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Cost of hospital management of Clostridium difficile infection in United States—a meta-analysis and modelling study

  • Shanshan Zhang1, 2Email author,
  • Sarah Palazuelos-Munoz3,
  • Evelyn M. Balsells1,
  • Harish Nair1,
  • Ayman Chit4, 5 and
  • Moe H. Kyaw4
BMC Infectious DiseasesBMC series – open, inclusive and trusted201616:447

https://doi.org/10.1186/s12879-016-1786-6

Received: 25 April 2016

Accepted: 18 August 2016

Published: 25 August 2016

Abstract

Background

Clostridium difficile infection (CDI) is the leading cause of infectious nosocomial diarrhoea but the economic costs of CDI on healthcare systems in the US remain uncertain.

Methods

We conducted a systematic search for published studies investigating the direct medical cost associated with CDI hospital management in the past 10 years (2005–2015) and included 42 studies to the final data analysis to estimate the financial impact of CDI in the US. We also conducted a meta-analysis of all costs using Monte Carlo simulation.

Results

The average cost for CDI case management and average CDI-attributable costs per case were $42,316 (90 % CI: $39,886, $44,765) and $21,448 (90 % CI: $21,152, $21,744) in 2015 US dollars. Hospital-onset CDI-attributable cost per case was $34,157 (90 % CI: $33,134, $35,180), which was 1.5 times the cost of community-onset CDI ($20,095 [90 % CI: $4991, $35,204]). The average and incremental length of stay (LOS) for CDI inpatient treatment were 11.1 (90 % CI: 8.7–13.6) and 9.7 (90 % CI: 9.6–9.8) days respectively. Total annual CDI-attributable cost in the US is estimated US$6.3 (Range: $1.9–$7.0) billion. Total annual CDI hospital management required nearly 2.4 million days of inpatient stay.

Conclusions

This review indicates that CDI places a significant financial burden on the US healthcare system. This review adds strong evidence to aid policy-making on adequate resource allocation to CDI prevention and treatment in the US. Future studies should focus on recurrent CDI, CDI in long-term care facilities and persons with comorbidities and indirect cost from a societal perspective. Health-economic studies for CDI preventive intervention are needed.

Keywords

Clostridium Difficile Economic analysisSystematic reviewMeta-analysis

Background

Clostridium difficile is the leading cause of infectious nosocomial diarrhoea in the United States (US) [1] and the incidence and severity of C. difficile infection (CDI) are increasing [2]. CDI is associated with significant morbidity and mortality; it represents a large clinical burden due to the resultant diarrhoea and potentially life-threatening complications, including pseudomembranous colitis, toxic megacolon, perforations of the colon and sepsis [35]. Up to 25 % of patients suffer from a recurrence of CDI within 30 days of the initial infection. Patients at increased risk of CDI are those who are immuno-compromised, such as those with human immunodeficiency virus (HIV) or who are receiving chemotherapy [68], patients receiving broad-spectrum antibiotic therapy [9, 10] or gastric acid suppression therapy [9, 11], patients aged over 65 years [10], patients with serious underlying disease [12], patients in intensive care units (ICUs) [10], or patients who have recently undergone non-surgical gastrointestinal procedures or those being tube-fed [10].

CDI represents a significant economic burden on US healthcare systems. Infected patients have an increased length of hospital stay compared to uninfected patients, besides there are significant costs associated with treating recurrent infections. A few systematic reviews of cost-of-illness studies on CDI cost are available [1321]. These reviews mainly listed the range of reported cost of their respective observation period or were limited by the small number of included studies or inadequate control for confounding factors. No meta-analysis of large number of cost data in the US has been conducted to date. The cost for patients discharged to long-term care facility (LTCF) and recurrent CDI management are understudied. The cost of case management and total financial burden of CDI treatment in the US is therefore underestimated and remains controversial.

The aim of the current study is to conduct a systematic review and meta-analysis of currently available data to identify and quantify the financial burden attributable to CDI, and to further estimate the total economic burden of CDI hospital management in the US.

Methods

Search strategy

English-language databases with online search tools were searched for to offer maximum coverage of the relevant literature: Medline (via the Ovid interface 1946 to July 2015); EMBASE (via the Ovid interface 1980 to July 2015); The Centre for Review and Dissemination Library (incorporating the DARE, NHS EED, and NHS HTA databases); The Cochrane Library (via the Wiley Online Library) and Health Technology Assessment Database (1989 to July 2015).

We supplemented our data by searching relevant published reports from: National epidemiological agencies, Google search for grey literature and hand searched the reference lists of the included studies. The general search headings identified were: Clostridium difficile, economic, costs, cost analysis, health care costs, length of stay, hospitalization. Examples of the strategy for Medline and EMBASE are listed in Additional file 1.

Study selection

All studies that reported novel direct medical cost and/or indirect costs related to CDI management were included. Review articles, comments, editorials, letters, studies of outbreaks, case reports, posters and articles reporting results from economic modelling of a single treatment measure (i.e. cost effectiveness of faecal transplantation) were excluded in the final analysis. All relevant publications from January 2005 to July 2015 were included in the search. We included the following healthcare settings: hospitals, long-term care facilities and community. Geographical scope covered the US. We did not apply any language restriction. Our predefined inclusion and exclusion criteria are shown in Additional file 1.

Data extraction

Two reviewers (SP, SZ) independently selected the included articles and extracted data. After combining their results, any discrepancies were solved by discussion with HN and MK.

The primary outcomes were CDI-related costs (total costs of those with CDI and other comorbidities) and CDI-attributable costs (total costs of CDI management only, after controlling for the confounders). For studies with control groups (e.g. matched patients without CDI), the CDI-attributable cost extracted was either the cost provided by the articles or calculated by reviewers using the CDI-related cost minus the treatment cost of control groups. The secondary outcome was resource utilization associated with CDI, i.e. CDI-related length of stay (LOS) in hospital and CDI-attributable LOS. The study characteristics of each article were extracted. These included basic publication information, study design, statistical methods, economic data reporting characteristics and population information.

When multiple cost data were presented in a study, we included only one cost estimate for each population subgroup as per the priority below:
  1. a.

    Matched data > Unmatched data.

     
  2. b.

    Adjusted model results > Unadjusted model results.

     
  3. c.

    Regression model results > Calculated difference.

     
  4. d.

    Total cost/charges > Subgroup cost/charge (i.e. survivors, died).

     
  5. e.

    Median (Interquantile Range: IQR) > Mean (Standard Deviation, SD).

     

All costs/charges data were inflated to 2015 US$ equivalent prices adjusted for the Consumer Price Index. If the price year was not reported, it was assumed to be the last year of the data collection period. In cases where charges were reported without cost-to-charge given, costs were estimated using a cost-to-charge ratio of 0.60, which is commonly used value in US health economic studies [22].

