027/ST1), and the remaining 91 (8%) belonged to clades 3, 4, and v (Supplementary Table one). The rough percentages with recurrence were slightly higher after initial clade ii CDI (90 of 300; 30%), compared with clade 1 (174 of 685; 25%; χ2 P = .13). Subsequently adjusting for adventure factors listed in Tabular array2, recurrence risk appeared to be slightly higher after clade 2, compared with one CDI (RR, one.17; 95% CI, .ninety–1.51; P = .24), but was compatible with chance. Recurrence hazard was significantly lower for Eia-positive culture-negative samples (RR [vs clade ane], 0.41 [95% CI, .29–.58]; P < .0001), supporting previous observations that this latter group likely represents faux Environmental impact assessment-positive results [27, 28].
Relapse Versus Reinfection
Of the 363 recurrences after the first CDI, 219 (60%) had STs determined from both episodes. Making comparisons on the basis of individual STs, non clade, 169 (77%) recurrences had the aforementioned ST as the initial episode and l (23%) had no STs in common (ie, were new infections). The gamble for aforementioned-ST recurrence was highest 14 days after starting time EIA-positive sample (Figure2), then declined slowly during the next 2–6 months. In dissimilarity, the risk for new ST infections peaked thirty days after the first CDI and so decreased sharply; recurrence hazard amidst the 41 patients (11%) with Environmental impact assessment-positive culture-negative beginning CDI followed a like pattern. For the other 103 recurrences (28%; STs not adamant for ≥one isolate), chance was a mixture distribution (data non shown).
Fourth dimension to recurrence ≥xiv days after first Clostridium difficile infection according to shared or not shared sequence types. A, Months to new enzyme immunoassay (EIA)–positive sample ≥14 days afterwards start-always Eia-positive sample. B, Daily chance of new post–fourteen-day EIA-positive sample. Abbreviations: CID, Clostridium difficile infection; Environmental impact assessment, enzyme immunoassay; ST, sequence blazon.
Predictors of the 169 recurrences with shared STs were very similar to predictors of all 363 recurrences (Table2); with relatively small numbers, power was as well low to conduct split up model selection. As expected, several factors appeared to have weaker effects on the 50 recurrences with no shared STs (presumed reinfections; information not shown).
Take a chance Score for Recurrence Following Showtime CDI
Because predictors of all CDI recurrences were similar to those for shared ST recurrences, we constructed an integer risk score (Table3) based on the multivariable model for all recurrences (Table2). The maximum possible score is 15 and minimum is −2; values of 0–thirteen were observed in our data set, with a median of 5 (IQR, 3–vi). Models including the single take a chance score as a predictor provided an overall fit similar to the total Table2 model. Four-month recurrence risk was 6%–48% across the score (Effigy3); the absolute hazard of recurrence 4 months after the beginning CDI increased by approximately 5% for every one-betoken increase in score.
Table 3.
Score to Predict Clostridium difficile Infection (CDI) Recurrence Following First-Ever CDI Diagnosis
| Factor | Scoring Criteria | Max | Min | |||
|---|---|---|---|---|---|---|
| Patient & health status | Age (y) | 60–69 | 70–79 | ≥80 | ||
| Score | 1 | 2 | iii | 3 | 0 | |
| Emergency access | Any emergency admission | 1 | ||||
| AND previous MRSA+ | 1 | |||||
| AND/OR previous dialysis/chemotherapy | 1 | iii | 0 | |||
| Severity of initial disease | Stool frequency | ≥iii unformed stools/da | one | |||
| Access with CDI | Sample taken on 24-hour interval of inpatient admission | 1 | ||||
| C-reactive poly peptideb (mg/50) | <35 | 85–<160 | ≥160 | |||
| Score | −ane | 1 | 2 | 4 | −1 | |
| Past wellness care exposure | Type of by admission | Past gastroenterology access | No past gastroenterology admission | |||
| Total inpatient elapsing before admission | Any by admission | >2–13 wk | >13 wk | |||
| Score | i | ii | 3 | 3 | 0 | |
| Antibiotic option | (Elective admission OR customs sample) AND previous MRSA isolatedc | −1 | 0 | −1 | ||
| Susceptibility to diarrhea several wk after hospital exposure | Primary CDI 4–12 wk later on hospital discharged | Community sample or sample taken within ≤2 d of inpatient admission AND patient discharged from hospital iv–12 wk previously | 2 | 2 | 0 | |
| Total | 15 | −two | ||||
Time to recurrence ≥14 days later on starting time Clostridium difficile infection according to risk score. Abbreviation: EIA, enzyme immunoassay.
