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Hospital cost of Clostridium difficile infection including the contribution of recurrences in French acute-care hospitals
Journal of Hospital Infection 91 (2015) 117e122 Available online at www.sciencedirect.com
Journal of Hospital Infection journal homepage: www.elsevierhealth.com/journals/jhin
Hospital cost of Clostridium difficile infection including the contribution of recurrences in French acute-care hospitals A. Le Monnier a, *, A. Duburcq b, J.-R. Zahar c, S. Corvec d, T. Guillard e, V. Cattoir f, P.-L. Woerther g, V. Fihman h, V. Lalande i, H. Jacquier j, A. Mizrahi a, ´ m, S. Coulomb b, E. Torreton b, F. Fagnani b, E. Farfour k, P. Morand l, G. Marcade F. Barbut n on behalf of the GMC study Groupy a
Laboratoire de Microbiologie Clinique, GH Paris Saint-Joseph, Paris, France CEMKA-EVAL, Bourg la Reine, France c Laboratoire de Microbiologie-Hygie`ne, Universite´ Paris Descartes, Sorbonne Paris Cite´, Hoˆpital Necker-Enfants malades, AP-HP, Paris, France d Service de Bacte´riologie-Hygie`ne hospitalie`re, CHU de Nantes, France e Laboratoire de bacte´riologie-virologie-hygie`ne hospitalie`re, CHU de Reims, Hoˆpital Robert Debre´, Universite´ de Reims Champagne Ardenne, France f Service de Microbiologie, CHU de Caen, Caen, France g Laboratoire de Microbiologie, Institut Gustave Roussy, Villejuif, France h Unite´ de Bacte´riologie-Hygie`ne, CHU Henri-Mondor, AP-HP, Cre´teil, France i De´partement de Bacte´riologie, Hoˆpitaux Universitaires Est Parisien, Hoˆpital Saint-Antoine, AP-HP, Paris, France j Laboratoire de Microbiologie, Groupe Hospitalier Lariboisie`re Fernand Widal, AP-HP, Paris, France k Laboratoire de Microbiologie, Centre Hospitalier de Versailles, Le Chesnay, France l Service de Bacte´riologie, Universite´ Paris Descartes, Sorbonne Paris Cite´, Hoˆpital Cochin, AP-HP, Paris, France m Service de Microbiologie-Hygie`ne, Hoˆpitaux Universitaires Paris Nord Val de Seine, Hoˆpital Louis Mourier, AP-HP, Colombes, France n Laboratoire Clostridium difficile associe´ au CNR des bacte´ries anae´robies, CHU Saint-Antoine, France b
A R T I C L E
I N F O
Article history: Received 10 December 2014 Accepted 30 June 2015 Available online 22 July 2015 Keywords: Caseecontrol study Clostridium difficile infection
S U M M A R Y
Background: The impact of Clostridium difficile infection (CDI) on healthcare costs is significant due to the extra costs of associated inpatient care. However, the specific contribution of recurrences has rarely been studied. Aim: The aim of this study was to estimate the hospital costs of CDI and the fraction attributable to recurrences in French acute-care hospitals. Methods: A retrospective study was performed for 2011 on a sample of 12 large acute-care hospitals. CDI costs were estimated from both hospital and public insurance perspectives. For each stay, CDI additional costs were estimated by comparison to controls without CDI
* Corresponding author. Address: Unite ´ de Microbiologie Clinique et de dosages des Antibiotiques, Groupe Hospitalier Paris Saint-Joseph, 185 rue Raymond Losserand, 75674 Paris Cedex 14, France. Tel.: þ33 1 44 12 79 32; fax: þ33 1 44 12 35 13. E-mail address: [email protected] (A. Le Monnier). y Members of the GMC Study Group are listed in the Appendix. http://dx.doi.org/10.1016/j.jhin.2015.06.017 0195-6701/ª 2015 The Healthcare Infection Society. Published by Elsevier Ltd. All rights reserved.
118 Costs analysis Recurrence
A. Le Monnier et al. / Journal of Hospital Infection 91 (2015) 117e122 extracted from the national DRG (diagnosis-related group) database and matched on DRG, age and sex. When CDI was the primary diagnosis, the full cost of stay was used. Findings: A total of 1067 bacteriological cases of CDI were identified corresponding to 979 stays involving 906 different patients. Recurrence(s) were identified in 118 (12%) of these stays with 51.7% of them having occurred within the same stay as the index episode. Their mean length of stay was 63.8 days compared to 25.1 days for stays with an index case only. The mean extra cost per stay with CDI was estimated at V9,575 (median: V7,514). The extra cost of CDI in public acute-care hospitals was extrapolated to V163.1 million at the national level, of which 12.5% was attributable to recurrences. Conclusion: The economic burden of CDI is substantial and directly impacts healthcare systems in France. ª 2015 The Healthcare Infection Society. Published by Elsevier Ltd. All rights reserved.
Introduction Clostridium difficile is responsible for 15e25% of antibioticassociated diarrhoea and represents one of the most frequent causes of infectious diarrhoea in hospitalized patients.1 Since 2003, the incidence of C. difficile infection (CDI) reported in hospitals worldwide has been increasing, with higher rates of severe cases and recurrences. In France, the incidence of CDI rose from 2.2 per 10,000 inpatient-days in 2009 to 3.6 per 10,000 in 2012.2,3 The increased incidence and virulence of infections are assumed to be due, at least in part, to the emergence and rapid spread of a fluoroquinolone-resistant strain belonging to the polymerase chain reaction ribotype 027.4 From an economic viewpoint, nosocomial CDI increases patient healthcare costs due to the extended length of hospitalization, re-admission, laboratory tests, and medication. However, the reported extra costs attributable to CDI vary widely according to the definitions and methodologies used.5,6 Estimates of the economic and clinical burden of CDI would help in the evaluation of the potential benefits, as judged by health expenditures and survival, of new therapies or preventive measures to control disease spreading and to reduce the risk of recurrence.7 Our objectives were to estimate the direct costs generated by CDI and the contribution of recurrences, in a sample of large acute-care hospitals in France.