Meta-analysis and estimation of national impact

We carried out meta-analysis for cost studies following a Monte Carlo simulation approach, as reported by Jha et al [23] and Zimlichman et al [17], bearing in mind the heterogeneity of the included studies. For each subgroup of CDI, we synthesized the data and reported a point estimate and 90 % confidence intervals (CIs) for the CDI-related cost, CDI-attributable cost and their respective LOS. For each included study, we simulated distribution with pooled results weighted by sample size. We fitted a triangular distribution for each of the included studies based on their reported measures of central tendency and dispersion, i.e. mean and 95 % CI, median and IQR, or median and range. Then we simulated 100,000 sample draws from the modeled distribution of each study. At each iteration, we calculated the weighted average of all included studies. Finally, we reported the mean and 90 % CI from the resulting distribution of the 100,000 weighted average of CDI. This approach facilitated the combination of cost data and eliminated the limitation of combining non-normally distributed data. Monte Carlo simulations were conducted using the Monte Carlo simulation software @RISK, version 7.0 (Palisade Corp).

We estimated the national financial impact of CDI on the US healthcare system, by determining the potential boundaries. The higher boundary was the total number of CDI cases in the US in 2011 extracted from Lessa et al [24], while the lower boundary was the result from a meta-analysis to estimate the total burden of CDI cases in the US [25] (For detailed results see Additional file 1). The total annual cost of CDI management was calculated multiplying the average cost of management per case of CDI, with the total number of CDI cases per year in the US (Fig. 1). We assumed that all CDI cases received treatment in hospital. A point estimate of the final cost (with range) was reported based on a Monte Carlo simulation of 100,000 sample draws.
Figure 1
Fig. 1

Formula for total annual cost calculation

Sensitivity analysis

We extracted the total number of CDI patients and CDI-attributable costs from previous studies [25] and reviews [17, 26] to carry out a sensitivity analysis of our total cost estimates.

Quality assessment

The quality of the studies included was assessed mainly based on the complexity of the statistical method (Fig. 2). All studies were included in the final analyses.
Figure 2
Fig. 2

Quality Assessment Method

Results

Search results

The search strategy identified 2671 references from databases. Seven additional references were identified through other sources. After screening the titles, abstracts and relevant full texts (Fig. 3), a total of 42 studies were included in this review.
Figure 3
Fig. 3

PRISMA diagram of economic burden search of C. difficile

Study characteristics

The characteristics of the 42 included studies [2768] are summarized in Table 1. Cost data collection periods ranged from 1997 to 2012. Most studies (n = 27) used national level databases, with 17 used National Independent Sample (NIS) database and the remaining 10 studies extracted data from various national databases. Fifteen studies were conducted at state level, of which 6 studies only collected data in single hospital. All studies reported cost in hospital level of care, no articles identified in LTCF and community. Nearly all identified references were retrospective hospital database studies (n = 40) and only 1 study was a prospective observational study [29] and another study was a decision tree model [48].
Table 1

Overview of selected references that assessed economic burden attributable to CDI by type of CDI considered in the US

ID

Reference

State, city

Data collection period

Type of CDI

Population

Sample size (Total)

Sample size (CDI cases)

Age of CDI patients

Mean ± SD or (Range), years

CDI definition (short)

Quality assessment

Statistical methodology

Data source

1

Ali 2012 [27]

National

2004–2008

Comp.

Liver transplant

193,714

5159

>18

ICD-9; 008.45 (Primary Diagnosis-PD, Secondary Diagnosis-SD)

Low

No matching; no regression

Nationwide Inpatient Sample (NIS)

2

Ananthakrishnan 2008 [28]

National

2003

Comp.

IBD

124,570

2804

>18

CDI: 73a;

CDI-IBD: 54a

ICD-9; 008.45 (PD)

Medium

No matching; regression

NIS

3

Arora 2011 [29]

Houston

2007–2008

Req.

General

85

85

Horn’s Index Score 1&2: 64 ± 19; Horn’s Index Score 3&4: 65 ± 15

Toxin assay

Low

No matching; no regression

St Luke’s Episcopal Hospital

4

Bajaj 2010 [30]

National

National: 2005

Tertiary: 2002–2006

Both

Cirrhosis

83,230

1165

CDI: 69 ± 20; Cirrhosis-CDI: 61 ± 15

ICD-9; 008.45 (PD, SD)

Medium

No matching; regression

NIS

5

Campbell 2013 [31]

National

2005–2011

Comp.

General

NR

4521

Renal impairment 72.9 ± 13.4; Advanced Age: 78.7 ± 7.4; Cancer/BMT 69.2 ± 14.0; IBD 61.2 ± 18.3; Cabx exposure 61.2 ± 14.8

Toxin assay

High

Matching; regression

Health Facts electronic health record (HER) database

6

Damle 2014 [14]

National

2008–2012

Comp.

Colorectal surgery

84,648

1266

>18

63 ± 17

ICD-9; 008.45 (PD, SD)

Medium

No matching; regression

University Health System Consortium database

7

Dubberke 2008 [33]

Missouri

2003–2003

Both

Non-

Surgical

24,691

439

67(18–101) a

Toxin assay

High

Matching; regression

Barnes-Jewish Hospital Electronic record

8

Dubberke 2014 [2, 34, 71]

Missouri

2003–2009

Both

Recurrent CDI

3958

421

>18

Toxin assay or clinical diagnosis for recurrent CDI

High

Matching; regression

Barnes-Jewish Hospital Electronic record

9

Egorova 2015 [35]

National

2000–2011

Comp.

Vascular surgery

NR

2808

68.4

ICD-9; 008.45 (PD, SD)

High

Matching: regression

NIS

10

Flagg 2014 [36]

National

2004–2008

Comp.

Cardiac surgery

349,112

2581

All age band

ICD-9; 008.45 (SD)

High

Matching: regression

NIS

11

Fuller 2009 [37]

Maryland and California

2007–2008 for Maryland 2005–2006 for California

Comp.

General

3760

3760

Clinical diagnosis

Medium

No matching; regression

Health Services and Cost Review Commission, Maryland; The Office of State-wide Planning and Development, California

12

Glance 2011 [38]

National

2005–2006

Comp.

Trauma

149,648

768

69(45–82) a

Clinical diagnosis

Medium

No matching; regression

NIS

13

Jiang 2013 [39]

Rhode Islands

2010–2011

Comp.

General

225,999

6053

>18

71.4 ± 15.8

ICD-9; 008.45 (SD)

Medium

Matching; no regression

Rhode Island’s 11 acute-care hospitals

14

Kim 2012 [40]

National

2001–2008

Comp.

Cystectomy

10,856

153

>18

68.49 ± 10.52

ICD-9 ; 008.45 (SD)

Medium

No matching; regression

NIS

15

Kuntz 2012 [41]

Colorado

2005–2008

Comp.

General

3067

3067

All age band, Outpatient 62.8 ± 19.4;

Inpatient 69.9 ± 16.3

ICD-9 + toxin assay

Medium

No matching; regression

Kaiser Permanente Colorado and Kaiser Permanente Northwest members

16

Lagu 2014 [42]

Massachusetts, Boston one hospital

2004–2010

Comp.

