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Estimate mortality, cost, and health care resource utilization for Medicare beneficiaries aged ≥65 years who suffered a primary Clostridioides difficile infection (CDI) episode only or any recurrent CDI, and understand how outcomes covary with death.
Design
Retrospective observational claims analysis.
Setting and Participants
Patients aged ≥65 years who had an inpatient or outpatient CDI diagnosis claim to Medicare and continuous enrollment in Medicare parts A, B, and D during the 12-month pre- and post-index periods.
Methods
Using 100% Medicare Fee-for-Service claims data for 2009–2017, primary (pCDI, n = 345,893) and recurrent (rCDI: n = 151,596) CDI episodes were identified. Demographic and clinical characteristics, mortality, health care resource utilization, and costs (per patient per month) were summarized for 12 months before and up to 12 months after episode start. Regression models were estimated for hospitalization risk, hospital length of stay (LOS), and cost to adjust for comorbidities.
Results
CDI-associated deaths were almost 10 times higher after recurrent CDI (25.4%) than primary CDI (2.7%). Compared with survivors, decedents were older, had higher Charlson Comorbidity Index scores, and were more likely Black. Adjusting for comorbidities, during follow-up, decedents had higher hospitalization rates [pCDI: odds ratio (OR) = 1.83, P < .001; rCDI: OR = 2.58, P < .001], and recurrent CDI decedents had more intensive care unit use (OR = 2.34, P < .001) compared with survivors. Decedents also had a longer length of stay (pCDI: +3.2 days, P < .001; rCDI: +2.6 days, P < .001), and higher total cost (pCDI: +303%, P < .001; rCDI: +297%, P < .001).
Conclusions and Implications
CDI is an important contributing diagnosis to all-cause mortality, particularly for recurrences. Prior to death, older Medicare beneficiaries who experienced CDI received longer, more intensive, and more costly care compared with survivors. Clinicians should be particularly attentive to prevention, identification, and appropriate treatment of CDI in older adults. Better treatments to reduce primary C difficile infection and recurrences in this vulnerable population can lower both mortality and economic burden.
Clostridioides difficile infection (CDI) is recognized as the most common health care–associated infection in the United States, especially in older patients, for whom it is associated with high mortality, cost, and clinical burden.
Recurrent CDI can amplify health care resource utilization (HRU) and associated medical costs, relative to those who experience only a primary CDI (pCDI) episode, for at-risk patients.
Direct medical costs related to recurrent CDI in the United States are estimated at $2.8 billion annually, with higher per-patient costs associated with CDI-related surgery or hospitalization during the year after recurrence, as well as a higher likelihood of death, compared to patients who do not experience a recurrence.
The burden of recurrent CDI, based on population incidence, has not improved despite a nationally decreasing trend of all CDI rates between 2011 and 2017.
Older people are at increased risk for initial infection and recurrence and are twice as likely to develop complicated CDI compared with younger people.
Much of the data on CDI in general, and in older adults specifically, is somewhat limited in its scope: being derived from smaller sample groups (eg, single medical center, 5% Medicare sample data, only patients hospitalized for CDI) or covering a modest time frame of 30-90 days following a primary CDI episode.
Risk of complications and mortality following recurrent and non-recurrent Clostridioides difficile infection: a retrospective observational database study in England.
Clinical practice guidelines for Clostridium difficile infection in adults and children: 2017 update by the Infectious Diseases Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA).
Additionally, there is a dearth of data on the relative characteristics and outcomes of patients who died vs those who survived after suffering CDI.
This study provides direct estimates of the mortality, cost, and HRU for Medicare beneficiaries aged ≥65 years who suffered either a primary CDI episode only or any recurrent CDI, stratified by those who survived and died, to understand how outcomes covary with death. The analyses were adjusted to account for patient risk factors.
Methods
Study Design
We conducted a retrospective cohort study to assess HRU and cost outcomes for older adults enrolled in traditional fee-for-service (FFS) Medicare with primary CDI and recurrent CDI from 2009 through 2017. The study utilized 100% of Medicare FFS final action claims and enrollment data via a research-focused Data Use Agreement with the Centers for Medicare & Medicaid Services (CMS). This includes 100% of Medicare Part A and Part B (medical) claims and 100% of Part D (pharmacy) prescription drug events (Supplementary Material 1).
The study included Medicare beneficiaries not enrolled in a private Medicare Advantage plan between 2009 and 2017 who had simultaneous, continuous enrollment in Parts A, B, and D during the same period (see specific enrollment criteria below). The use of these data abided by Health Insurance Portability and Accountability Act (HIPAA) requirements for the privacy and security of protected health information as well as additional CMS requirements.
