Outcomes among inpatients with cirrhosis and Clostridioides difficile infection in the modern era: results from an analysis of the National Inpatient Sample

Introduction

The United States (US) burden of Clostridioides difficile infection (CDI) is estimated at 500,000 cases annually with 15,000-30,000 US deaths, and associated acute care inpatient costs alone exceeding $4.8 billion [1,2]. Primary and secondary infections have been implicated as major causes of morbidity and mortality among patients with cirrhosis [1,2]. Patients with cirrhosis are uniquely predisposed to develop CDI, given their frequent hospitalizations, acquired immune dysfunction, and alterations of gut microbiota with advancing disease [3-7].

Older studies of a national registry have demonstrated that CDI has been associated with significantly higher rates of mortality, longer lengths of stay (LOS) and greater hospital charges in hospitalized patients with cirrhosis [7,8]. While CDI has become increasingly prevalent in patients with cirrhosis over the last 2 decades, prior studies have observed that the inpatient mortality has significantly decreased over the same time period [7,8]. This is probably related to increasing awareness of CDI, efforts toward prevention and infection control, as well as advancements in treatment options over time [1,2]. Despite this, CDI continues to be associated with higher healthcare utilization among hospitalized cirrhosis patients. Healthcare costs and LOS have been so significant that a modelling study by Saab et al proposed screening of asymptomatic hospitalized cirrhotics for CDI [4,8]. We performed an analysis of the most current data available from the National Inpatient Sample (NIS) 2016-2017 to investigate clinical outcomes and healthcare utilization in hospitalized cirrhotic patients with CDI and to look for changes from outcomes reported in older studies.

Materials and methods

Study population

We used the newest ICD-10-CM codes to identify the following: (A) patients with a primary diagnosis of CDI; and (B) patients with a secondary diagnosis of cirrhosis. Patients were excluded if they were <18 years old. The ICD-10-CM diagnostic and procedural codes used in this study are presented in Supplementary Table 1. Fig. 1 shows the inclusion and exclusion criteria in a flow diagram. This study was deemed exempt from approval by the institutional review board of the University of Toledo and University of Utah, as it was performed using de-identified and publicly available data.

Figure 1 Flow diagram showing patient selection process

CDI, Clostridioides difficile infection

Results

Patient and hospital characteristics

We identified 202,830 patients admitted with a primary diagnosis of CDI in 2016 and 2017. We excluded 5885 patients under the age of 18 years. A total of 196,945 adult patients with CDI were included in the final analysis. Mean age was 65.95 years, and most patients were female (64.64%). Medicare was the primary payer (66.54%), followed by private insurance (19.87%). The majority of patients were white (77.8%). Patients were predominantly admitted to teaching hospitals (60.55%). A total of 8245 (4.18%) patients had a concurrent diagnosis of cirrhosis, of whom 1.79% had portal hypertensions. Diagnostics codes including “esophageal varices,” “variceal bleed,” “ascites,” and “portal hypertension” were used as surrogates for portal hypertension. Patients with portal hypertension had higher mortality compared to patients without portal hypertension (2.97% vs. 1.31%, P<0.001). The complete patient and hospital characteristics are presented in Tables 1 and 2. The in-hospital outcomes of patients with CDI are shown in Table 3.

Table 1 Characteristics of patients admitted to hospital with Clostridioides difficile infection

Table 2 Characteristics of patients admitted to hospital with Clostridioides difficile infection: cirrhosis vs. no-cirrhosis

Table 3 In-hospital outcomes of patients admitted with Clostridioides difficile infection: cirrhosis vs. no-cirrhosis

Discussion

This study examined outcomes associated with hospitalizations of patients with cirrhosis and CDI, including LOS, all-cause in-hospital mortality and hospital charges, utilizing the de-identified NIS 2016-2017. As in the NIS analysis performed by Bajaj et al a decade ago, patients with cirrhosis and CDI were younger than those without cirrhosis (61.76 vs. 66.12, P<0.001) and continued to exhibit greater healthcare utilization with a longer LOS and higher hospital charges [7]. Older data from the NIS database were further investigated by Rosenblatt et al and corroborated that CDI in hospitalized patients with cirrhosis was associated with a significantly longer hospital stay (13.7 vs. 6.9 days, P<0.001) [8]. Of key importance, the overall mean LOS in patients with cirrhosis and CDI has declined from an average of 14.4 days, as noted in prior studies, to 5.4 days, possibly as a result of greater awareness of CDI, as well as new and more effective CDI treatments and improved care of advanced liver disease [8].

Patients with cirrhosis and CDI continued to have higher hospital charges compared to patients without cirrhosis [7,8]. Higher hospital charges are presumably related to the greater LOS among patients with cirrhosis and CDI. However, additional diagnostic testing and treatment cannot be excluded, since the difference in LOS compared to non-cirrhotic patients with CDI showed only slight statistical significance. Rosenblatt et al observed that CDI increased total charges by 20.0% (95%CI 18.0-21.0%; P<0.001) and, aside from LOS, was also the most powerful factor in predicting total charges [8]. Similar patterns have been observed with other infections occurring among cirrhotic patients: a population-based study performed by Zou et al in 2018 observed higher adjusted hospital charge among patients with cirrhosis and acute respiratory infection (ARI) compared to patients with cirrhosis but without ARI ($122,555 vs. $79,685 per patient per admission; P<0.001) [11].