DISCUSSION
In our cohort of nigh 1700 patients surviving 2 weeks afterwards their offset CDI, 22% developed a symptomatic CDI recurrence during the 4-year study period. This is similar to commonly cited recurrence rates of approximately 20% [ii] despite our considerably longer follow-up and robust design accounting for mortality. Most recurrences occurred within 2 months, but iv% of patients had recurrences at ii–four months. The decrease in recurrence over time may reflect the eventual success of multiple handling cycles [1, 9] or recovery from underlying affliction with consequent lower exposure to antibiotics and restoration of more than normal bowel flora able to suppress C. difficile growth in the colon [29]. Structural changes in bowel flora with historic period may impair such recovery [30]. Alternatively, because recurrence is associated with inadequate immune responses [31, 32], repeated relapse eventually may generate constructive immunity, for example, to all stage variants of the cell surface–expressed proteins [33].
Two possible explanations be for symptomatic recurrence: relapse of the same infection and reinfection. These can exist distinguished, at least partially, by using strain typing data. In our study, 23% of recurrences were reinfection with a different strain, similar to the 26% reported in [xiv], but lower than the approximately 50% found past others [x–thirteen]. Relapse may exist more mutual in our accomplice because of older age, compared with some other studies [xi, 13]. Implementation of rigorous infection command measures [34] may besides have reduced the incidence of reinfection. Of involvement, reinfection with a different ST occurred most frequently 1 calendar month after the first CDI (2–iii weeks after treatment cessation), possibly representing reexposure to C. difficile after clearance of the initial infection, whereas risks for new CDI with the aforementioned ST were greatest fourteen days later on the first CDI. Like trends have been seen in other smaller studies [x, eleven]. The relatively high prevalence of ST1/027/NAP-ane, in 18% of cases, illustrates the difficulty distinguishing reinfection and relapse using genotyping schemes, such as MLST or ribotyping, with limited discriminatory ability; the number of reinfections thus may be underestimated [15]. In the future, whole-genome sequencing may distinguish same-ST relapses from reinfections with different variants of mutual STs. Such distinctions are complicated further by the possibility of mixed initial or subsequent CDI; this was rarely identified in our cohort [35].
Our proposed score (Tableiii) provides a summary of important run a risk factors for recurrence that would be nowadays in electronic patient record systems. Several markers of underlying health status were either risk factors themselves or augmented the result of other take chances factors in our big unselected contemporaneous population, including increasing age, emergency admission, previous MRSA infection or colonization, and previous dialysis or chemotherapy. An initial CDI astringent enough to be the probable cause of admission, to merit testing on the basis of clinical suspicion, or to increment levels of inflammatory markers, in detail, C-reactive poly peptide, increased recurrence risk. Nosotros too found smaller take chances increases with higher EIA optical density of the first CDI, which may reverberate initial bacterial burden and/or toxin production [36]. Increasing by hospital exposure or gastrointestinal ward access before the first CDI was also associated with recurrence. The increased recurrence risk later on gastrointestinal admission requires confirmation in additional studies simply may reverberate increased CDI risk associated with inflammatory bowel disease [37, 38], nasogastric tube placement, perchance gastrointestinal endoscopy [39], and gastrointestinal surgery [40]. The credible protective consequence confronting CDI recurrence of previous MRSA infection or colonization on elective admissions is likely to reflect differences in the perioperative (and other) antibiotics received by this group, in item, the replacement of broad-spectrum β-lactam antibiotics with glycopeptides and aminoglycosides. Conversely, previous MRSA was associated with college recurrence risk in emergency admissions, possibly reflecting greater comorbidity in this group of patients who were likewise probable to receive broad-spectrum β-lactams in add-on to glycopeptides. Initial CDI occurring 4–12 weeks subsequently hospital discharge was too independently associated with recurrence. The delay in onset of the initial CDI in such cases may reflect prolonged susceptibility to the effects of infirmary exposure (eg, mediated through failure of the immune system or change in bowel flora that also later on increases recurrence take a chance). Previously proposed scores for recurrence take chances have been developed on much smaller hospital populations and have incorporated clinician opinion [5]. Nevertheless, further piece of work to validate the score proposed hither is essential. Of notation, our hazard score was constructed to capitalize on the types of data bachelor in electronic patient records; nosotros envisage that information technology could, for instance, be incorporated into routine reports of positive CDI exam results (if validated). This goal contrasts with other approaches to chance scoring for recurrence [5] and severity [41], which accept been designed for apply by clinicians at the bedside and often include assessments, such as temperature and endoscopy results not available in our study.
