Immune Profiling To Predict Outcome of Clostridioides difficile Infection.

There is a pressing need for biomarker-based models to predict mortality from and recurrence of Clostridioides difficile infection (CDI). Risk stratification would enable targeted interventions such as fecal microbiota transplant, antitoxin antibodies, and colectomy for those at highest risk. Because severity of CDI is associated with the immune response, we immune profiled patients at the time of diagnosis. The levels of 17 cytokines in plasma were measured in 341 CDI inpatients. The primary outcome of interest was 90-day mortality. Increased tumor necrosis factor alpha (TNF-α), interleukin 6 (IL-6), C-C motif chemokine ligand 5 (CCL-5), suppression of tumorigenicity 2 receptor (sST-2), IL-8, and IL-15 predicted mortality by univariate analysis. After adjusting for demographics and clinical characteristics, the mortality risk (as indicated by the hazard ratio [HR]) was higher for patients in the top 25th percentile for TNF-α (HR = 8.35, P = 0.005) and IL-8 (HR = 4.45, P = 0.01) and lower for CCL-5 (HR = 0.18, P ≤ 0.008). A logistic regression risk prediction model was developed and had an area under the receiver operating characteristic curve (AUC) of 0.91 for 90-day mortality and 0.77 for 90-day recurrence. While limited by being single site and retrospective, our work resulted in a model with a substantially greater predictive ability than white blood cell count. In conclusion, immune profiling demonstrated differences between patients in their response to CDI, offering the promise for precision medicine individualized treatment.IMPORTANCEClostridioides difficile infection is the most common health care-associated infection in the United States with more than 20% patients experiencing symptomatic recurrence. The complex nature of host-bacterium interactions makes it difficult to predict the course of the disease based solely on clinical parameters. In the present study, we built a robust prediction model using representative plasma biomarkers and clinical parameters for 90-day all-cause mortality. Risk prediction based on immune biomarkers and clinical variables may contribute to treatment selection for patients as well as provide insight into the role of immune system in C. difficile pathogenesis.

Colitis-Induced Th17 Cells Increase the Risk for Severe Subsequent Clostridium difficile Infection.

Clostridium difficile infection (CDI) is the number one hospital-acquired infection in the United States. CDI is more common and severe in inflammatory bowel disease patients. Here, we studied the mechanism by which prior colitis exacerbates CDI. Mice were given dextran sulfate sodium (DSS) colitis, recovered for 2 weeks, and then were infected with C. difficile. Mortality and CDI severity were increased in DSS-treated mice compared to controls. Severe CDI is dependent on CD4+ T cells, which persist after colitis-associated inflammation subsides. Adoptive transfer of Th17 cells to naive mice is sufficient to increase CDI-associated mortality through elevated IL-17 production. Finally, in humans, the Th17 cytokines IL-6 and IL-23 associate with severe CDI, and patients with high serum IL-6 are 7.6 times more likely to die post infection. These findings establish a central role for Th17 cells in CDI pathogenesis following colitis and identify them as a potential target for preventing severe disease.

Development and Validation of a Prediction Model for Mortality and Adverse Outcomes Among Patients With Peripheral Eosinopenia on Admission for Clostridium difficile Infection.

Importance: Recent evidence from an animal model suggests that peripheral loss of eosinophils in Clostridium difficile infection (CDI) is associated with severe disease. The ability to identify high-risk patients with CDI as early as the time of admission could improve outcomes by guiding management decisions. Objective: To construct a model using clinical indices readily available at the time of hospital admission, including peripheral eosinophil counts, to predict inpatient mortality in patients with CDI. Design, Setting, and Participants: In a cohort study, a total of 2065 patients admitted for CDI through the emergency department of 2 tertiary referral centers from January 1, 2005, to December 31, 2015, formed a training and a validation cohort. The sample was stratified by admission eosinophil count (0.0 cells/µL or >0.0 cells/µL), and multivariable logistic regression was used to construct a predictive model for inpatient mortality as well as other disease-related outcomes. Main Outcomes and Measures: Inpatient mortality was the primary outcome. Secondary outcomes included the need for a monitored care setting, need for vasopressors, and rates of inpatient colectomy. Results: Of the 2065 patients in the study, 1092 (52.9%) were women and patients had a mean (SD) age of 63.4 (18.4) years. Those with an undetectable eosinophil count at admission had increased in-hospital mortality in both the training (odds ratio [OR], 2.01; 95% CI, 1.08-3.73; P = .03) and validation (OR, 2.26; 95% CI, 1.33-3.83; P = .002) cohorts in both univariable and multivariable analysis. Undetectable eosinophil counts were also associated with indicators of severe sepsis, such as admission to monitored care settings (OR, 1.40; 95% CI, 1.06-1.86), the need for vasopressors (OR, 2.08; 95% CI, 1.32-3.28), and emergency total colectomy (OR, 2.56; 95% CI, 1.12-5.87). Other significant predictors of mortality at admission included increasing comorbidity burden (for each 1-unit increase: OR, 1.13; 95% CI, 1.05-1.22) and lower systolic blood pressures (for each 1-mm Hg increase: OR, 0.99; 95% CI, 0.98-1.00). In a subgroup analysis of patients presenting without initial tachycardia or hypotension, only patients with undetectable admission eosinophil counts, but not those with an elevated white blood cell count, had significantly increased odds of inpatient mortality (OR, 5.76; 95% CI, 1.99-16.64). Conclusions and Relevance: This study describes a simple, widely available, inexpensive model predicting CDI severity and mortality to identify at-risk patients at the time of admission.