Patient Identification
We analyzed claims for Medicare beneficiaries aged 65 years and older with a first CDI diagnosis (index date) and continuous enrollment in Medicare Parts A, B, and D during the 12 months prior to (baseline) and up to 12 months following the index event date (follow-up), except in cases of disenrollment or death. Allowable dates for the index CDI episode were January 1, 2010, through December 31, 2016. By study design, there were no CDI-related claims during pre-index baseline. We identified an episode of CDI based on either an inpatient stay attributed to a CDI diagnosis code (primary or secondary diagnosis) or an outpatient medical claim with CDI diagnosis plus evidence of use of a CDI treatment. Inpatient settings included acute hospitals, long-term care hospitals [also known as long-term acute care hospitals (LTCHs)], and inpatient rehabilitation facilities (IRFs). Acceptable CDI treatments included vancomycin, fidaxomicin, metronidazole, rifaximin, bezlotoxumab, or fecal microbiota transplant (FMT) (Supplementary Table 1).
CDI episodes began on the date of the first CDI medical claim and included all subsequent claims with a CDI diagnosis with no more than a 14-day gap between claims (a longer gap between CDI claims ended the episode). A minimum 14-day CDI-claim-free period separated one episode from a subsequent episode (Supplementary Figure 1). A recurrent episode was one with an index date no later than 8 weeks following the end of a previous episode.
Patients who experienced only a primary CDI episode during the study period comprised the pCDI cohort, and patients with a primary episode plus 1 or more recurrent CDI episodes comprised the rCDI cohort. We defined deaths as CDI associated if the most proximal health care visit to the date of death had CDI as the primary or secondary diagnosis.
Baseline Characteristics
We extracted demographic characteristics at the date of index CDI episode: age; gender; race/ethnicity; geographic region; dual eligible status; and original reason for entitlement to Medicare. We identified clinical characteristics during the baseline period: Charlson Comorbidity Index (CCI); individual CCI conditions; select other comorbid conditions; frailty indicators; medication exposure (any use of gastric acid–suppressing agents, antimicrobials, or immunosuppressant agents) reported by National Drug Codes; and baseline medical procedures and treatments (transplants, gastrointestinal surgery, enteral feeding, chemotherapy). HRU included mean number of stays, days, visits, and average length of stay by setting. Total cost included the sum of Medicare program cost plus patient responsibility (eg, private pay, coinsurance), stratified by spending category. Utilization and total cost are reported for the 6 months immediately prior to index CDI episode (to identify potential precipitating events of CDI), and the 7-12 months preceding the index CDI episode.
Outcomes
Outcomes analyzed included mortality (overall and CDI-associated), HRU [hospital admissions and hospital length of stay; intensive care unit (ICU) stays; emergency department (ED) visits; non-ED outpatient visits; post-acute care (PAC) stays]; and total cost on a per-patient per-month (PPPM) basis for the follow-up period. Post-acute care settings are composed of skilled nursing facilities (SNFs), home health agencies (HHAs), inpatient rehabilitation facilities, long-term care hospitals, and hospices. We stratified outcomes by whether the patient suffered primary CDI only (pCDI) or recurrent CDI (rCDI), whether the patient survived or died during the study period, and whether the death was CDI associated or not.
Data Analysis
The analyses described the demographic and clinical characteristics, utilization, and total cost, as well as differences in hospitalization rates, ICU use rates, hospital length of stay, and total cost, adjusted for demographic and baseline risk factors (diagnoses, treatments, and frailty characteristics). We calculated counts and percentages of categorical factors (eg, age between 65 and 74 years, dual eligible status, and comorbid conditions), and means and SDs of continuous factors (eg, age, CCI, and total cost). Survival analysis by study cohort was performed with the Kaplan-Meier method. We adjusted costs to 2018 values using the medical care component of the Consumer Price Index.
We adjusted outcomes using logit models for hospitalization and ICU use rates and log-link gamma-distributed generalized linear models for length of stay and total cost. We reported odds ratios for rates and percentage increases for length of stay and total cost, and reported adjusted means for survivors and decedents, calculated for a balanced population.
Covariates associated with utilization and cost outcomes were examined for differences between decedents and survivors during baseline and follow-up periods. The final set of adjustors were age; gender; race; census region; Medicare-Medicaid dual eligibility; original reason for entitlement; CCI score; presence of each CCI condition in the 12 months prior to index date; presence of other chronic conditions (Crohn disease, ulcerative colitis) and frailty conditions (abnormality of gait, abnormal weight loss, failure to thrive, debility, difficulty walking, risk of falls, muscle weakness, pressure ulcer); and selected treatments and procedures that occurred during the 12-month baseline period (transplants, gastrointestinal surgery, enteral feeding, chemotherapy). All analyses were conducted with Base SAS software, version 9.4M4, and SAS/STAT software, version 14.2, of the SAS System for Linux x64.