Methods The French discharge database in acute-care hospitals A discharge database using 2300 different diagnosis-related groups (DRGs) is used in France as a tool for activity-based funding of acute care hospitals. Each patient is identified by a unique identification code, which allows tracking of hospital stays in all French acute-care hospitals.8 Costs per DRG are set and regularly updated at the national level based on mean full costs derived from the ‘Etude Nationale de Cou ` me ´thodologie Commune’ (ENCC), a cost study ˆts a performed annually using the analytical accounting data from a national representative sample of hospitals and clinics.9 The current 11th version of the discharge coding system associates up to four degrees of ‘severity level’ for each DRG depending primarily on comorbidities (ICD-10), length of stay (LOS), and patients’ age. The occurrence of nosocomial infection and especially of CDI episode is among the list of events that trigger
an upgrade to the highest degree of severity (level 4), which yields the highest tariff paid to the facility by the French public health insurance system.
Hospital sample and data collection A retrospective multi-centre study was performed on a sample of 12 large public acute-care hospitals (nine university hospitals, two tertiary care hospitals, and one oncology hospital) representing 5.82% of the cumulated annual number of patient-days spent in public acute-care hospitals in France in 2011. Clinical microbiologists in each hospital were asked to retrieve all episodes with diagnosis of CDI for adult patients (>18 years of age) recorded in 2011. Ten laboratories used a diagnostic strategy based on a two-step algorithm in accordance with the European guidelines effective at that time, whereas two laboratories used NAAT as a stand-alone test.10 They were asked to exclude cases from patients treated in rehabilitation and long-term care wards located in the hospital itself or referred from external facilities. In parallel, all hospitalizations in the 2011 discharge database of each hospital for which patients received a primary or secondary diagnosis of CDI (ICD-10 A04.7) were examined and matched with microbiological data from each facility. We assumed that when microbiological diagnosis of CDI was not coded in the discharge database, it corresponded to a secondary diagnosis. A recurrence was defined as a new positive sample identified in a period from 10 days to two months after a first positive sample (index case) in a given patient.11 The identification of recurrence was restricted by our method to those occurring in the same hospital as the index episode.
Cost analysis Cost estimation of CDI considered both costs incurred by public insurance and by the hospital itself. Hospital costs associated with CDI were estimated differently depending on whether CDI (ICD-10, A04.7) was recorded as a primary cause of hospitalization or as a secondary diagnosis (patients hospitalized for another cause with concurrent CDI) in the hospital discharge database. For hospital stays with CDI as a cause of hospitalization, the full cost incurred by the hospital stay was considered (case 1). For stays with CDI coded as a secondary diagnosis, the incremental cost due to CDI was calculated as the cost difference
A. Le Monnier et al. / Journal of Hospital Infection 91 (2015) 117e122 with control patients without CDI, matched to CDI cases on age, sex, and DRG. This analysis was performed on the nationwide discharge database to ensure sufficient statistical power. In most cases, the incremental cost corresponded to a modification of the severity level of the DRG in absence of CDI (levels 3, 2 or 1) to the highest severity level, level 4 (case 2). In cases where CDI did not trigger an upgrade in severity level (already at level 4), the incremental cost of CDI was based on the estimated LOS increase (case 3). In this last case, the occurrence of CDI was incurred only by the hospital budget. The total cost was the sum of the cost for all CDI-related primary hospitalizations and the incremental cost of secondary hospitalizations. The same estimation method was used for index episodes of CDI as well as for recurrences. In the case of an index episode of CDI with one or several recurrence(s) within the same stay, the corresponding cost was attributed to the recurrence(s). Costs expressed in euros were based on full unit cost per DRG in hospitals at their 2010 values. In an exploratory manner, a whole-country extrapolation was performed by using a ratio based on the cumulated number of hospital-days spent in acute care in the study sample and nationwide.
Statistical analysis Different statistical tests were performed according to the type of variables analysed: for categorical variables, chisquare tests were applied except for sample size <5 where the Fisher exact test was used; for continuous variables, Student’s t-test was used. In other cases, non-parametric tests were used (Wilcoxon, KruskaleWallis). Median values and 5th to 95th percentiles of costs were calculated. SAS version 9.2 (SAS Institute, Cary, NC, USA) was used for all statistical analyses.
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corresponded to 906 different patients admitted in 2011 for a total of 979 acute-care stays. The mean annual incidence of CDI episodes based on laboratory reporting was 3.74 cases per 10,000 patient-days (range: 2.1e7.9) or 1.6 cases per 1000 admissions (range: 0.94e3.84). Among the 1067 positive samples collected, the overall proportion of recurrences was 13.2% (141 samples in 118 different hospital stays). However, as several recurrences could occur during the same stay, the proportion of stays with recurrences of CDI is slightly lower (12%). The mean number of recurrences was 1.38 among the subgroup of 159 patients with at least one recurrence: 111 (69.8%) had one, 36 (22.7%) had two, and 12 (7.5%) three or more. A mean time of 14.4 days (11.8) was observed between the end of treatment of the index episode and the onset of the first recurrence. In 51.7% of cases, recurrence(s) occurred within the same hospital stay as the index episode. Table I presents the main characteristics of the 979 stays for patients hospitalized in acute-care according to the presence or not of recurrence(s) either alone or with an index episode within the same stay. In total, CDI was recorded as the principal diagnosis of admission in 13.9% of cases. The characteristics of stays with a single CDI episode, either index or recurrence, were similar; however, stays with multiple episodes [index and recurrence(s) within the same stay] differed in terms of age, sex, LOS and mortality (Table I). For example, for stays with recurrence within the same stay as the index episode, the mean LOS was 63.8 days versus 25.1 for those with an index episode only. As those stays concerned only 4.9% of CDI coded as primary diagnosis, the longer LOS might have also resulted from the severity of the underlying condition, and this result should therefore not be interpreted as attributable solely to recurrence.