Sepsis

218,915

2348

70.9 ± 15.1

ICD-9; 008.45 (PD, SD) + toxin assay

Medium

Matching; no regression

Baystate Medical Center (Premier Healthcare Informatics database, a voluntary, fee-supported database)

17

Lameire 2015

National

2002–2009

Comp.

Cardiac surgery

512,217

421,294

>40

CABG 65.4 ± 10.5

VS 66.1 ± 12.3

ICD-9; 008.45 (PD, SD)

Medium

No matching; regression

NIS

18

Lawrence 2007 [44]

Missouri

1997–1999

Both

ICU

1872

76

Primary 68.9 (34–93)

Secondary 58.7 (16–91)

Toxin assay

Medium

No matching; regression

A 19-bed medical ICU in a Midwestern tertiary care referral center.

19

Lesperance 2011 [45]

National

2004–2006

Comp.

Elective colonic resections

695,010

10,077

>18

All 69.8; Surgery-CDI 68.7

ICD-9; 008.45 (SD)

Medium

No matching; regression

NIS

20

Lipp 2012 [46]

New York

2007–2008

Comp.

General

4,853,800

3883

>17

ICD-9; 008.45 (SD)

Medium

No matching; regression

- The SPARCS database- acute care non-federal hospitals in New York State

21

Maltenfort 2013 [47]

National

2002–2010

Both

Arthroplasty

NR

NR

All age band

ICD-9; 008.45 (PD, SD)

Low

No matching; no regression

NIS

22

McGlone 2012 [48]

National

2008

Comp.

General

NR

NR

>65

ICD-9; 008.45 (SD)

Low

No matching; no regression

Decision tree model

23

Nguyen 2008 [49]

National

1998–2004

Comp.

IBD

527,187

2372

47.4 ± 0.2

ICD-9; 008.45 (secondary diagnosis)

Medium

No matching; regression

NIS

24

Nylund 2011 [50]

National

1997,2000, 2003,2006

Both

Children

10,495,728

21,274

CDI 9.5 ± 0.07(SEM)

ICD-9; 008.45 (PD, SD)

High

Matching: regression

Healthcare Cost and Utilization Project Kids’Inpatient Database

25

O’Brien 2007 [51]

Massachusetts

1999–2003

Req.

General

3692

1036

Primary 70 ± 17.6; Secondary 70 ± 17.2

ICD-9; 008.45 (PD, SD)

Low

No matching; no regression

Massachusetts hospital discharge data

26

Pakyz 2011 [52]

National

2002–2007

Comp.

General

30,071

10,857

CDI 61 ± 17

ICD-9; 008.45 (SD)

High

Matching; regression

University Health System Consorsoum (UHC)

27

Pant 2012 [53]

National

2009

Both

Organ transplant (OT)

244,955

6451

>18,

OT-CDI 58 ± 16 a; CDI-only 73 ± 22 a

ICD-9; 008.45 (PD, SD)

Medium

No matching; regression

NIS

28

Pant 2012 (2) [54]

National

2009

Both

Renal disease

184,139

5151

>18,

ESRD + CDI 66 ± 14 CDI ONLY 70 ± 17

ICD-9; 008.45 (PD, SD)

Medium

No matching; regression

NIS

29

Pant 2013 [55]

National

2009

Both

Children with IBD

12,610

447

<20,

15.1 ± 4.1

ICD-9; 008.45 (PD, SD)

Medium

No matching; regression

The Healthcare Cost and Utilization Project Kids’ Inpatient Database (HCUP-KID)

30

Peery 2012 [56]

National

From 2009

Req.

General

110,533

110,533

All age band

ICD-9; 008.45 (PD)

Low

No matching; no regression

National Ambulatory Medical Care Survey (NAMCS) and NIS

31

Quimbo 2013 [57]

National

2005–2010

Comp.

High Risk subgroups

21,177

26,620

>18

67.5 ± 17.6

ICD-9; 008.45 (PD, SD)

High

Matching: regression

HealthCare Integrated Research Database

32

Reed 2008

Pennsylvania

2002–2006

Comp.

High Risk subgroups

9164

524

>17

Hospital acquired CDAD

Low

No matching; no regression

A large academic community hospital

33

Sammons 2013 [59]

National

2006–2011

Both

Children

13,295

4447

1–18

6 (2–13) a

ICD-9; 008.45 (PD, SD) + toxin assay

High

Matching; regression

Free-standing children’s hospitals via the Paediatric Health Information System (PHIS)

34

Singal 2014 [60]

National

2007

Comp.

Cirrhosis

89,673

1444

All age band

ICD-9; 008.45 (PD, SD)

Medium

No matching; regression

NIS

35

Song 2008 [61]

Maryland

2000–2005

Both

General

9025

630

>18

unmatched 57.6 matched 60.3

Toxin assay

High

Matching; regression

The Johns Hopkins hospital

36

Stewart 2011 [62]

National

2007

Both

General

82,214

41,207

All age band,

70

ICD-9; 008.45 (PD, SD)

Medium

Matching; no regression

NIS

37

Tabak 2013 [63]

Pennsylvania

2007–2008

Comp.

General

77,257

255

All 64.8 ± 17.6

CDI 71.1 ± 14.8

Toxin assay

High

Matching; regression

Six Pennsylvania hospitals via a clinical research database

38

VerLee 2012

Michigan

2002–2008

Req.

General

517,413

517,413

All age band

ICD-9; 008.45 (PD)

Low

No matching; no regression

All Michigan acute care hospitals

39

Wang 2011 [65]

Pennsylvania

2005–2008

Both

General

7,227,788

78,273

All age band

ICD-9; 008.45 (PD, SD)

High

Matching; regression

The Pennsylvania Health Care Cost Containment Council (PHC4) database

40

Wilson 2013 [66]

National

2004–2008

Comp.

Ileostomy

13,245

217

All age band

ICD-9; 008.45 (SD)

High

Matching; regression

NIS

41

Zerey 2007 [67]

National

1999–2003

Both

Surgical

1,553,597

8113

All age band

70 am

ICD-9; 008.45 (PD, SD)

Medium

No matching; regression

NIS

42

Zilberberg 2009 [68]

National

2005

Both

Prolonged acute mechanical ventilation

64,910

3468

>18

66.7 ± 15.9

ICD-9; 008.45 (PD, SD)

Medium

Matching; no regression

NIS

Abbreviations: NR not reported, IBD inflammatory bowel disease, LOS length of stay, ICU intensive care unit, retrosp. retrospective, Comp. complicating, Req. requiring, both requiring and complicating, PD primary diagnosis, SD secondary diagnosis

a Median (Range)

Most studies (n = 15) investigated economic outcomes in all age inpatients. Three studies reported cost data in children less than 20 years old. The mean/median age of the CDI patient groups ranged from 47.4 to 73.0 years. Other studies investigated complicated CDI in high-risk patient groups, such as those with major surgery (n = 16), inflammatory bowel diseases (n = 2), liver or renal disease (n = 4), elderly (n = 2) and ICU patients (n = 1). There was 1 study each in non-surgical inpatients, sepsis inpatients and patients with prolonged acute mechanical ventilation. There was 1 study focusing only on recurrent CDI in the general population.