Results
Summary of CDI Patient Mortality
Of 497,489 Medicare beneficiaries ≥65 years with CDI who were included in the study, 30.5% experienced recurrent CDI. In total, 186,996 patients with primary CDI survived (37.6% of total sample), 158,897 patients with primary CDI died (31.9% of sample), 97,738 patients with recurrent CDI survived (19.6% of sample), and 53,858 patients with recurrent CDI died during the 12-month follow-up (10.8% of sample; Table 1 and Supplementary Figure 2). Of the patients who died during the follow-up period, the CDI-associated mortality rate was 2.7% for patients who suffered primary CDI only and 25.4% for patients who suffered recurrent CDI, nearly 10 times higher than for those with primary CDI (Table 2). The survival analysis showed that most deaths occurred early during the follow-up year. By 16 weeks after the index CDI, half or more of decedents in each cohort had died (Figure 1). Non-CDI-associated deaths after primary CDI, potentially owing to an inciting illness that precipitated the index CDI, occurred the soonest. The other cohorts of decedents (CDI-associated deaths in primary CDI, CDI-associated deaths in recurrent CDI, and non–CDI-associated deaths in recurrent CDI) had similar patterns of early mortality during the follow-up year, though less pronounced.
Table 1Selected Baseline Characteristics for Patients With Primary or Recurrent
Supplementary Table 5 provides an analogous table for pCDI-only and rCDI patient decedents, stratifying by whether death can be associated with CDI. Supplementary Tables 6–10 provide details on additional baseline characteristics.
0-6-month baseline per-patient per-month (PPPM) cost computed as the cost (Medicare program payments plus beneficiary responsibility) for each service setting for the 6-month period immediately prior to the index CDI event, divided by 6 months.
, $
Total
6702
10,502
8204
11,717
Acute hospitalization
2171
3599
2690
3979
ED
173
156
180
165
Outpatient (excluding ED)
555
744
691
890
Long-term care hospital
377
846
331
775
Inpatient rehabilitation facility
222
207
214
248
Skilled nursing facility
750
1450
992
1638
Home health agency
190
258
191
263
Hospice
14
36
10
25
Physician services and tests
1607
2491
1860
2669
DME
176
225
523
533
Pharmacy
468
490
523
533
DME, durable medical equipment; ED, emergency department.
∗ Any recurrent CDI during follow-up period of 12 months.
‡ “Other” races (not White or Black) included Asian, Hispanic, North American Native, and Other.
§ Top 5 conditions are the 5 individual CCI conditions most prevalent among all CDI patients.
‖ 0-6-month baseline per-patient per-month (PPPM) cost computed as the cost (Medicare program payments plus beneficiary responsibility) for each service setting for the 6-month period immediately prior to the index CDI event, divided by 6 months.
For in-hospital deaths, based on the primary and secondary diagnosis fields documented on the hospital discharge claim. For other deaths, based on the primary and secondary diagnoses from the most proximal visit to the date of death.
Ratio of the number of decedents in the row to the sum of the number of primary and all recurrent CDI decedents.
, %
Primary Only (n = 345,893)
186,996
158,897
45.9
2.7
74.7
Recurrent (n = 151,596)
All
97,738
53,858
35.5
25.4
25.3
First
40,277
27,806
40.8
16.4
13.1
Second
24,033
12,713
34.6
30.9
6.0
All subsequent
33,428
13,339
28.5
39.0
6.3
∗ Ratio of the number of decedents to sum of survivors plus decedents in each row.
† For in-hospital deaths, based on the primary and secondary diagnosis fields documented on the hospital discharge claim. For other deaths, based on the primary and secondary diagnoses from the most proximal visit to the date of death.
‡ Ratio of the number of decedents in the row to the sum of the number of primary and all recurrent CDI decedents.
Fig. 1Survival analysis during 12-month follow-up, by study cohort. By week 16, half or more of the decedents in each cohort had died. CDI cohorts: primary CDI only (pCDI); recurrent CDI (rCDI): patients with ≥1 recurrence during a follow-up period of up to 12 months. Kaplan-Meier survival curves estimated with SAS/STAT version 14.2 PROC LIFETEST.
Of those who suffered rCDI and died during follow-up, CDI-associated mortality rates increased with number of recurrences: 16.4% CDI-associated mortality for those with 1 rCDI episode, 30.9% for those with 2 rCDI episodes, and 39.0% for those with 3+ rCDI episodes. Sepsis and acute respiratory failure were the 2 most frequent non-CDI causes of death for patients with either primary or recurrent CDI (Supplementary Tables 2 and 3). The average follow-up time from index episode to death was 63 days for patients with primary CDI and 77 days for those with recurrent CDI (Supplementary Table 4).
Baseline Patient Characteristics
Certain baseline characteristics were different between decedents and survivors regardless of whether they were in the primary or recurrent CDI cohort (Table 1 and Supplementary Tables 5 and 6). Decedents were more likely to be aged ≥85 years (P < .001) relative to survivors. Survivors were an average of 78 years, with decedents 3.1 years older on average in the primary CDI cohort and 2.4 years older on average in the recurrent cohort (P < .001). Decedents were more often dual eligible than survivors (40.6%-44.5% vs 32.9%-35.4%; P < .001).