Costs analysis
Results Index cases and recurrences of CDI In 2011, a total of 1067 CDI-positive microbiological samples were identified in the 12 participating hospitals. They
Three different estimations were performed according to the status of the CDI as either primary or secondary diagnosis, and to the type of DRGs. According to our classification of stays, 136 stays were case 1 (CDI as primary diagnosis), 712 case 2 (CDI as secondary diagnosis), and 131 case 3 (extended LOS).
Table I Characteristics of acute-care stays and patients with Clostridium difficile index (CDI) [index and/or recurrence(s)]
No. of stays with CDI Age (years), mean (SD) Female LOS, mean (SD) CDI coded as primary diagnosis Discharge location or vital status Home Transfer Other In-hospital all-cause mortality LOS, length of stay. a Student’s t-test. b Wilcoxon rank sum test. c Chi-square test. d Fisher exact test.
Index episode only
Recurrence(s) only
Index þ recurrence(s)
Total
P
861 59.6 (23.6) 449 (52.8%) 25.1 (26.1) 122 (14.2%)
57 59.4 (22.6) 27 (47.4%) 20.1 (22.4) 11 (19.3%)
61 64.7 (21.4) 18 (29.5%) 63.8 (43.0) 3 (4.9%)
979 59.9 (23.4) 494 (51.0%) 27.2 (28.8) 136 (13.9%)
0.2562a 0.0017c <0.0001b 0.0622c
497 203 48 113
(57.7%) (23.6%) (5.6%) (13.1%)
34 14 4 5
(59.6%) (24.6%) (7.0%) (8.8%)
24 18 7 11
(40.0%) (30.0%) (11.7%) (18.0%)
555 235 59 129
(56.7%) (24.0%) (6.0%) (13.2%)
0.0249c 0.5281c 0.1478d 0.3286c
12.5% V1,191,028 2,264e23,822 DRG, diagnosis-related group; LOS, length of stay.
V9,695 (7,164) V17,075 979
V9,575 (7,514) 2,263e23,517 V9,490,503 121 (12.4%)
10.5% 12.8% 12.4% V86,567 V1,022,947 V81,514 2,366e9,878 2,264e26,798 0e6,922 V6,183 (6,557) V11,366 (8,616) V4,795 (4,979) 14 (10.3%) 90 (12.6%) 17 (13.0%) V6,056 V6,056 (4,410) 2,366e9,878 V823,656 V19,125 V11,251 (8,822) 2,324e24,145 V8,010,872 V12,444 V5,004 (4,460) 0e16,452 V655,975 136 712 131
Primary CDI diagnosis Secondary CDI diagnosis DRG not modified/LOS increased All
Total extra No. of stays Extra cost per stay 5the95th percentile Total extra cost of % of total cost (% of all stays) [mean (median)] recurrences extra cost 5the95th percentile No. of Mean cost Extra cost/stay stays per stay [mean (median)]
These results highlight the significant economic burden of CDI on hospitals in France (V163.1 million) and the fraction of direct costs attributable to recurrences (12.5%). This extrapolation of CDI cost to France is based on the assumption that our sample was representative of public hospitals at a national level and should be interpreted with caution and considered as only exploratory; our sample was probably only representative of large tertiary hospitals. Our estimate was based on matching individual bacteriological and discharge ICD-10 data which allowed us to identify the frequency of recurrences, including those within the same stay as the index episode. Our results were conservative in different respects: they did not integrate indirect costs associated with premature mortality and consequences on quality of life. Moreover, they did not cover associated direct costs incurred outside the acute-care setting. The annual incidence of CDI based on laboratory reporting was estimated to 3.74 cases per 10,000 patient-days and was in line with the incidence of 3.6 2.9 cases per 10,000 patientdays reported in a 2011 study that included 70 French healthcare facilities.3 Although this was not the objective of this study, the incidence rate is likely to be underestimated during this period in France due to a lack of clinical awareness from physicians and inappropriate testing methods as has been described recently.3 Our estimate of a 12% recurrence rate for hospital stays with CDI was lower than those reported from recent clinical trials (between 25.3% and 26.9% after vancomycin treatment) , but more in line with those published in European observational studies based on the same definition (second episode within 60
All stays with CDI (N ¼ 979)
Discussion
Hospital diagnosis status
In DRGs with CDI as primary diagnosis (case 1), the mean cost per stay was V6,056 (median: V4,410) and the cumulated cost for the whole set of stays observed in 2011 in our sample of hospitals was V823,656. The extra costs per stay due to severity level change in patients with CDI as secondary diagnosis (case 2) adjusted on age, sex, and DRG for cases without CDI were calculated for a total of 712 stays with a mean extra cost estimated at V11,251 (median: V8,822) per stay. For the 131 remaining stays (case 3), the occurrence of CDI did not affect the cost of the stay and thus did not generate an extra charge for third-party payers (public insurance), but rather an extra cost for the hospital budget. These DRGs concerned mainly palliative care stays and chemotherapy sessions. The mean extra LOS was estimated at 8.9 days corresponding to an extra cost of V5,004 (median: V4,460) per stay. The cumulated costs for the whole sample of acute-care hospital stays observed in this study are presented in Table II with the fraction of costs that might be specifically attributed to recurrences. A mean extra cost per stay with CDI of V9,575 (median: V7,514) was estimated, which totals approximately V9.5 million in 2011 for the 12 facilities included in the study sample. The fraction of that total cost attributable to recurrences was 12.5%. The extrapolated annual nationwide cost of CDI in 2011 was V163.1 million, using a ratio of 1:0.0582 based on the sampling rate of the total annual number of patient-days spent in acutecare public facilities in the whole country.