The sample sizes of included studies ranged from 85 to 7,227,788, with a median sample size of 83,939. A total of 28.8 million inpatient hospital-days were analysed, of which 1.31 million inpatient hospital-days were CDI patients. The median sample size of CDI population was 2938.

The methods to identify CDI varied according to the type of CDI that was assessed in the study. CDI cases were identified either with laboratory test, i.e. positive C. diffcile toxin assay, or hospital discharge diagnosis of C. difficile (primary and/secondary) from administrative datasets using the International Classifications of diseases, Ninth, Clinical Modification, ICD-9-CM 008.45. Clinical diagnosis was also used in two studies.

CDI was classified in three types: Community-onset CDI (CO-CDI) requiring hospitalization, Hospital-onset CDI (HO-CDI) complicating other diseases, or both CDI (Table 2). Most of included studies considered HO-CDI (n = 23) or both CDI types (n = 17). Only four studies investigated CO-CDI only. However, subgroup data of CO-CDI is also available in studies that reported both CDI types.
Table 2

Classification of CDI Cases by Setting of Acquisition

Case definition

Criteria for classification

CO-CDI

- Discharge code ICD-9-CM 008.45 as Primary diagnosis

HO-CDI

- Discharge code ICD-9-CM 008.45 as secondary diagnosis, without a primary diagnosis of a CDI-related symptom (e.g. diarrhea)

- Study population ≥ 48 h of hospitalization

- Symptom onset and/or positive laboratory assay at least ≥ 48 h hospitalization

Both CDI

- No distinction of settings of acquisition

- Discharge code ICD-9-CM 008.45 in any position

Abbreviations: CO-CDI community-onset CDI, HO-CDI hospital-onset CDI, ICD-9-CM The International Classification of Diseases, Ninth Revision, Clinical Modification

CDI costs and LOS

The mean CDI-attributable costs per case of CO-CDI were $20,085 (Range: $7513–$29,662), lower than HO-CDI $34,149 (Range:$1522–$122,318). HO-CDI showed a wider range within which the additional cost for CDI in the general population ranged from $6893 to $90,202 and in high risk groups ranged from $7332 in congestive heart failure patients to $122,318 in renal impairment patients. The mean CDI-attributable LOS was 5.7 days (Range: 2.1–33.4) for CO-CDI, 7.8 (Range:2.3–21.6) days for HO-CDI, and 13.6 (Range: 2.2–16) days for both groups. Cost data and LOS for individual studies are presented in Tables 3 and 4.
Table 3

CDI-attributable costs/charges and CDI-related management costs/charges

Author, Year

Population

Outcome

Statistic

Incremental CDI-attributable cost/charges

CDI-related cost/charges

Note

Sample size

Attributable cost 2015$

SD or 95 % CI

Sample size

CDI only cost 2015$

SD, 95 % CI or IQR

CO-CDI Inpatient Cost

Arora 2011 [29]

General

Cost

Median

85

25,436

  

85

25,436

   

O’Brien 2007 [51]

General

Cost

Mean

4015

14,736

  

4015

14,736

   

Peery 2012 [56]

General

Cost

Median

110,553

7513

  

110,553

7513

   

VeerLee 2012 [64]

General

Charges

Mean

68,686

74,211

120,156

 

68,686

74,211

120,156

  

Kuntz 2012 [41]

General

Cost

Mean

1650

929

4800

 

1650

929

4800

 

Outpatient

Kuntz 2012 [41]

General

Cost

Mean

1316

11,877

35,923

 

1316

11,877

35,923

 

Inpatient

O’Brien 2007 [51]

General

Cost

Median

1036

7263

  

1036

7263

  

PD

VeerLee 2012 [64]

General

Charges

Mean

17,413

27,463

40,484

 

17,413

27,463

40,484

 

PD

O’Brien 2007 [51]

General

Cost

Mean

3327

16,946

34,655

 

3327

16,946

  

Rehospitalisation

Sammons 2013 [59]

Children

Cost

Mean

2060

19,993

15,973

24,013

2060

19,993

15,973

24,013

Community onset

Ananthakrishnan 2008 [28]

IBD

Charges

Median

    

44,400

16,864

  

CDI only

Pant 2013 [55]

IBD

Charges

Mean

12,610

12,761

6868

18,655

447

50,050

  

CDI only

Bajaj 2010 [30]

Cirrhosis

Charges

Mean

    

58,220

70,309

  

CDI only

Quimbo 2013 [57]

CDI History

Cost

Mean

1866

29,662

20,798

42,300

933

51,863

36,641

73,411

CDI only

Total numbers/Weighted Mean

  

224,617

20,085

  

314,141

23,322

   

HO-CDI Inpatient Cost

Fuller 2009 [37]

General

Cost

Coefficient

1282

18,466

288

 

1282

18,466

288

 

Maryland, SD

Fuller 2009 [37]

General

Cost

Coefficient

2478

29,980

271

 

2478

29,980

271

 

California, SD

Lipp 2012 [46]

General

Cost

Mean

3826

32,050

  

3826

32,050

  

SD

McGlone 2012 [48]

General

Cost

Median

54,046

10,016

8547

12,055

54,046

10,016

8547

12,055

SD Cost-hospital perspective-6 days LOS

McGlone 2012 [48]

General

Cost

Median

54,046

11,116

9476

13,366

54,046

11,116

9476

13,366

10 days LOS

McGlone 2012 [48]

General

Cost

Median

54,046

12,194

10,146

14,896

54,046

12,194

10,146

14,896

14 days LOS

O’Brien 2007 [51]

General

Cost

Median

2656

6630

  

2656

6630

  

SD

VeerLee 2012 [64]

General

Charges

Mean

51,273

90,202

146,767

 

51,273

90,202

146,767

 

SD

Jiang 2013 [39]

General

Cost

Median

7264

11,689

  

1211

21,751

   

Pakyz 2011 [52]

General

Cost

Mean

30,071

31,180

  

10,857

64,732

  

Unadjusted

Pakyz 2011 [52]

General

Cost

Median

30,071

24,456

  

10,857

39,598

22,400

88,537

Unadjusted

Pakyz 2011 [52]

General

Cost

Mean

30,071

31,169

  

10,857

64,000

63,541

64,458

Adjusted

Tabak 2013 [63]

General

Cost

Mean

1020

6893

1365

13,617

255

22,992

12,222

42,470

 

Campbell 2013 [31]

Age > = 65

Cost

Mean

3064

7536

4302

10,771

3064

48,932

67,727

  

Quimbo 2013 [57]

Elderly

Cost

Mean

34,732

45,749

43,279

48,359

10,933

83,004

78,548

87,713

 

Sammons 2013 [59]

Children

Cost

Mean

2414

99,012

84,626

113,398

2414

99,012

84,626

113,398

 