Decedents, on average, had a higher burden of comorbid conditions than survivors at baseline. Decedents' CCI scores were higher than survivors' scores, and decedents were more likely to have the 5 most common CCI conditions: congestive heart failure, chronic obstructive pulmonary disease, diabetes without complications, peripheral vascular disease, and renal disease (all P < .001 relative to survivors).
Decedents had greater utilization of acute hospitalizations and post-acute care stays vs survivors during the baseline period 0-6 months before the index CDI episode (P < .001) (Supplementary Table 7). Decedents' acute hospital length of stay in 0-6 months baseline was also longer by about 1 day (8.1 vs 7.0-7.1, P < .001). Decedents had higher total medical costs than survivors during 0-6 months baseline ($63,014-$70,304 vs $40,210-$49,223, P < .001), including higher costs for acute hospitalizations, nonemergency hospital outpatient, long-term care hospitals, skilled nursing facilities, and physician services (all P < .001; Supplementary Table 8). Baseline utilization and costs for the 7-12-month preindex period are provided in Supplementary Tables 9 and 10, respectively.
Unadjusted Outcomes
In contrast to baseline HRU and costs, there were few quantitative differences in unadjusted outcomes between primary CDI and recurrent CDI cohorts when examining decedent and survivor data. For both primary and recurrent CDI cohorts, total costs were about 4.5 times higher among decedents compared with survivors (P < .001). We separated acute hospital costs into those associated with the index hospital stay vs those associated with 30-day readmissions (Figure 2, Supplementary Figure 3, and Supplementary Table 11). Decedents had much higher inpatient costs (pCDI: 23 times higher; rCDI: 8 times higher; P < .001) and 30-day readmission costs (pCDI and rCDI: nearly 5.5 times higher; P < .001) than survivors. In addition, decedents had 2-3 times higher total costs for nonemergency outpatient care, and 2.6-4.5 times higher post-acute care costs than survivors. Decedents' greater post-acute care costs were driven by skilled nursing facility and long-term care hospital stays (all P < .001). Emergency department, home health agency, and physician office visit costs were similar among decedents and survivors.
Fig. 2Follow-up per-patient per-month cost of care for patients with primary or recurrent∗ CDI† by survival outcome and relatedness of mortality. Top: For both primary and recurrent CDI cohorts, decedents had higher follow-up costs than survivors, with inpatient costs and post-acute care constituting the largest portions of costs. Bottom: For those who died during the follow-up period, overall costs for deaths not associated with Clostridioides difficile infection (CDI) were higher than those for CDI-associated deaths. For reference, the average annual Medicare cost per beneficiary in 2020 was $15,673, which corresponds to a monthly cost of $1306.
2021 annual report of the boards of trustees of the federal hospital insurance and federal supplementary medical insurance trust funds. Accessed August 31, 2021.
CDI cohorts: primary CDI only (pCDI); recurrent CDI (rCDI): patients with ≥1 recurrence during a follow-up period of up to 12 months. Total per-patient per-month (PPPM) costs across all settings noted at the top of each column. Settings with PPPM cost >$2000 are shown in each individual stacked bar. Acute 30-day readmissions are to an acute hospital within 30 days of the prior hospitalization. Supplementary Table 11 provides details on additional follow-up costs. DME, durable medical equipment.
Decedents' health care utilization exceeded survivors' during the 12-month follow-up period, with at least double the odds for ≥1 acute hospital or long-term care hospital stay, and higher odds of ICU use or having a 30-day readmission (all P < .001). However, decedents were half as likely to have an ED visit or home health agency visit, and much less likely to use nonemergency outpatient services (all P < .001). Unsurprisingly, decedents' use of hospice was greater than survivors' (P < .001) (Supplementary Table 12).
The length of stay at a skilled nursing facility was 40% shorter for decedents than survivors in both primary and recurrent CDI cohorts (P < .001). However, decedents' acute hospital stays tended to be longer than survivors by 3.0-3.7 days for primary and recurrent CDI cohorts (P < .001). This is consistent with decedents dying more often in a post-acute care setting (long-term care hospital or skilled nursing facility), or even before admission to these settings.
Adjusted Outcome Differences Between Survivors and Decedents
Adjusted outcomes were calculated for hospitalization rates, ICU rates, acute hospital length of stay, and total cost (covariates are listed in the Methods section) (Table 3). During the 12-month follow-up period, decedents' adjusted difference in hospitalizations was 4.3% greater for primary CDI patients and 3.6% greater for recurrent CDI patients than survivors (both P < .001). The adjusted ICU rate difference was 20.6% higher for recurrent CDI patients who died (P < .001). Decedents' acute inpatient length of stay was longer than survivors for both primary CDI (38.3%) and recurrent CDI (32.6%; both P < .001), and total cost was 3 times higher for primary CDI and recurrent CDI (both P < .001).