Contribution of recurrences (N ¼ 118)
A. Le Monnier et al. / Journal of Hospital Infection 91 (2015) 117e122
Table II Summary of Clostridium difficile index (CDI) cost (V) according to hospital diagnosis status and contribution of recurrences (12 acute-care hospitals, 2011)
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A. Le Monnier et al. / Journal of Hospital Infection 91 (2015) 117e122 days of the index episode): Austria 16%, Ireland 18%, The Netherlands 16%, and UK 8e11%.12e17 These discrepancies may be explained by the impossibility in our study of identifying recurrences in other non-acute-care facilities such as rehabilitation or long-term care facilities. However, a similar recurrence rate was observed by Dubberke et al. in a recent US study characterized by the same limitations.18 From an economic perspective, it is meaningful to note that recurrences (alone or following an index episode within the same stay) occurring in acute-care settings were present in 12.0% of hospital stays with CDI. In addition, we found that 9.3% (11/118) of recurrences were coded as primary diagnosis and led to a re-admission of the patients, which resulted in a prolonged hospital stay and additional medical costs. Our approach to estimating CDI hospital costs was directly dependent on the design of the French DRG system and the associated unit cost measurement. The use of DRGs incorporating severity levels made the calculation more complicated than in most other published studies which used increased LOS as a main cost driver.19,20 Recent analyses by Mitchell et al. suggested that the simple consideration of LOS without using time-dependent covariate was subjected to biases.21 In our study, this method was used only in 13% of cases and was made necessary due to the lack of relevant data. In a recent publication by Dubberke, attributable inpatient cost of recurrence over a 180-day period after an index episode was estimated at $11,631, very similar to our estimate cost, despite the differences in setting and design.18 Costs of hospital stays with CDI as principal diagnosis (case 1) were considered to be entirely borne by third-party payers assuming that the full cost estimates reflected the real burden of those stays to the hospitals. It should be noted that a substantial proportion (38.2%) of stays with bacteriological evidence of CDI had no mention of CDI in their discharge database. Therefore, corresponding costs were actually accrued by hospitals on their own budget due to the lack of reporting by physicians. Our cost analysis method was not limited to a simple budget impact on a third-party payer (the public health insurance). We did not use the DRG tariff but rather full cost estimates and we cumulated costs directly paid by a third-party payer and those incurred on hospital budgets. In this respect, our approach was comprehensive and may be qualified as a ‘societal’ perspective restricted to the acute-care setting and direct costs.22 A substantial fraction of CDI identified in our sample of hospitals was removed as it related to patients in rehabilitation and longterm care facilities. Our data did not allow us to estimate the associated cost in such facilities and therefore our results were probably conservative as they underestimate the total societal burden of CDI.23,24 Previous literature reviews in Europe or the USA have mentioned that the key outcomes used in most studies for measuring the burden of CDI in acute-care settings are relatively similar and include mortality, recurrence rate, increased LOS, and extra cost per stay.4,5 In reality, the definition and measurement of these outcomes are very diverse among studies and comparisons need to be made with caution and limited to results obtained in a comparable manner. Our data indicated that among patients with DRG without a change in severity level or those with a level 4 of severity irrespective of CDI diagnosis (case 3), the increased LOS was
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estimated at 8.9 days compared to matched controls. Because of the specificity of the French DRG system, these results are difficult to compare to previous published data since they focus on a specific subpopulation of patients (palliative care, autologous stem-cell grafting of HIV-related care). Despite the aforementioned limitations, our results for global cost were in line with those reported in a recent comprehensive review which provided median incremental hospital costs per episode in the range of US$10,156 (CDI recorded as primary diagnosis) to US$9,298 (CDI recorded as secondary diagnosis).25 In conclusion, this cost study was performed in France on a sample of large acute-care hospitals using a case-matched control approach to quantify the direct cost burden of CDI. The mean extra costs with CDI were estimated at around V9,575 per hospital stay and around V163.1 million in public acute-care hospitals at the national level. Any strategies aiming at preventing CDI or recurrences should contribute to reduce the CDI-associated costs.
Acknowledgements We thank G. Jones for careful reading of the manuscript. Funding source This work was supported by an unrestricted grant from Astellas Pharma SAS (France). Conflict of interest statement A.L.M. has received honoraria for consultancy work from Astellas and financial support to attend meetings from Astellas and Cepheid. V.C. has received honoraria for consultancy work and financial support to attend meetings from Astellas. V.F. has received financial support to attend meetings from Astellas. F.B. has received consulting or lecture fees from Astellas, Cepheid, MSD, Sanofi-Pasteur, and Summit; grants for scientific studies from Astellas, bioMe ´rieux, Cubist, Diasorin, Sanofi-Pasteur, and Roche. F.F., A.D., S.C., E.T. are employed by CEMKA-EVAL, a contact research organization that received funding from Astellas. J.R.Z., S.C., T.G., P.L.W., V.L., H.J., A.M., E.F., P.M., G.M. and all the other investigators of the GMC study group declare no conflicts of interest.
Appendix The GMC study Group includes the following investigators: O. Billuart (Paris), S. Bouam (Paris), E. Chachaty (Villejuif), M.P. Chaillet (Nantes), D. Dakova (Colombes), R. De Mil (Caen), J.-W. Decousser (Cre ´teil), C. Duteil (Paris), S. Gue ´ant (Paris), F. He ´mery (Cre ´teil), M.-E. Juvin (Nantes), B. Lemaire (Le Chesnay), A. Limelette (Reims), M. Mons (Villejuif), D. Nidegger (Reims), A. Perozziello (Paris), H. Poupet (Paris), J. ReboulMarty (Paris), C. Segouin (Paris), P. Taupin (Paris).