In a study by Rosenblatt et al, which analyzed the NIS database from 1998-2014, CDI prevalence in advanced cirrhotics increased from 0.8% to 2.6%, an annual percent change (APC) of 8.8% (compared to 7.6% for the general population), while CDI-related mortality decreased from 20.7% to 11.3%, APC -3.4% (compared to -2.0% for the general population), from 1998-2014 [8]. An investigation of the NIS in 2015 observed that patients with cirrhosis and CDI had an in-hospital mortality rate of 13.8%, significantly greater than that of inpatients with cirrhosis alone (8.2%; P<0.001) or CDI alone (9.6%; P<0.001) [7]. Based on our new data, there appears to be no significant difference in all-cause in-hospital mortality between patients with cirrhosis and those without cirrhosis; this represents a significant change in recent years and is a key finding of our study. There was also no difference between the groups in the likelihood of sepsis, shock, ICU admission or home discharge. This may be reflective of increased vigilance, prevention and treatment over time, as rates of CDI have plateaued in the US since about 2010 [1,2].

Organ failure significantly impacts survival in patients with cirrhosis who are hospitalized with infection [3,7,8]. Sepsis can be a precipitating factor in acute-on-chronic liver failure, which can lead to rapidly worsening liver function in patients with cirrhosis [12]. Cirrhotics with healthcare-acquired infections have more severe liver disease, hypothesized to be secondary to an excessive imbalance in their cytokine response, leading to sepsis-related organ failures [12,13]. In our investigation, 1.79% of patients were identified as having portal hypertension and had higher mortality compared to patients without portal hypertension (2.97% vs. 1.31%, P<0.01). Diagnostic codes for cirrhosis and associated complications, except for ascites, have been found to have relatively high positive predictive value and accuracy within a single healthcare system. However, ICD codes for cirrhosis alone may be insufficiently sensitive, and should probably be combined with ICD codes for cirrhosis complications to better identify patients [14]. Further stratification of liver disease by model for end-stage liver disease and Child-Pugh scores was limited by the lack of laboratory data.

AKI is an independent prognostic risk factor for mortality among patients with CDI and without cirrhosis [8,15,16]. Prior studies have observed that CDI was more commonly associated with concurrent AKI (35.1%) compared to urinary tract infections, pneumonia, spontaneous bacterial peritonitis, and cellulitis in hospitalized patients with cirrhosis. While spontaneous bacterial peritonitis has a strong association with both AKI and hepatorenal syndrome, CDI significantly increased the risk of both of these conditions [3,7,8]. Our study observed that while 24.31% of patients with cirrhosis and 23.29% of patients without cirrhosis had AKI, patients with cirrhosis were less likely to develop AKI than patients without cirrhosis, another key finding of this study. This could potentially be related to the earlier recognition of AKI and hence earlier intervention in patients with cirrhosis.

While using a de-identified population database such as NIS permits the study of clinical outcomes and associations across a spectrum of the nation’s healthcare systems, it has inherent limitations. The NIS does not identify hospital-acquired vs. community-acquired CDI or distinguish recurrent hospitalizations, which are relevant risk factors in the transmission of infections. Inpatient observation and medical care received across multiple healthcare settings may be underrepresented [17,18]. Lack of granular data points precluded the assessment of severity of CDI, disease recurrence, methods of testing, timing of diagnosis, and treatment. Complications including sepsis, shock, and death are presumably related to CDI, since it has been analyzed as a primary diagnosis. However, limitations of the database preclude discriminating between direct consequence vs. sequelae of critical illness or other process. Inability to review medication lists also precludes identification of potential associated protective and risk factors, implemented treatments and changes in therapy.

While the mortality associated with CDI has declined over time, its ongoing prevalence remains impactful on healthcare utilization, including longer LOS and greater hospital costs. Interestingly, Saab et al found that screening and treating for CDI among asymptomatic inpatients with cirrhosis was cost-saving, and was associated with lower mortality compared to those who did not undergo screening [4]. Contrary to published guidelines, screening asymptomatic hospitalized cirrhotics may allow the early detection and treatment of CDI [2,19]. Similar screening paradigms have been used for methicillin-resistant Staphylococcus aureus infections, and for patients with inflammatory bowel disease who present with a flare [19]. Future studies are also needed to investigate the complex microbiota in patients with cirrhosis and the impact of therapies including lactulose and rifaximin used for the management of hepatic encephalopathy [8,19,20,21].

In conclusion, this study analyzed the most recent data available regarding CDI among patients with cirrhosis, using the NIS 2016-2017 to investigate clinical outcomes and healthcare utilization. Mortality outcomes associated with CDI have improved over the last decade among hospitalized patients with or without cirrhosis. Patients with cirrhosis continue to exhibit longer LOS and greater hospital costs. Prevention, early detection, advancements in treatment, and vigilant management of end-organ involvement, including AKI, are checkpoints in reducing mortality and optimizing healthcare utilization [8].