Outcomes for decedents vs survivors were adjusted for age; sex; race; census region; Medicare-Medicaid dual eligibility; original reason for Medicare entitlement; CCI; presence of each CCI condition in the 12 months prior to index date; presence of other conditions (Crohn disease, ulcerative colitis) and frailty (abnormality of gait, abnormal weight loss, failure to thrive, debility, difficulty walking, risk of falls, muscle weakness, pressure ulcer); and selected conditions in prior 12 months (transplants, gastrointestinal surgery, enteral feeding, chemotherapy). Inpatient hospitalizations and ICU stay were adjusted with logit model; ALOS and total cost were adjusted with gamma-distributed generalized linear model with log link. Outcome adjustments were made using SAS/STAT LSMEANS. Supplementary Tables 6–10 provide details on additional baseline characteristics.
Adjusted mean calculated at mean of covariates other than whether survivor or decedent.
Adjusted Mean, Decedents
pCDI
Acute hospitalization, %
86.1
93.6
1.83
1.78, 1.88
89.9
94.2
pCDI
ICU stay, %
21.3
22.5
0.94
0.92, 0.96
23.1
22.0
pCDI
ALOS, d
7.6
11.3
+38.3%
+37.6%, +39.1%
8.2
11.4
pCDI
Total cost
Total cost (sum of Medicare program payments plus patient responsibility) inflation-adjusted to 2018.
, $ PPPM
6348
29,150
+303%
+300%, +305%
7520
30,279
rCDI
Acute hospitalization, %
88.6
96.6
2.58
2.45, 2.72
94.0
97.6
rCDI
ICU stay, %
29.8
53.2
2.34
2.29, 2.40
34.1
54.7
rCDI
ALOS, d
7.6
10.6
+32.6%
+31.7%, +33.5%
7.9
10.5
rCDI
Total cost, $ PPPM
7959
35,767
+297%
+294%, +301%
9256
36,766
ALOS, average length of stay; CCI, Charlson Comorbidity Index; ICU, intensive care unit; OR, odds ratio; PPPM, per patient per month.
∗ Outcomes for decedents vs survivors were adjusted for age; sex; race; census region; Medicare-Medicaid dual eligibility; original reason for Medicare entitlement; CCI; presence of each CCI condition in the 12 months prior to index date; presence of other conditions (Crohn disease, ulcerative colitis) and frailty (abnormality of gait, abnormal weight loss, failure to thrive, debility, difficulty walking, risk of falls, muscle weakness, pressure ulcer); and selected conditions in prior 12 months (transplants, gastrointestinal surgery, enteral feeding, chemotherapy). Inpatient hospitalizations and ICU stay were adjusted with logit model; ALOS and total cost were adjusted with gamma-distributed generalized linear model with log link. Outcome adjustments were made using SAS/STAT LSMEANS. Supplementary Table 10, Supplementary Table 6, Supplementary Table 7, Supplementary Table 8, Supplementary Table 9 provide details on additional baseline characteristics.
† CDI cohorts: pCDI: patients with primary CDI only; rCDI: patients with recurrent CDI during a follow-up period of up to 12 months.
CDI is associated with relatively high mortality among Medicare beneficiaries aged ≥65 years, between 35% and 45% within 1 year of a first CDI episode.
Centers for Disease Control and PreventionNational Center for Health Statistics Underlying cause of death 1999-2019 on CDC WONDER Online Database, released in 2020. Data are from the multiple cause of death files, 1999-2019, as compiled from data provided by the 57 vital statistics jurisdictions through the Vital Statistics Cooperative Program. Accessed August 31, 2021.
and our study showing that each recurrence brings additional CDI-attributable mortality risk, we now have a better understanding of the concerning associated risks of recurrent disease in older adults. Here, the CDI-associated mortality rate increased substantially from 2.7% for patients who had only a primary CDI episode, to 25% for patients who had 1 or more recurrences, providing yet another reason to be particularly attentive to prevention, identification, and appropriate (rather than overly conservative) treatment, to break the vicious cycle of recurrent CDI and its burden on the health care system and patients' lives. Our study interestingly also shows that, of those who died following CDI, most of the deaths occurred after primary CDI within a few weeks of CDI diagnosis, with few deaths in the primary CDI cohort that were associated with CDI itself (eg, 2.7%). This implies that those decedents with only a primary CDI episode were likely severely ill with another disease and CDI was a complication of that; their deaths may have been due to factors that increased the risk of both death and CDI. Therefore, clinicians should consider CDI as a potential indicator of short-term mortality risk and consider care goals appropriately. The background mortality rates of this older population may have partially obscured the mortality trends over the follow-up period. Future research with more precise cause of death data could elicit further insights.
CDI is also costly in older adults, especially if it occurs during the last year of life. On average, Medicare spends about $1300 per month, per beneficiary across the entire Medicare population.
2021 annual report of the boards of trustees of the federal hospital insurance and federal supplementary medical insurance trust funds. Accessed August 31, 2021.