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Journal of Hospital Infection journal homepage: www.elsevierhealth.com/journals/jhin
Hospital cost of Clostridium difficile infection including the contribution of recurrences in French acute-care hospitals A. Le Monnier a, *, A. Duburcq b, J.-R. Zahar c, S. Corvec d, T. Guillard e, V. Cattoir f, P.-L. Woerther g, V. Fihman h, V. Lalande i, H. Jacquier j, A. Mizrahi a, ´ m, S. Coulomb b, E. Torreton b, F. Fagnani b, E. Farfour k, P. Morand l, G. Marcade F. Barbut n on behalf of the GMC study Groupy a
Laboratoire de Microbiologie Clinique, GH Paris Saint-Joseph, Paris, France CEMKA-EVAL, Bourg la Reine, France c Laboratoire de Microbiologie-Hygie`ne, Universite´ Paris Descartes, Sorbonne Paris Cite´, Hoˆpital Necker-Enfants malades, AP-HP, Paris, France d Service de Bacte´riologie-Hygie`ne hospitalie`re, CHU de Nantes, France e Laboratoire de bacte´riologie-virologie-hygie`ne hospitalie`re, CHU de Reims, Hoˆpital Robert Debre´, Universite´ de Reims Champagne Ardenne, France f Service de Microbiologie, CHU de Caen, Caen, France g Laboratoire de Microbiologie, Institut Gustave Roussy, Villejuif, France h Unite´ de Bacte´riologie-Hygie`ne, CHU Henri-Mondor, AP-HP, Cre´teil, France i De´partement de Bacte´riologie, Hoˆpitaux Universitaires Est Parisien, Hoˆpital Saint-Antoine, AP-HP, Paris, France j Laboratoire de Microbiologie, Groupe Hospitalier Lariboisie`re Fernand Widal, AP-HP, Paris, France k Laboratoire de Microbiologie, Centre Hospitalier de Versailles, Le Chesnay, France l Service de Bacte´riologie, Universite´ Paris Descartes, Sorbonne Paris Cite´, Hoˆpital Cochin, AP-HP, Paris, France m Service de Microbiologie-Hygie`ne, Hoˆpitaux Universitaires Paris Nord Val de Seine, Hoˆpital Louis Mourier, AP-HP, Colombes, France n Laboratoire Clostridium difficile associe´ au CNR des bacte´ries anae´robies, CHU Saint-Antoine, France b
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Article history: Received 10 December 2014 Accepted 30 June 2015 Available online 22 July 2015 Keywords: Caseecontrol study Clostridium difficile infection
S U M M A R Y
Background: The impact of Clostridium difficile infection (CDI) on healthcare costs is significant due to the extra costs of associated inpatient care. However, the specific contribution of recurrences has rarely been studied. Aim: The aim of this study was to estimate the hospital costs of CDI and the fraction attributable to recurrences in French acute-care hospitals. Methods: A retrospective study was performed for 2011 on a sample of 12 large acute-care hospitals. CDI costs were estimated from both hospital and public insurance perspectives. For each stay, CDI additional costs were estimated by comparison to controls without CDI
* Corresponding author. Address: Unite ´ de Microbiologie Clinique et de dosages des Antibiotiques, Groupe Hospitalier Paris Saint-Joseph, 185 rue Raymond Losserand, 75674 Paris Cedex 14, France. Tel.: þ33 1 44 12 79 32; fax: þ33 1 44 12 35 13. E-mail address: [email protected] (A. Le Monnier). y Members of the GMC Study Group are listed in the Appendix. http://dx.doi.org/10.1016/j.jhin.2015.06.017 0195-6701/ª 2015 The Healthcare Infection Society. Published by Elsevier Ltd. All rights reserved.
118 Costs analysis Recurrence
A. Le Monnier et al. / Journal of Hospital Infection 91 (2015) 117e122 extracted from the national DRG (diagnosis-related group) database and matched on DRG, age and sex. When CDI was the primary diagnosis, the full cost of stay was used. Findings: A total of 1067 bacteriological cases of CDI were identified corresponding to 979 stays involving 906 different patients. Recurrence(s) were identified in 118 (12%) of these stays with 51.7% of them having occurred within the same stay as the index episode. Their mean length of stay was 63.8 days compared to 25.1 days for stays with an index case only. The mean extra cost per stay with CDI was estimated at V9,575 (median: V7,514). The extra cost of CDI in public acute-care hospitals was extrapolated to V163.1 million at the national level, of which 12.5% was attributable to recurrences. Conclusion: The economic burden of CDI is substantial and directly impacts healthcare systems in France. ª 2015 The Healthcare Infection Society. Published by Elsevier Ltd. All rights reserved.
Introduction Clostridium difficile is responsible for 15e25% of antibioticassociated diarrhoea and represents one of the most frequent causes of infectious diarrhoea in hospitalized patients.1 Since 2003, the incidence of C. difficile infection (CDI) reported in hospitals worldwide has been increasing, with higher rates of severe cases and recurrences. In France, the incidence of CDI rose from 2.2 per 10,000 inpatient-days in 2009 to 3.6 per 10,000 in 2012.2,3 The increased incidence and virulence of infections are assumed to be due, at least in part, to the emergence and rapid spread of a fluoroquinolone-resistant strain belonging to the polymerase chain reaction ribotype 027.4 From an economic viewpoint, nosocomial CDI increases patient healthcare costs due to the extended length of hospitalization, re-admission, laboratory tests, and medication. However, the reported extra costs attributable to CDI vary widely according to the definitions and methodologies used.5,6 Estimates of the economic and clinical burden of CDI would help in the evaluation of the potential benefits, as judged by health expenditures and survival, of new therapies or preventive measures to control disease spreading and to reduce the risk of recurrence.7 Our objectives were to estimate the direct costs generated by CDI and the contribution of recurrences, in a sample of large acute-care hospitals in France.