Dialysis Requirement and Long-Term Major Adverse Cardiovascular Events in Patients with Chronic Kidney Disease and Superimposed Acute Kidney Injury.

BACKGROUND: Chronic kidney disease (CKD) patients who experience superimposed acute kidney injury (AKI) have been shown to be at higher risk of long-term sequelae of AKI when compared to those who do not experience AKI. It remains unclear whether the need for temporary dialysis intervention following superimposed AKI in patients with CKD has any effect on the long-term major adverse cardiovascular events (MACE). This study examines the relationship between temporary dialysis therapy following AKI and long-term major cardiovascular events in patients with background CKD. METHODS: The study population consists of adults who developed AKI while on admission at the University of Virginia Medical Center between January 1, 2002 and December 31, 2012, and who had preadmission estimated glomerular filtration rate (eGFR) between 20 and 60 mL/min/1.73 m2 and survived beyond 30 days of AKI. Demographic and baseline clinical variables were used to generate propensity score. Survivors who had temporary dialysis were matched to those managed conservatively according to the propensity score in a ratio of 1:3. RESULTS: Overall, 6,634 (n = 381 and 6,253 in the temporary dialysis-requiring AKI and non-dialysis AKI groups respectively) met entry criteria for the full cohort. Of these, 381 (5.7%) received temporary dialysis. There were 3,147 (47.4% of all patients) MACE events during the study period. The crude incidence for MACE after 30 days of AKI was similar in both dialyzed and non-dialyzed patients. After the propensity score matching, the adjusted hazard ratio for MACE in dialyzed versus non dialyzed patients was 1.162 (95% CI 0.978-1.381). CONCLUSIONS: Treatment of AKI with temporary dialysis in hospitalized patients with baseline eGFR between 20 and 60 mL/min/1.73 m2 was not associated with an increased risk for subsequent admission for MACE. If confirmed by prospective studies, clinicians may not need to worry that the dialysis procedure may contribute to additional risk for long-term MACE in CKD patients with superimposed AKI.

Major Depression and Long-Term Outcomes of Acute Kidney Injury.

BACKGROUND: The prevalence of depression and its relationship to poor outcomes in chronic kidney disease are established facts. Such prognostic impact in acute kidney injury (AKI) is not known. This study determines the prognostic implication of a diagnosis of depression on renal recovery and major adverse cardiovascular events (MACE), a new diagnosis of myocardial infarction, cerebrovascular disease (CVD, stroke or transient ischemic attack) or congestive heart failure (CHF) after hospitalization with AKI. METHODS: The study population comprises adults admitted to the University of Virginia Medical Center between January 1, 2002 and December 31, 2012 who suffered AKI during admission. Long-term outcomes, MACE and all-cause mortality, were compared between 2 groups; patients with preexisting diagnosis of major depression and those without. Risk adjusted multivariable Cox proportional hazards regression examined the association between major depression and these outcomes. RESULTS: Patients with AKI numbering 11,425 survived beyond 90 days and had data available. Of these patients, 2,519 (22%) were majorly affected by depression; more often, younger patients, females, African Americans, and those with more comorbid conditions, especially CHF, CVD, diabetes, peptic ulcer disease, chronic pulmonary disease and liver disease were found to be affected with depression. Crude hazard ratio for MACE was 1.245, 95% CI 1.150-1.348 and for all-cause mortality 1.186, 95% CI 1.091-1.290; p < 0.001, that is, the cohort with major depression had a long-term risk for MACE and all-cause mortality increased by 24 and 18%, respectively. CONCLUSION: Patients who develop AKI in hospital and have preexisting major depression are at greater long-term risk of MACE and all-cause mortality.