In the last 3 months of life, the average per-patient per-month cost of care in the national Medicare population increases to approximately $10,400 per Medicare beneficiary, based on 2016 costs.
Here, we documented average per-patient per-month costs of $29,000 to almost $36,000 for patients who experienced primary CDI only or recurrent CDI, respectively, who had an average of 2.5 months of follow-up after the first CDI event.
This study was designed to estimate the real-world differences in HRU and total cost outcomes in older Medicare beneficiaries, between decedents and survivors of primary and recurrent CDI. This approach has not been a previous focus of the literature. Our study extends existing research by measuring how mortality may modulate these outcomes following a CDI episode, vs analyzing mortality separately from other outcomes, as is more common in the literature.
It also includes patients with community-acquired CDI, which has been less studied in the literature that often solely focuses on hospital-acquired infections.
In general, older patients are more at risk for CDI; therefore, the 100% Medicare sample is a particularly useful population in which to understand the broader impact of CDI in older adults.
The demographics and baseline characteristics of our CDI cohorts are broadly similar to those found in other studies of patients who suffer CDI,
including being more likely to be female, and more likely to be dual eligible for Medicaid (indicating low income) compared to all older Medicare FFS beneficiaries. Compared with other studies that often look at the general adult population (≥18 years) who suffer CDI and to the national Medicare population, our Medicare population had more chronic conditions, including congestive heart failure, chronic obstructive pulmonary disease, diabetes, peripheral vascular disease, and renal disease.
The risk factors we identified that were associated with a greater risk of mortality from CDI (eg, age, comorbid conditions, and recent post-acute care) were consistent with other studies,
and those factors were similar for both primary and recurrent CDI cohorts. These risk factors, importantly, have also been shown to increase the risk of primary and recurrent CDI.
Risk factors for primary Clostridium difficile infection; results from the observational study of risk factors for Clostridium difficile infection in hospitalized patients with infective diarrhea (ORCHID).
Therefore, the cycle of recurrence, potentially ending in death, feeds on itself with the same risk factors. It is essential for clinicians to understand these risk factors, modify those they can, and aggressively try to break the cycle of recurrence with therapeutics available to them, including emerging therapies such as bezlotoxumab and fecal microbiota transplantation.
All decedents (primary and recurrent cohorts) had greater rates of hospitalization after the index CDI episode than survivors, likely indicating that they suffered from more severe CDI. ICU use and readmissions were also more common among recurrent CDI decedents than survivors; however, this was not the case for patients with primary CDI, for which the utilization of decedents and survivors were similar. Although this may be due in part to the shorter follow-up period (because of higher all-cause mortality) for primary vs recurrent CDI, the higher readmission rate among decedents vs survivors with recurrent CDI suggests that recurrence increases the risk of having a severe or fulminant case, further increasing mortality and HRU.
Survivors' greater use of outpatient facilities, EDs, and home health is likely due to decedents having shorter follow-up time to use these services. A similar reason may underlie why decedents with recurrent CDI had increased use of skilled nursing facilities compared to decedents with primary CDI only. Using a skilled nursing facility may indicate worse health status or may confer an increased risk of health care–acquired infection, and the relatively short follow-up for decedents with primary CDI only makes them less likely to survive to the point of being admitted to a skilled nursing facility (eg, if they expire in an acute setting). Coinciding with greater HRU, the costs for acute hospital and post-acute care stays were substantially higher for decedents than survivors. These were largely driven by differences in acute hospital costs, but among patients with recurrent CDI, costs for post-acute care and outpatient services also contributed to the difference. These data continue to support the idea that those who died did not have the opportunity to utilize certain services during follow-up, but they were acutely sicker and required acute expensive interventions in the efforts to keep them alive.
The strengths of this study include the large sample (all Medicare FFS beneficiaries aged ≥65 years with CDI during the study period) as well as the longitudinal nature of these claims data that capture utilization and costs across a variety of health care settings. However, features of the Medicare claims data may limit the generalizability of results. Because the study focuses on older Medicare FFS beneficiaries, excluding those in private Medicare health plans, younger patients, or those covered by other insurance such as commercial, Medicaid only, or Veterans Affairs, the results may not be representative of those populations. However, these results are consistent with studies of CDI mortality in Veterans Affairs facilities.
Medicare claims indicate costs that are the patient's responsibility but not who ultimately pays those charges, which could be paid by the patient out of pocket or covered by Medicare supplemental insurance. Furthermore, long-term care in a skilled nursing facility is not covered by Medicare; we lose insight into costs beyond 100 days, the length covered by Medicare. This study can only identify associations in cost and utilization differences between survivors and decedents, not specific causal relationships; however, the adjusted outcomes do account for many clinical and social confounders. Future studies could be conducted to explore longitudinal patterns of CDI episodes and long-term health outcomes in the Medicare population.