Methods The French discharge database in acute-care hospitals A discharge database using 2300 different diagnosis-related groups (DRGs) is used in France as a tool for activity-based funding of acute care hospitals. Each patient is identified by a unique identification code, which allows tracking of hospital stays in all French acute-care hospitals.8 Costs per DRG are set and regularly updated at the national level based on mean full costs derived from the ‘Etude Nationale de Cou ` me ´thodologie Commune’ (ENCC), a cost study ˆts a performed annually using the analytical accounting data from a national representative sample of hospitals and clinics.9 The current 11th version of the discharge coding system associates up to four degrees of ‘severity level’ for each DRG depending primarily on comorbidities (ICD-10), length of stay (LOS), and patients’ age. The occurrence of nosocomial infection and especially of CDI episode is among the list of events that trigger
an upgrade to the highest degree of severity (level 4), which yields the highest tariff paid to the facility by the French public health insurance system.
Hospital sample and data collection A retrospective multi-centre study was performed on a sample of 12 large public acute-care hospitals (nine university hospitals, two tertiary care hospitals, and one oncology hospital) representing 5.82% of the cumulated annual number of patient-days spent in public acute-care hospitals in France in 2011. Clinical microbiologists in each hospital were asked to retrieve all episodes with diagnosis of CDI for adult patients (>18 years of age) recorded in 2011. Ten laboratories used a diagnostic strategy based on a two-step algorithm in accordance with the European guidelines effective at that time, whereas two laboratories used NAAT as a stand-alone test.10 They were asked to exclude cases from patients treated in rehabilitation and long-term care wards located in the hospital itself or referred from external facilities. In parallel, all hospitalizations in the 2011 discharge database of each hospital for which patients received a primary or secondary diagnosis of CDI (ICD-10 A04.7) were examined and matched with microbiological data from each facility. We assumed that when microbiological diagnosis of CDI was not coded in the discharge database, it corresponded to a secondary diagnosis. A recurrence was defined as a new positive sample identified in a period from 10 days to two months after a first positive sample (index case) in a given patient.11 The identification of recurrence was restricted by our method to those occurring in the same hospital as the index episode.
Cost analysis Cost estimation of CDI considered both costs incurred by public insurance and by the hospital itself. Hospital costs associated with CDI were estimated differently depending on whether CDI (ICD-10, A04.7) was recorded as a primary cause of hospitalization or as a secondary diagnosis (patients hospitalized for another cause with concurrent CDI) in the hospital discharge database. For hospital stays with CDI as a cause of hospitalization, the full cost incurred by the hospital stay was considered (case 1). For stays with CDI coded as a secondary diagnosis, the incremental cost due to CDI was calculated as the cost difference
A. Le Monnier et al. / Journal of Hospital Infection 91 (2015) 117e122 with control patients without CDI, matched to CDI cases on age, sex, and DRG. This analysis was performed on the nationwide discharge database to ensure sufficient statistical power. In most cases, the incremental cost corresponded to a modification of the severity level of the DRG in absence of CDI (levels 3, 2 or 1) to the highest severity level, level 4 (case 2). In cases where CDI did not trigger an upgrade in severity level (already at level 4), the incremental cost of CDI was based on the estimated LOS increase (case 3). In this last case, the occurrence of CDI was incurred only by the hospital budget. The total cost was the sum of the cost for all CDI-related primary hospitalizations and the incremental cost of secondary hospitalizations. The same estimation method was used for index episodes of CDI as well as for recurrences. In the case of an index episode of CDI with one or several recurrence(s) within the same stay, the corresponding cost was attributed to the recurrence(s). Costs expressed in euros were based on full unit cost per DRG in hospitals at their 2010 values. In an exploratory manner, a whole-country extrapolation was performed by using a ratio based on the cumulated number of hospital-days spent in acute care in the study sample and nationwide.
Statistical analysis Different statistical tests were performed according to the type of variables analysed: for categorical variables, chisquare tests were applied except for sample size <5 where the Fisher exact test was used; for continuous variables, Student’s t-test was used. In other cases, non-parametric tests were used (Wilcoxon, KruskaleWallis). Median values and 5th to 95th percentiles of costs were calculated. SAS version 9.2 (SAS Institute, Cary, NC, USA) was used for all statistical analyses.
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corresponded to 906 different patients admitted in 2011 for a total of 979 acute-care stays. The mean annual incidence of CDI episodes based on laboratory reporting was 3.74 cases per 10,000 patient-days (range: 2.1e7.9) or 1.6 cases per 1000 admissions (range: 0.94e3.84). Among the 1067 positive samples collected, the overall proportion of recurrences was 13.2% (141 samples in 118 different hospital stays). However, as several recurrences could occur during the same stay, the proportion of stays with recurrences of CDI is slightly lower (12%). The mean number of recurrences was 1.38 among the subgroup of 159 patients with at least one recurrence: 111 (69.8%) had one, 36 (22.7%) had two, and 12 (7.5%) three or more. A mean time of 14.4 days (11.8) was observed between the end of treatment of the index episode and the onset of the first recurrence. In 51.7% of cases, recurrence(s) occurred within the same hospital stay as the index episode. Table I presents the main characteristics of the 979 stays for patients hospitalized in acute-care according to the presence or not of recurrence(s) either alone or with an index episode within the same stay. In total, CDI was recorded as the principal diagnosis of admission in 13.9% of cases. The characteristics of stays with a single CDI episode, either index or recurrence, were similar; however, stays with multiple episodes [index and recurrence(s) within the same stay] differed in terms of age, sex, LOS and mortality (Table I). For example, for stays with recurrence within the same stay as the index episode, the mean LOS was 63.8 days versus 25.1 for those with an index episode only. As those stays concerned only 4.9% of CDI coded as primary diagnosis, the longer LOS might have also resulted from the severity of the underlying condition, and this result should therefore not be interpreted as attributable solely to recurrence.