Ananthakrishnan 2008 [28]

IBD

Charges

Median

80,170

7655

  

2804

24,623

   

Ananthakrishnan 2008 [28]

IBD

Charges

Mean

80,170

14,368

9467

19,270

    

Campbell 2013 [31]

IBD

Cost

Mean

84

1522

−14,932

11,888

84

40,194

44,845

  

Quimbo 2013 [57]

IBD

cost

Mean

3618

11,825

9851

14,181

1206

42,035

35,918

49,191

 

Ananthakrishnan 2008 [28]

Ulcerative colitis (UC)

Charges

Median

    

1843

26,750

   

Nguyen 2008 [49]

UC

Charges

Mean

43,645

14,749

  

196

43,381

  

Regression

Ananthakrishnan 2008 [28]

Crohn's disease (CD)

Charges

Median

    

961

22,738

   

Nguyen 2008 [49]

CD

Charges

Mean

73,197

14,316

  

329

41,453

  

Regression

Reed 2008

Digestive disorders

Charges

Mean

2394

3670

  

320

9076

8068

  

Damle 2014 [14]

Colorectal surgery

Cost

Median

84,648

14,644

13,700

15,589

1266

21,309

38,218

 

Kim 2012 [40]

Cystectomy

Cost

Mean

10,856

25,014

  

153

57,379

50,204

64,554

 

Lesperance 2011 [45]

Elective colonic resection

Charges

Mean

695,010

84,899

  

10,077

158,401

   

Reed 2008

Major bowel procedures

Charges

Mean

1035

25,476

  

45

47,064

31,302

  

Wilson 2013 [66]

Ileostomy

Cost

Mean

13,462

20,272

  

217

35,076

   

Wilson 2013 [66]

Ileostomy

Cost

Coefficient

13,462

17,513

14,106

20,921

     

Egorova 2015 [35]

Vascular surgery

Cost

Median

450,251

14,250

  

4708

36,847

22,912

62,903

 

Flagg 2014 [36]

Cardiac surgery

Cost

Median

5160

19,524

  

2580

213,661

  

Adjusted

Flagg 2014 [36]

Cardiac surgery

Cost

Median

349,122

38,320

  

2580

72,730

  

Unadjusted

Lemaire 2015 [43]

Cardiac surgery

Cost

Median

421,294

35,968

  

72,685

  

CABG

Lemaire 2015 [43]

Cardiac surgery

Cost

Median

90,923

59,696

  

106,141

  

VS

Reed 2008

OR procedure for infectious /parasitic diseases

Charges

Mean

449

7462

  

32

35,524

25,498

  

Glance 2011 [38]

Trauma

Cost

Median

149,656

24,131

  

768

39,296

   

Campbell 2013 [31]

Cabx

Cost

Mean

1641

18,567

10,448

26,687

1641

78,948

99,739

  

Quimbo 2013 [57]

Cabx

Cost

Mean

17,716

38,413

35,195

41,922

4429

64,242

59,145

69,780

 

Lagu 2014 [42]

Sepsis

Cost

Median

4736

5792

4933

6665

2368

28,576

16,496

50,494

 

Reed 2008

Septicaemia

Charges

Mean

1211

9141

  

92

22,378

20,591

  

Campbell 2013 [31]

Renal impairment

Cost

Mean

3236

5024

1118

8928

3236

50,586

72,180

  

Quimbo 2013 [57]

RI

Cost

Mean

22,132

122,318

111,315

134,405

5533

201,212

183,706

220,386

 

Ali 2012 [27]

Liver transplant

Charges

Mean

193,714

77,361

  

5159

158,038

   

Singal 2014 [60]

Cirrhosis

Charges

Mean

89,673

23,310

  

1444

47,401

   

Reed 2008

Congestive Heart Failure

Charges

Mean

2542

7332

  

35

14,738

13,841

  

Quimbo 2013 [57]

Immunocompromised

Cost

Mean

14,344

33,632

30,151

37,516

3586

73,612

66,048

82,041

 

Campbell 2013 [31]

Cancer/BMT

Cost

Mean

782

687

−6480

7855

782

48,280

72,605

  

Total numbers/Weighted mean

  

3,020,827

34,149

  

207,801

49,712

   

Dubberke 2014 [2, 34, 71]

Recurrent CDI

Cost

Mean

3958

12,163

  

3958

11,523

4728

26,167

Total cost difference

Dubberke 2014 [2, 34, 71]

Recurrent CDI

Cost

Mean

3958

12,692

9752

15,919

    

Adjusted

Song 2008 [61]

General

Cost

Median

1260

373

  

630

30,305

   

Stewart 2011 [62]

General

Cost

Mean

82,414

9670

  

41,207

26,790

   

Wang 2011 [65]

General

Cost

Median

7,227,788

4914

  

78,273

12,081

   

Nylund 2011 [50]

Children

Charges

Median

3565

15,937

  

3565

25,549

  

1997

Nylund 2011 [50]

Children

Charges

Median

4356

20,750

  

4356

31,858

  

2000

Nylund 2011 [50]

Children

Charges

Median

5574

23,627

  

5574

33,625

11,348

97,822

2003

Nylund 2011 [50]

Children

Charges

Median

7779

23,362

  

7779

35,444

13,601

110,343

2006

Sammons 2013 [59]

Children

Cost

Mean

698,616

51,304

44,746

57,969

698,616

51,304

44,746

57,969

 

Dubberke 2008 [33]

Non-surgical

Cost

Median

24,691

11,749

  

439

20,569

  

Raw data

Dubberke 2008 [33]

Non-surgical

Charges

Median

24,691

23,961

  

439

42,154

  

Raw data

Dubberke 2008 [33]

Non-surgical

Cost

Mean

24,691

3173

3078

3815

    

Linear regression

Dubberke 2008 [33]

Non-surgical

Cost

Median

24,691

4190

  

342

18,842

  

Matched cases

Dubberke 2008 [33]

Non-surgical

Cost

Mean

24,691

6520

4910

8381

    

Linear regression, 180 days

Dubberke 2008 [33]

Non-surgical

Cost

Median

24,691

9284

  

342

35,414

  

Matched cases, 180 days

Zerey 2007 [67]

Surgical

Charges

Median

1,553,597

59,424

  

8113

81,708

   

Zerey 2007 [67]

Surgical

Charges

Coefficient

1,553,597

94,402

91,589

97,216

    

Multivariate regression analysis

Zilberberg 2009 [68]

Prolonged acute mechanical ventilation (PAMV)

Cost

Median

64,910

48,065

  

3468

190,188

107,689

333,290

Unadjusted

Zilberberg 2009 [68]

PAMV

Cost

Mean

3370

12,616

9186

16,046

3468

91,039

71,306

 

Adjusted

Lawrence 2007 [44]

ICU

Cost

Median

1872

7043

  

76

15,016

  

ICU stay

Lawrence 2007 [44]

ICU

Cost

Median

1872

36,095

  

76

60,723

  