Conclusions and Implications
This study found that CDI-related mortality rates among older Medicare beneficiaries were almost 10 times higher for patients who experienced recurrent CDI relative to patients who experienced primary CDI only. Each recurrence brought additional risk for death attributable to CDI. Along with high mortality, CDI is associated with high cost and health care utilization near the end of life. We believe that advances in therapeutic options to reduce recurrent CDI can potentially ease the economic, physical, and mortality burden among the frail older population.
Supplementary Data
Supplementary Table 1Clinical Codes to Identify CDI-related Claims
For in-hospital deaths, based on the primary and secondary diagnosis fields documented on the hospital discharge claim. For other deaths, based on the primary and secondary diagnoses from the most proximal visit to the date of death.
(excluding CDI-Related Diagnoses), Primary CDI
Diagnosis Rank
ICD-10-CM
Description
Number of Episodes
Percentage of Episodes
Total
154,580
100
1
A419
Sepsis, unspecified organism
31,229
20.2
2
J9600
Acute respiratory failure, unspecified whether with hypoxia or hypercapnia
Acute and chronic respiratory failure, unspecified whether with hypoxia or hypercapnia
4144
2.7
14
I10
Essential (primary) hypertension
3750
2.4
15
G309
Alzheimer's disease, unspecified
3624
2.3
16
F0390
Unspecified dementia without behavioral disturbance
3361
2.2
17
N390
Urinary tract infection, site not specified
3292
2.1
18
C3490
Malignant neoplasm of unspecified part of unspecified bronchus or lung
3112
2.0
19
R627
Adult failure to thrive
3047
2.0
20
I4891
Unspecified atrial fibrillation
2738
1.8
CDI, Clostridioides difficile infection; ICD-10-CM, International Classification of Diseases, Tenth Revision, Clinical Modifications.
∗ For in-hospital deaths, based on the primary and secondary diagnosis fields documented on the hospital discharge claim. For other deaths, based on the primary and secondary diagnoses from the most proximal visit to the date of death.
For in-hospital deaths, based on the primary and secondary diagnosis fields documented on the hospital discharge claim. For other deaths, based on the primary and secondary diagnoses from the most proximal visit to the date of death.
(excluding CDI-Related Diagnoses), Recurrent CDI
Diagnosis Rank
ICD-10-CM
Description
Number of Episodes
Percentage of Episodes
Total
40,169
100
1
A419
Sepsis, unspecified organism
7402
18.4
2
J9600
Acute respiratory failure, unspecified whether with hypoxia or hypercapnia
Acute and chronic respiratory failure, unspecified whether with hypoxia or hypercapnia
1343
3.3
11
R5381
Other malaise
1220
3.0
12
N179
Acute kidney failure, unspecified
1053
2.6
13
I10
Essential (primary) hypertension
971
2.4
14
G309
Alzheimer's disease, unspecified
953
2.4
15
Z5189
Encounter for other specified aftercare
948
2.4
16
N390
Urinary tract infection, site not specified
881
2.2
17
F0390
Unspecified dementia without behavioral disturbance
872
2.2
18
I4891
Unspecified atrial fibrillation
818
2.0
19
R627
Adult failure to thrive
811
2.0
20
I2510
Atherosclerotic heart disease of native coronary artery without angina pectoris
720
1.8
CDI, Clostridioides difficile infection; ICD-10-CM, International Classification of Diseases, Tenth Revision, Clinical Modifications.
∗ For in-hospital deaths, based on the primary and secondary diagnosis fields documented on the hospital discharge claim. For other deaths, based on the primary and secondary diagnoses from the most proximal visit to the date of death.
0-6-month baseline per-patient per-month (PPPM) cost computed as the cost (Medicare program payments plus beneficiary responsibility) for each service setting for the 6-month period immediately prior to the index CDI event, divided by 6 months.
($)
Total
8889
10,547
9548
12,110
Acute hospitalization
2937
3618
3293
4212
Emergency department
183
155
178
160
Outpatient
791
743
817
915
Long-term care hospital
336
861
306
935
Inpatient rehabilitation facility
259
205
261
243
Skilled nursing facility
1191
1457
1413
1714
Home health agency
285
257
284
256
Hospice
21
36
17
28
Physician services and tests
2097
2502
2222
2822
DME
242
225
242
285
Pharmacy
548
489
515
539
CCI, Charlson Comorbidity Index; CDI, Clostridioides difficile infection; DME, durable medical equipment; HRU, health care resource utilization.
∗ Any recurrent CDI during a follow-up period of 12 months.
† Deaths are considered CDI-associated if the most proximal health care visit to date of death was with CDI as the primary or secondary diagnosis.
§ Top 5 conditions are the 5 individual CCI conditions most prevalent among all CDI patients.
‖ 0-6-month baseline per-patient per-month (PPPM) cost computed as the cost (Medicare program payments plus beneficiary responsibility) for each service setting for the 6-month period immediately prior to the index CDI event, divided by 6 months.