Costs analysis
Results Index cases and recurrences of CDI In 2011, a total of 1067 CDI-positive microbiological samples were identified in the 12 participating hospitals. They
Three different estimations were performed according to the status of the CDI as either primary or secondary diagnosis, and to the type of DRGs. According to our classification of stays, 136 stays were case 1 (CDI as primary diagnosis), 712 case 2 (CDI as secondary diagnosis), and 131 case 3 (extended LOS).
Table I Characteristics of acute-care stays and patients with Clostridium difficile index (CDI) [index and/or recurrence(s)]
No. of stays with CDI Age (years), mean (SD) Female LOS, mean (SD) CDI coded as primary diagnosis Discharge location or vital status Home Transfer Other In-hospital all-cause mortality LOS, length of stay. a Student’s t-test. b Wilcoxon rank sum test. c Chi-square test. d Fisher exact test.
Index episode only
Recurrence(s) only
Index þ recurrence(s)
Total
P
861 59.6 (23.6) 449 (52.8%) 25.1 (26.1) 122 (14.2%)
57 59.4 (22.6) 27 (47.4%) 20.1 (22.4) 11 (19.3%)
61 64.7 (21.4) 18 (29.5%) 63.8 (43.0) 3 (4.9%)
979 59.9 (23.4) 494 (51.0%) 27.2 (28.8) 136 (13.9%)
0.2562a 0.0017c <0.0001b 0.0622c
497 203 48 113
(57.7%) (23.6%) (5.6%) (13.1%)
34 14 4 5
(59.6%) (24.6%) (7.0%) (8.8%)
24 18 7 11
(40.0%) (30.0%) (11.7%) (18.0%)
555 235 59 129
(56.7%) (24.0%) (6.0%) (13.2%)
0.0249c 0.5281c 0.1478d 0.3286c
12.5% V1,191,028 2,264e23,822 DRG, diagnosis-related group; LOS, length of stay.
V9,695 (7,164) V17,075 979
V9,575 (7,514) 2,263e23,517 V9,490,503 121 (12.4%)
10.5% 12.8% 12.4% V86,567 V1,022,947 V81,514 2,366e9,878 2,264e26,798 0e6,922 V6,183 (6,557) V11,366 (8,616) V4,795 (4,979) 14 (10.3%) 90 (12.6%) 17 (13.0%) V6,056 V6,056 (4,410) 2,366e9,878 V823,656 V19,125 V11,251 (8,822) 2,324e24,145 V8,010,872 V12,444 V5,004 (4,460) 0e16,452 V655,975 136 712 131
Primary CDI diagnosis Secondary CDI diagnosis DRG not modified/LOS increased All
Total extra No. of stays Extra cost per stay 5the95th percentile Total extra cost of % of total cost (% of all stays) [mean (median)] recurrences extra cost 5the95th percentile No. of Mean cost Extra cost/stay stays per stay [mean (median)]
These results highlight the significant economic burden of CDI on hospitals in France (V163.1 million) and the fraction of direct costs attributable to recurrences (12.5%). This extrapolation of CDI cost to France is based on the assumption that our sample was representative of public hospitals at a national level and should be interpreted with caution and considered as only exploratory; our sample was probably only representative of large tertiary hospitals. Our estimate was based on matching individual bacteriological and discharge ICD-10 data which allowed us to identify the frequency of recurrences, including those within the same stay as the index episode. Our results were conservative in different respects: they did not integrate indirect costs associated with premature mortality and consequences on quality of life. Moreover, they did not cover associated direct costs incurred outside the acute-care setting. The annual incidence of CDI based on laboratory reporting was estimated to 3.74 cases per 10,000 patient-days and was in line with the incidence of 3.6 2.9 cases per 10,000 patientdays reported in a 2011 study that included 70 French healthcare facilities.3 Although this was not the objective of this study, the incidence rate is likely to be underestimated during this period in France due to a lack of clinical awareness from physicians and inappropriate testing methods as has been described recently.3 Our estimate of a 12% recurrence rate for hospital stays with CDI was lower than those reported from recent clinical trials (between 25.3% and 26.9% after vancomycin treatment) , but more in line with those published in European observational studies based on the same definition (second episode within 60
All stays with CDI (N ¼ 979)
Discussion
Hospital diagnosis status
In DRGs with CDI as primary diagnosis (case 1), the mean cost per stay was V6,056 (median: V4,410) and the cumulated cost for the whole set of stays observed in 2011 in our sample of hospitals was V823,656. The extra costs per stay due to severity level change in patients with CDI as secondary diagnosis (case 2) adjusted on age, sex, and DRG for cases without CDI were calculated for a total of 712 stays with a mean extra cost estimated at V11,251 (median: V8,822) per stay. For the 131 remaining stays (case 3), the occurrence of CDI did not affect the cost of the stay and thus did not generate an extra charge for third-party payers (public insurance), but rather an extra cost for the hospital budget. These DRGs concerned mainly palliative care stays and chemotherapy sessions. The mean extra LOS was estimated at 8.9 days corresponding to an extra cost of V5,004 (median: V4,460) per stay. The cumulated costs for the whole sample of acute-care hospital stays observed in this study are presented in Table II with the fraction of costs that might be specifically attributed to recurrences. A mean extra cost per stay with CDI of V9,575 (median: V7,514) was estimated, which totals approximately V9.5 million in 2011 for the 12 facilities included in the study sample. The fraction of that total cost attributable to recurrences was 12.5%. The extrapolated annual nationwide cost of CDI in 2011 was V163.1 million, using a ratio of 1:0.0582 based on the sampling rate of the total annual number of patient-days spent in acutecare public facilities in the whole country.