We did not detect statistical evidence to support higher recurrence risk in clade 2 strains (well-nigh exclusively ST1/027/NAP1), although we had low power (<40%) to detect a significant divergence in recurrence rates of 25% and 30% (as observed). More than than three times as many cases would exist needed to detect such a difference with fourscore% ability, although information technology might all the same be clinically important, because every symptomatic recurrence reflects an boosted opportunity for C. difficile transmission. However, it also is articulate that CDI virulence remains poorly understood, with the variable virulence of PCR ribotype 027 strains demonstrated in vivo [42] and in vitro [43, 44], suggesting that factors at levels other than strain type may play a part.
Study limitations include the lack of prescribing data, pregnant that nosotros could non directly assess the potentially important roles of antibiotics and proton pump inhibitors [3, 45]. The limited sensitivity/specificity of Environmental impact assessment testing [28] also has implications for assessing recurrence; the reduced recurrence charge per unit after EIA-positive culture-negative initial test results (Effigy2) supports that these do not stand for truthful CDI. Several factors included in our risk score may not interpret to other healthcare systems and practices, especially diarrhea severity. Investigating whether they are specific to our hospitals or reflect important underlying run a risk determinants is essential. Finally, the underlying electronic information sources practice not capture resolution or onset of symptoms, and therefore, our assessment of recurrence is based on time since the initial diagnosis and samples that were really submitted. A proportion of our recurrences therefore may be persistent diarrhea. However, nosotros are unlikely to have missed new symptomatic episodes because fecal sampling was common (500–1400 EIAs/calendar month; median, 960) with a low clinical threshold to investigate patients with diarrhea; but seven% of samples were EIA positive. This limitation also ways that we are unable to distinguish betwixt effects of previously resolved and ongoing episodes of MRSA infection/colonization or dialysis/chemotherapy in risk models.
In summary, recurrence after CDI is an important problem. Early recurrence often represents relapse of the same infection. Risk factors, including increasing age, severity of initial illness, and hospital exposure, can predict recurrence, in particular, relapse of the same infection, and may place patients who would benefit from enhanced treatment of an initial CDI episode. Tardily recurrences highlight the ongoing need for interventions to prevent C. difficile transmission.
Notes
Acknowledgments. We thank all the people of Oxfordshire who contribute to the Infections in Oxfordshire Enquiry Database. Research Database Team: P. Bejon, T. Berendt, C. Agglomeration, D. West. Crook, J. Finney, J. Gearing (customs), H. Jones, L. O'Connor, T. Due east. A. Peto (chief investigator), J. Robinson (community), B. Smooth, A. S. Walker, D. Waller, and D. Wyllie.
Financial back up. This work was supported by the Oxford National Establish for Health and Research, NIHR Biomedical Research Center, United kingdom.
Supplement sponsorship. This article was published as part of a supplement entitled "Fidaxomicin and the Evolving Approach to the Treatment of Clostridium difficile Infection," sponsored by Optimer Pharmaceuticals, Inc.
Potential conflicts of involvement. The institution of D. W. C. and T. Eastward. A. P. received per-example funding from Optimer Pharmaceuticals to support fidaxomicin trial patient expenses. D. W. C. and T. East. A. P. also received honoraria from Optimer Pharmaceuticals for participation in additional meetings related to investigative planning for fidaxomicin. One thousand. H. W. has received honoraria for consultancy work, financial back up to attend meetings, and research funding from bioMérieux, Optimer, Novacta, Pfizer, Pinnacle, The Medicines Company, and Viropharma. All other authors report no potential conflicts.
All authors have submitted the ICMJE Grade for Disclosure of Potential Conflicts of Involvement. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.
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