Entire hospital stay

Bajaj 2010 [30]

Cirrhosis

Charges

Mean

83,230

49,460

  

1165

96,678

   

Maltenfort 2013 [47]

Arthroplasty

Charges

Median

43,648

  

84,877

52,498

142,827

 

Pant 2012 [53]

Organ transplant

Charges

Mean

49,198

77,246

73,412

81,080

63,651

42,054

69,033

  

Pant 2012 (2) [54]

Renal disease

Charges

Coefficient

184,139

69,679

68,338

71,020

59,793

87,982

   

Pant 2013 [55]

IBD

Charges

Mean

12,610

39,453

32,470

46,436

     

Total numbers/Weighted Mean

  

10,012,927

14,403

  

981,005

45,421

   

Abbreviations: CO-CDI community-onset CDI, HO-CDI hospital-onset, PAMV prolonged acute mechanical ventilation, Cabx concomitant antibiotic use, UC ulcerative colitis, CD Crohn’s disease, IBD inflammatory bowel disease, ICU intensive care unit, CABG coronary artery bypass grafting, VS valvular surgery, BMT, PD primary diagnosis, SD secondary diagnosis, Calculated numbers were marked in Italic, attributable cost = cost of CDI group- cost of control non-CDI group

Table 4

CDI-attributable LOS and CDI-related LOS

Reference

Population

Statistic

CDI VS NO CDI LOS (Days)

CDI LOS (Days)

Sample size

Value

SD or 95 % CI

Sample size

Value

SD or 95 % CI

CO-CDI Inpatient days

 

Arora 2011 [29]

Horn’s index 1&2

Mean

33

15.1

16.2

 

33

15.1

16.2

 

Arora 2011 [29]

Horn’s index 3&4

Mean

52

33.4

33.3

 

52

33.4

33.3

 

Kuntz 2012 [41]

General outpatient

Mean

1650

10.0

17.0

 

1650

10.0

17.0

 

Kuntz 2012 [41]

General inpatient

Mean

1316

14.9

20.9

 

1316

14.9

20.9

 

O’Brien 2007 [51]

General

Mean

4015

6.4

  

4015

6.4

  

Pant 2013 [55]

IBD

Coefficient

12,610

2.1

1.4

2.8

 

2.1

1.4

2.8

Peery 2012 [56]

General

Median

110,553

5.0

  

110,553

5.0

  

Quimbo 2013 [57]

CDAD History

Mean

1866

2.9

2.4

3.6

933

8.9

7.2

11.0

Sammons 2013 [59]

Children

Median

2060

5.6

4.5

6.6

2060

6.0

4.0a

13.0a

VeerLee 2012 [64]

General

Mean

68,686

7.1

7.0

 

68,686

7.1

7.0

 

Weighted Mean

 

202,841

5.7

  

189,298

5.9

  

HO-CDI inpatient days

Jiang 2013 [39]

General

Median

7264

8.0

  

1211

13.0

  

Lipp 2012 [46]

General

Mean

3826

12.0

  

3826

12.0

  

Pakyz 2011 [52]

General

Mean

30,071

11.1

  

10,857

21.1

21.0

21.2

Tabak 2013 [63]

General

Median

1020

2.3

0.9

3.8

255

12.0

9.0a

21.0a

Wang 2013

General

Median

7,227,788

7.0

  

78,273

6.0

4.0a

11.0a

Campbell 2013 [31]

Age > = 65

Mean

3064

3.0

1.4

4.6

3064

21.3

25.3

 

Quimbo 2013 [57]

Elderly

Mean

34,732

7.8

7.5

8.1

10,933

18.8

18.2

19.5

Sammons 2013 [59]

Children

Median

2414

21.6

19.3

23.9

2414

23.0

12.0a

44.0a

Ananthakrishnan 2008 [28]

IBD

Median

80,170

3.0

  

2804

7.0

  

Campbell 2013 [31]

IBD

Mean

84

3.0

−2.3

8.3

84

21.0

19.1

 

Quimbo 2013 [57]

IBD

Mean

3618

3.3

2.9

3.7

1206

12.8

11.6

14.2

Nguyen 2008 [49]

Crohn’s disease

Mean

73,197

3.8

  

329

9.5

  

Nguyen 2008 [49]

Ulcerative colitis

Mean

43,645

3.2

  

196

9.9

  

Reed 2008

Digestive disorders

Mean

2394

3.0

  

320

6.9

5.2

 

Damle 2014 [14]

Colorectal surgery

Median

84,648

8.4

8.0

8.9

1266

13.0

18.0

 

Lesperance 2011 [45]

Elective colonic resection

Mean

695,010

11.7

  

10,077

22.6

  

Reed 2008

Major bowel procedures

Mean

1035

10.0

  

45

20.9

11.3

 

Wilson 2013 [66]

Ileostomy

Mean

13,462

11.6

  

217

18.7

  

Campbell 2013 [31]

Cabx exposure

Mean

1641

7.8

5.7

9.9

1641

29.3

34.7

 

Quimbo 2013 [57]

Concomitant Antibiotic Use

Mean

17,716

7.8

7.4

8.3

4429

17.9

17.0

18.9

Lagu 2014 [42]

Sepsis

Mean

4736

5.1

4.4

5.7

2368

19.2

  

Reed 2008

Septicemia

Mean

1211

5.0

  

92

10.7

7.6

 

Egorova 2015 [35]

Vascular surgery

Median

450,251

6.7

  

4708

15.0

9.0a

25.0a

Flagg 2014 [36]

Cardiac surgery

Median

349,122

10.0

  

2580

21.0

  

Glance 2011 [38]

Trauma

Median

149,656

10.0

  

768

16.0

  

Lemaire 2015 [43]

Cardiac surgery (CABG)

Median

421,294

12.0

   

19.0

  

Lemaire 2015 [43]

Cardiac surgery (VS)

Median

90,923

16.0

   

24.0

  

Reed 2008

Congestive Heart Failure

Mean

2542

5.0

  

35

9.7

7.0

 

Reed 2008

OR procedure for infectious /parasitic diseases

Mean

449

2.0

  

32

14.7

8.6

 

Lawrence 2007 [44]

ICU

Median

    

76

14.9

1.0b

86.0b

Lawrence 2007 [44]

ICU

Median

    

76

38.3

4.0b

184.0b

Ali 2012 [27]

Liver transplant

Mean

193,714

10.1

  

5159

17.8

  

Singal 2014 [60]

Cirrhosis

Mean

89,673

7.5

  

1444

13.9

  

Quimbo 2013 [57]

Immunocompromised

Mean

14,344

8.4

7.9

9.0

3586

22.1

20.6

23.7

Campbell 2013 [31]

Renal impairment

Mean

3236

4.0

2.9

5.1

3236

22.7

28.2

 

Quimbo 2013 [57]

Renal impairment

Mean

22,132

17.3

16.4

18.3

5533

37.5

35.5

39.6

Campbell 2013 [31]

Cancer/BMT

Mean

782

4.0

2.3

5.7

782

21.3

18.5

 