Contribution of recurrences (N ¼ 118)
A. Le Monnier et al. / Journal of Hospital Infection 91 (2015) 117e122
Table II Summary of Clostridium difficile index (CDI) cost (V) according to hospital diagnosis status and contribution of recurrences (12 acute-care hospitals, 2011)
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A. Le Monnier et al. / Journal of Hospital Infection 91 (2015) 117e122 days of the index episode): Austria 16%, Ireland 18%, The Netherlands 16%, and UK 8e11%.12e17 These discrepancies may be explained by the impossibility in our study of identifying recurrences in other non-acute-care facilities such as rehabilitation or long-term care facilities. However, a similar recurrence rate was observed by Dubberke et al. in a recent US study characterized by the same limitations.18 From an economic perspective, it is meaningful to note that recurrences (alone or following an index episode within the same stay) occurring in acute-care settings were present in 12.0% of hospital stays with CDI. In addition, we found that 9.3% (11/118) of recurrences were coded as primary diagnosis and led to a re-admission of the patients, which resulted in a prolonged hospital stay and additional medical costs. Our approach to estimating CDI hospital costs was directly dependent on the design of the French DRG system and the associated unit cost measurement. The use of DRGs incorporating severity levels made the calculation more complicated than in most other published studies which used increased LOS as a main cost driver.19,20 Recent analyses by Mitchell et al. suggested that the simple consideration of LOS without using time-dependent covariate was subjected to biases.21 In our study, this method was used only in 13% of cases and was made necessary due to the lack of relevant data. In a recent publication by Dubberke, attributable inpatient cost of recurrence over a 180-day period after an index episode was estimated at $11,631, very similar to our estimate cost, despite the differences in setting and design.18 Costs of hospital stays with CDI as principal diagnosis (case 1) were considered to be entirely borne by third-party payers assuming that the full cost estimates reflected the real burden of those stays to the hospitals. It should be noted that a substantial proportion (38.2%) of stays with bacteriological evidence of CDI had no mention of CDI in their discharge database. Therefore, corresponding costs were actually accrued by hospitals on their own budget due to the lack of reporting by physicians. Our cost analysis method was not limited to a simple budget impact on a third-party payer (the public health insurance). We did not use the DRG tariff but rather full cost estimates and we cumulated costs directly paid by a third-party payer and those incurred on hospital budgets. In this respect, our approach was comprehensive and may be qualified as a ‘societal’ perspective restricted to the acute-care setting and direct costs.22 A substantial fraction of CDI identified in our sample of hospitals was removed as it related to patients in rehabilitation and longterm care facilities. Our data did not allow us to estimate the associated cost in such facilities and therefore our results were probably conservative as they underestimate the total societal burden of CDI.23,24 Previous literature reviews in Europe or the USA have mentioned that the key outcomes used in most studies for measuring the burden of CDI in acute-care settings are relatively similar and include mortality, recurrence rate, increased LOS, and extra cost per stay.4,5 In reality, the definition and measurement of these outcomes are very diverse among studies and comparisons need to be made with caution and limited to results obtained in a comparable manner. Our data indicated that among patients with DRG without a change in severity level or those with a level 4 of severity irrespective of CDI diagnosis (case 3), the increased LOS was
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estimated at 8.9 days compared to matched controls. Because of the specificity of the French DRG system, these results are difficult to compare to previous published data since they focus on a specific subpopulation of patients (palliative care, autologous stem-cell grafting of HIV-related care). Despite the aforementioned limitations, our results for global cost were in line with those reported in a recent comprehensive review which provided median incremental hospital costs per episode in the range of US$10,156 (CDI recorded as primary diagnosis) to US$9,298 (CDI recorded as secondary diagnosis).25 In conclusion, this cost study was performed in France on a sample of large acute-care hospitals using a case-matched control approach to quantify the direct cost burden of CDI. The mean extra costs with CDI were estimated at around V9,575 per hospital stay and around V163.1 million in public acute-care hospitals at the national level. Any strategies aiming at preventing CDI or recurrences should contribute to reduce the CDI-associated costs.
Acknowledgements We thank G. Jones for careful reading of the manuscript. Funding source This work was supported by an unrestricted grant from Astellas Pharma SAS (France). Conflict of interest statement A.L.M. has received honoraria for consultancy work from Astellas and financial support to attend meetings from Astellas and Cepheid. V.C. has received honoraria for consultancy work and financial support to attend meetings from Astellas. V.F. has received financial support to attend meetings from Astellas. F.B. has received consulting or lecture fees from Astellas, Cepheid, MSD, Sanofi-Pasteur, and Summit; grants for scientific studies from Astellas, bioMe ´rieux, Cubist, Diasorin, Sanofi-Pasteur, and Roche. F.F., A.D., S.C., E.T. are employed by CEMKA-EVAL, a contact research organization that received funding from Astellas. J.R.Z., S.C., T.G., P.L.W., V.L., H.J., A.M., E.F., P.M., G.M. and all the other investigators of the GMC study group declare no conflicts of interest.
Appendix The GMC study Group includes the following investigators: O. Billuart (Paris), S. Bouam (Paris), E. Chachaty (Villejuif), M.P. Chaillet (Nantes), D. Dakova (Colombes), R. De Mil (Caen), J.-W. Decousser (Cre ´teil), C. Duteil (Paris), S. Gue ´ant (Paris), F. He ´mery (Cre ´teil), M.-E. Juvin (Nantes), B. Lemaire (Le Chesnay), A. Limelette (Reims), M. Mons (Villejuif), D. Nidegger (Reims), A. Perozziello (Paris), H. Poupet (Paris), J. ReboulMarty (Paris), C. Segouin (Paris), P. Taupin (Paris).
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