Supplementary Fig. 3Follow-up PPPM cost of care for patients with primary or recurrent CDI by survival outcome and relatedness of mortality, with detailed post-acute care setting costs. CDI cohorts: pCDI: patients with primary CDI only; rCDI: patients with recurrent CDI during a follow-up period of up to 12 months. Total per-patient per-month (PPPM) costs across all settings are noted at the top of each column. Settings with PPPM cost >$2000 are shown in each individual stacked bar. Acute 30-day readmissions are to an acute hospital within 30 days of the prior hospitalization. Supplementary Table 11 provides details on additional follow-up costs. DME, durable medical equipment.
Description of Data Use Agreement With the Centers for Medicare & Medicaid Services (CMS)
Avalere accessed 100% of Medicare fee-for-service (FFS) final action claims via a research-focused Data Use Agreement with CMS. This includes 100% of Medicare Part A and Part B Medicare FFS claims data and 100% of Part D event data for all Part D plans (including Medicare Advantage Part D plans). Specifically, these data were extracted from the Chronic Condition Warehouse Standard Analytic Files, Medicare Beneficiary Summary File Base, and PDE File data administered by the Centers for Medicare & Medicaid Services (CMS) and its contractors. The medical claims data files for each year are created 6 months after the end of the respective calendar year and are final action claims (adjustment claims are rolled up into a single claim, and payment information is final as of the creation date). The Part D event file contains final action events that include posttransaction adjustments that occur between plans and pharmacy, between plan (for misenrollees), and between plans and CMS.
Claims data contain medical service and final payment information from bills submitted to and reimbursed by Medicare from institutional and professional providers for services covered by Medicare Parts A and B. PDE data include prescription and final payment information from Part D transactions. Enrollment data contain demographic and enrollment information, including age, sex, dual-eligible status for Medicaid, original reason for Medicare entitlement (age or disability/end-stage renal disease), and race or ethnicity for all Medicare FFS beneficiaries.
The use of these data abided by the Health Insurance Portability and Accountability Act (HIPAA) requirements for the privacy and security of protected health information as well as additional CMS requirements.
Avalere Health accessed these data through their parent company, Inovalon, which has been designated by CMS as an organization approved through the Qualified Entity Certification Program (QECP). Research with this data source is allowed under a HIPAA-compliant, research-focused data use agreement. Information about the QECP and the Medicare RIF data can be found at https://resdac.org/research-identifiable-files-rif-requests.
References
Ma G.K.
Brensinger C.M.
Wu Q.
Lewis J.D.
Increasing incidence of multiply recurrent Clostridium difficile infection in the United States.
Risk of complications and mortality following recurrent and non-recurrent Clostridioides difficile infection: a retrospective observational database study in England.
Clinical practice guidelines for Clostridium difficile infection in adults and children: 2017 update by the Infectious Diseases Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA).
Underlying cause of death 1999-2019 on CDC WONDER Online Database, released in 2020. Data are from the multiple cause of death files, 1999-2019, as compiled from data provided by the 57 vital statistics jurisdictions through the Vital Statistics Cooperative Program. Accessed August 31, 2021.
2021 annual report of the boards of trustees of the federal hospital insurance and federal supplementary medical insurance trust funds. Accessed August 31, 2021.
Risk factors for primary Clostridium difficile infection; results from the observational study of risk factors for Clostridium difficile infection in hospitalized patients with infective diarrhea (ORCHID).
Funding Source: Funding for this study was provided by Ferring Pharmaceuticals Inc.
Previous Presentation: Portions of this work were presented at the Academy of Managed Care Pharmacy (AMCP), Virtual, April 13-14, 2021.
Conflicts of interest: I.M., E.M.D., and C.T. are employees of Avalere Health. J.D. and A.W. were employees of Avalere Health at the time of the research and manuscript development. W.W.N. was an employee of Ferring Pharmaceuticals Inc at the time of the research and manuscript development. D.D. is an employee of Ferring Pharmaceuticals Inc. P.F. has served on the speaker's bureau for Merck and Co, has served as a consultant for Ferring Pharmaceuticals Inc, SERES Therapeutics, and Roche Pharmaceuticals. A.A. reported serving as principal investigator or coinvestigator of clinical trials sponsored by National Institutes of Health and National Institute of Allergy and Infectious Diseases, NeuroRx Pharma, Pulmotect, Blade Therapeutics, Novartis, Takeda, Humanigen, Eli Lilly, PTC Therapeutics, Octapharma, Fulcrum Therapeutics, and Alexion, unrelated to the present study. He has served as speaker and/or consultant for BMS, Pfizer, BI, Portola, Sunovion, Mylan, Salix, Alexion, AstraZeneca, Novartis, Nabriva, Paratek, Bayer, Tetraphase, Achogen LaJolla, Millennium, Ferring, Seres, PeraHealth, HeartRite, Aseptiscope, and Sprightly.
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