Weighted Mean

  

10,120,864

7.8

  

168,892

13.5

  

Both CO-CDI and HO-CDI inpatient cost

Song 2008 [61]

General

Median

1260

4.0

  

630

22.0

  

Stewart 2011 [62]

General

Mean

82,414

5.1

  

41,207

13.0

14.0

 

Nylund 2011 [50]

Children, 1997

Median

3565

3.0

  

3565

5.0

3.0a

14.0a

Nylund 2011 [50]

Children, 2000

Median

4356

4.0

  

4356

6.0

3.0a

15.0a

Nylund 2011 [50]

Children, 2003

Median

5574

4.0

  

5574

6.0

3.0a

14.0a

Nylund 2011 [50]

Children, 2006

Median

7779

4.0

  

7779

6.0

3.0a

15.0a

Sammons 2013 [59]

Children

Median

698,616

12.2

10.6

13.8

698,616

10.0

5.0a

23.0a

Bajaj 2010 [30]

Cirrhosis

Mean

83,230

7.1

  

1165

14.4

  

Bajaj 2010 [30]

CDI only

Mean

    

58,220

12.7

  

Pant 2013 [55]

IBD

Mean

12,610

2.2

1.5

2.8

447

8.2

  

Dubberke 2008 [33]

Non-surgical

Median

24,691

6.0

  

439

10.0

2. 0b

87.0b

Lawrence 2007 [44]

ICU stay

Median

1872

3.1

  

76

6.1

1.0b

86.0b

Lawrence 2007 [44]

Hospital stay

Median

1872

14.4

  

76

24.5

2.0b

184.0b

Maltenfort 2013 [47]

Arthroplasty

Median

7.0

  

10.0

7.0a

17.0a

Zerey 2007 [67]

Surgical

Median

1,553,597

16.0

15.6

16.4

8113

18.0

  

Pant 2012 [53]

Organ transplant

Median

49,198

9.6

9.3

9.9

63,651

   

Pant 2012 (2) [54]

Renal disease

Coefficient

184,139

9.4

9.2

9.5

59,793

   

Zilberberg 2009 [68]

Prolonged acute mechanical ventilation

Median

3370

6.1

4.9

7.4

3468

25.0

15.0a

40.0a

Weighted Mean

 

2,718,143

13.6

  

957,175

9.0

  

Abbreviations: CO-CDI community-onset CDI, HO-CDI Hospital-onset CDI, PAMV prolonged acute mechanical ventilation, Cabx concomitant antibiotic use, UC ulcerative colitis, CD Crohn’s disease, IBD inflammatory bowel disease, ICU intensive care unit, CABG coronary artery bypass grafting, VS valvular surgery, BMT, PD primary diagnosis, SD secondary diagnosis, Calculated numbers were marked in Italic, attributable cost = cost of CDI group- cost of control non-CDI group

aQ1-Q3

bMin-Max

Using a Monte Carlo simulation, we generated point estimates and 90 % CI for both cost and LOS; the meta-analysis results are shown in Table 5. The total cost of inpatient management of CDI-related disease was $42,316 (90 % CI: $39,886–$44,765) per case, of which the total CDI-attributable cost was $21,448 (90 % CI: 21,152–21,744) per case. For the inpatient management, the attributable cost for those HO-CDI was $34,157 (90 % CI: $33,134–$35,180), which was 1.5 times as much as CO-CDI management $20,095 (90 % CI: $4991–$35,204).
Table 5

Meta analysis results of cost and LOS of CDI management

CDI category

CDI-attributable cost per case

(2015 US$)

CDI-related cost per case

(2015 US$)

CDI-attributable LOS per case (Days)

CDI-related LOS per case (Days)

 

Weighted mean

90 % CI

Weighted mean

90 %CI

Weighted mean

90 % CI

Weighted mean

90 % CI

CO-CDI

20,095

4991

35,204

23,329

12,520

34,141

5.7

4.1

7.3

5.7

4.1

7.3

HO-CDI

34,157

33,134

35,180

53,487

42,054

66,326

9.7

9.7

9.7

14.1

13.0

15.4

Both CO-CDI and HO-CDI

17,650

17,292

18,009

46,000

42,502

49,533

10.4

9.7

11.0

11.8

7.1

17.6

Overall inpatient

21,448

21,152

21,744

42,316

39,886

44,765

9.7

9.6

9.8

11.1

8.7

13.6

Abbreviations: CO-CDI community-onset CDI, HO-CDI Hospital-onset CDI

Similar patterns were observed in LOS data. The total CDI-related LOS was 11.1 days (90 % CI: 8.7–13.6) and CDI-attributable LOS was 9.7 (90 % CI: 9.6–9.8). The HO-CDI patients had longer CDI-attributable LOS 9.7 days (90 % CI: 9.7–9.7) than CO-CDI patients 5.7 days (90 % CI: 4.1–7.3).

CDI annual national impact estimate

The total burden of healthcare facility CDI in US was estimated 293,300 (Range: 264,200–453,000) cases per year [25]. The total financial burden of CDI inpatient management was estimated to be US$6.3 (Range: $1.9–$7.0) billion in 2015, which required 2.4 million days of hospital stay. The total CDI related disease management cost was nearly doubled at US$12.4 (Range: $3.7–$14.4) billion in 2015 (Table 6). A sensitivity analysis showed that the total CDI-attributable cost ranged from $1.31 to $13.61, which covers our estimates (Additional file 1).
Table 6

Total cost of CDI management in US

Total number of HCF CDI cases per year (2011) [25]

Mean

95 % CI

All population ≥2 years Median

293,300

264,200

322,500

 Adults ≥18 Upper boundary

288,900

261,100

316,700

 Adults ≥18 Lower boundary

133,887

91,780

195,402

Cost per CDI case management (2015 US$)

Weighted Mean

90 % CI

 Overall CDI-attributable cost

21,448

21,152

21,744

 Overall CDI-related cost

42,316

39,886

44,765

Total cost per year (in Billions, 2015 US$)

Weighted Mean

Range

Total CDI-attributable cost per year

6.29

1.94

7.01

Mean

6.29

5.59

7.01

 Upper boundary

6.19

5.52

6.88

 Lower boundary

2.87

1.94

4.25

Total CDI-related cost per year

12.41

3.66

14.44

Mean

12.41

5.59

14.44

 Upper boundary

12.25

10.41

14.18

 Lower boundary

5.67

3.66

8.75

Abbreviations: HCF healthcare facility, CDI clostridium difficile infection, CI confidence intervals

Quality assessment

A summary of the quality assessment for statistical methods in included studies is shown in Additional file 1. There were 13 studies of high quality, 21 studies with medium quality and 8 low quality studies.

Discussion

We systematically reviewed 42 published cost studies of CDI case management in the past 10 years (2005–2015) and found a significant financial burden associated with CDI in the US. The total CDI-attributable cost was US$6.3 billion, which is higher than previously reported (range US$1.1–4.8 billion) [14, 16, 17]. The mean cost for CDI-attributable hospitalized patients per case was US$21,448, nearly half of the mean CDI-related inpatient cost.

This review facilitated a meta-analysis of a large number of cost studies for costs related to CDI management and provided an uncertainty range. Zimlichman et al [17] applied this method to calculate CDI cost based on cost data from two cost-of-illness studies (O’Brian 2007 [51] & Kyne 2002 [69]) and obtained a lower cost [2012US $11,285 ($9118–$13,574)] than ours. Our review combined 100-point estimates and ranges from 42 individual studies, which provided more accurate and comprehensive data of the cost result. Despite the methodological heterogeneity in perspectives, treatment procedure and statistical analysis, each included study met our inclusion criteria, which were defined to identify studies that provided real world estimates of costs, therefore the combination of these data with uncertainty range represented a valuable and reliable summary of CDI-related cost.

Furthermore, we evaluated hospital onset CDI and community onset CDI separately. We found that CDI complicating hospitalization cost more than CDI requiring hospitalization and the former had longer attributable hospital stay. Therefore, other factors, such as comorbidity, may contribute to infections and increase the difficulty of CDI treatment.

We estimated that the total cost attributable to CDI management in the US was nearly US$6.3 (Range: $1.9–$7.0) billion, which is similar to Dubberke and Olsen’s estimates at $4.8 billion [14], but significantly higher than other studies (US$ 1.5 billion in Zimlichman et al [17] and $1.1 billion in Ghantoji et al [16]). The later studies reported lower attributable cost per case based on a limited number of studies before 2005, which arguably is out-of-date. To compare with the latest review on global CDI cost (Nanwa et al [26]), this review identified 8 additional studies with recent data. Nanwa et al [26] found that the mean attributable CDI costs ranged from US$8911 to US$30,049, which is similar to our results.

In this study, we only assessed the quality of study emphasizing statistical methods and did not use the modified economic evaluation guideline as other COI systematic reviews. Cost and LOS estimation of healthcare-associated infections has the potential to be misleading if the confounders such as patients’ comorbidities or daily severity of illness were not properly controlled for. Using either the matching design or multivariable regression analysis allows to control known confounders and may, in part, address selection bias [70]. We found that whether advanced statistical methods were used and described was crucial for the assessment of data quality, which has not be fully captured by the existing quality assessment tool. Therefore in this study we assessed quality of included studies using this new method. Moreover, Nanwa et al [26] has evaluated the methodological completeness of most included studies (34 out of 42); we agree with their recommendations regarding possible improvement of future cost-of-illness study. However, we need to bear in mind that cost effects or excess LOS are still likely to be overestimated if the interval to onset of HAI is not properly accounted for in the study design or analysis [70].

Our systematic review has some limitations. First, all included studies reported direct medical costs from hospital perspective, therefore indirect cost to patients and society and costs of additional care after hospital discharge, have not been captured. No studies reported indirect cost (productivity loss due to work day losses) of patients or care-givers, and we failed to identify studies assessing cost of CDI in long-term care facilities, where about 9 % of CDI patients were discharged to for an average of 24 days of after-care. This would result in an additional US$141 million burden on the healthcare system and society due to LTCF transfers [14]. Second, we did not separate primary CDI from recurrent CDI cost in our review because only two studies reported cost specifically to recurrent CDI $12,592 (Range: $9752, $15,919) [2]. Moreover, we found it difficult to exactly match the CDI case definition in cost study (e.g. ICD10 Code primary diagnosis and secondary diagnosis) with the case definition in epidemiology studies (e.g. community onset, hospital onset), therefore we did not estimate CDI patients managed at outpatient and community settings due to lack of both epidemiology and economic data. The total costs of CDI management may be higher than our current estimate. Fourth, unlike other published reviews, we did not include cost studies from countries other than the US nor facilitate any international comparison. This study initially aimed to identify cost-of-illness studies in North America, but we did not find any studies reporting cost data from Canada. This is likely because we restricted our search to English language databases. Therefore the cost of CDI management in Canada remains unknown. However, we did not apply any language restrictions to the current review.

Effective prevention can reduce the burden of diseases. Strategies have been promoted such as appropriate use of antimicrobials, use of contact precautions and protective personal equipment to care for infected patients, effective cleaning and disinfection of equipment and the environment, and early recognition of disease as primary prophylaxis [71]. As CDI is an infectious disease, the population at risk would benefit from an effective vaccine, which is currently under development [72, 73].

More cost of illness studies for recurrent CDI, or in LTCF, and indirect cost from a societal perspective are needed in the future. We would also recommend that published studies report their methods and include point estimates with uncertainty range. Further economic studies for CDI preventive interventions are needed.

Conclusion

This review indicates that CDI places a significant financial burden on the US healthcare system. In addition, our findings suggest that the economic burden of CDI is greater than previously reported in the US. This review provides strong evidence to aid policy-making on adequate resource allocation to CDI prevention and treatment in US.

Abbreviations

CDI: 

clostridium difficile infection

CIs: 

confidence intervals

CO CDI: 

community-onset CDI

HCF: 

healthcare facility

HIV: 

human immunodeficiency virus

HO-CDI: 

hospital-onset cdi

ICD-9-CM: 

the international classification of diseases, ninth revision, clinical modification

ICUs: 

intensive care units

IQR: 

interquantile range

LTCF: 

long-term care facility

NIS: 

national independent sample

SD: 

standard deviation

US: 

United States

Declarations

Acknowledgements

We gratefully acknowledge the comments and suggestions from Guy De Bruyn, Clarisse Demont, Kinga Borsos (Sanofi Pasteur) during manuscript preparation. We thank Sanofi Pasteur for financial support for this work. The findings and conclusions in this report are those of the authors and do not necessarily represent the official views or policies of Sanofi Pasteur.

Funding

Sanofi Pasteur funded this study.

Availability of data and materials

The datasets supporting the conclusions of this article are included within the article and its Additional file 2.

Authors’ contributions

Study design (MK, HN, AC); data collection (SZ, SP, EB); data analysis (SZ, EB); data interpretation (SZ, EB, HN, AC, MK); development of initial draft manuscript (SZ, EB, HN), critical revisions for intellectual content of manuscript (SZ, SP, EB, HN, AC, MK); study supervision (HN, MK). All authors reviewed and approved the final draft of manuscript.

Competing interests

SP, AC, MK are employees of Sanofi Pasteur.

Consent for publication

Not applicable.

Ethics approval and consent to participate

Not applicable.

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

Authors’ Affiliations

(1)
Usher Institute of Population Health Sciences and Informatics, University of Edinburgh, Medical School, Edinburgh, UK
(2)
Department of Preventive Dentistry, Peking University School and Hospital of Stomatology, Beijing, China
(3)
Sanofi Pasteur, Lyon, France
(4)
Sanofi Pasteur, Swiftwater, USA
(5)
Lesli Dan Faculty of Pharmacy, University of Toronto, Toronto, Canada

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Copyright

© The Author(s). 2016

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