Dialysis requirement, long-term major adverse cardiovascular events (MACE) and all-cause mortality in hospital acquired acute kidney injury (AKI): a propensity-matched cohort study.

BACKGROUND: Dialysis-requiring acute kidney injury (D-AKI) is common in hospitalized patients. Many patients survive the immediate post AKI period, thus at risk of suffering long-term sequelae of AKI. Prior studies examining long term outcomes lack non-dialyzed AKI control groups. Without non-dialyzed AKI control group, these studies cannot provide relevant information on long-term risks or benefits associated with dialysis intervention following AKI. METHODS: The study cohort comprises of adults admitted to the University of Virginia Medical Center between January 1, 2002 and December 31, 2012 with baseline eGFR ≥60 ml/min per 1.73 m2, who developed AKI during hospitalization and survived beyond 30 days of the AKI event. Follow up was done until MACE, death or through Dec 31, 2013 (n = 11,779). AKI was defined according to KDIGO definition. MACE was defined as subsequent admission for Myocardial Infarction (MI), cerebrovascular disease (CVD) and heart failure using ICD 9-CM codes. The date of MACE was defined as the date of the first qualifying event. Demographic and premorbid clinical variables were used to generate propensity score. Patients who had temporary dialysis were matched with those managed conservatively according to propensity score in a ratio of 1:3. RESULTS: After the propensity score match, the adjusted hazard ratio for MACE, all-cause mortality and composite end point "all-cause mortality or MACE" in dialyzed versus non dialyzed patients were 1.081 (95 % CI 0.848-1.378), 1.107 (95 % CI 0.869-1.410) and 1.107 (95 % CI 0.880-1.307), respectively. CONCLUSION: Management of AKI with temporary dialysis in hospitalized patients with baseline eGFR of ≥60 ml/min per 1.73 m2 was NOT associated with an increased risk for subsequent admission for MACE or all-cause mortality. Clinicians may not need to worry that the dialysis procedure itself may confer additional risk for long-term MACE and all-cause mortality in AKI patients with normal pre-hospitalization GFR.

Acute kidney injury (AKI) outcome, a predictor of long-term major adverse cardiovascular events (MACE).

BACKGROUND AND OBJECTIVES: The incidence of acute kidney injury (AKI) in hospitalized patients is increasing. Many of these patients survive the immediate post-AKI period and may be prone to developing long-term complications of AKI. This study aimed to determine whether complete recovery following an episode of AKI is associated with a lower risk of long-term major adverse cardiovascular events (MACE). DESIGN: Retrospective cohort study. SETTING AND PARTICIPANTS: Adults admitted to the University of Virginia Medical Center between January 1, 2002 and December 31, 2012 who developed hospital-acquired AKI. PREDICTOR: AKI was defined as an increase in serum creatinine (SCr) by ≥ 0.3 mg/dL from the baseline and or requirement for acute dialysis during index hospitalization. Complete recovery was defined as a return of SCr to less than 1.25 times the baseline value and not dialysis dependent. Outcome and measurement: MACE was defined as subsequent admission for myocardial infarction, stroke or transient ischemic attach and heart failure using ICD- 9-CM codes. RESULTS: Overall, 11,538 patients survived beyond 90 days of AKI and had data available for analysis. Of the 9,673 survivors of AKI in whom recovery could be assessed, 7170 (74.12%) had complete renal recovery. MACE occurred in 27.28% of our study population over a median follow-up period of 399 days. 28.19% of patients who completely recovered renal function developed MACE, while only 32.48% did in those who did not recover completely. Patients who had complete recovery had a lower risk of long-term MACE when compared with those without complete recovery (adjusted hazard ratio 95% confidence interval (CI): 0.774 (0.713, 0.842)). LIMITATION: Measurement of albuminuria was not available. CONCLUSION: Complete renal recovery after an episode of AKI in patients with normal baseline kidney function is associated with a lower risk of long-term MACE when compared with those who did not fully recover.

Role of leptin-mediated colonic inflammation in defense against Clostridium difficile colitis.

The role of leptin in the mucosal immune response to Clostridium difficile colitis, a leading cause of nosocomial infection, was studied in humans and in a murine model. Previously, a mutation in the receptor for leptin (LEPR) was shown to be associated with susceptibility to infectious colitis and liver abscess due to Entamoeba histolytica as well as to bacterial peritonitis. Here we discovered that European Americans homozygous for the same LEPR Q223R mutation (rs1137101), known to result in decreased STAT3 signaling, were at increased risk of C. difficile infection (odds ratio, 3.03; P = 0.015). The mechanism of increased susceptibility was studied in a murine model. Mice lacking a functional leptin receptor (db/db) had decreased clearance of C. difficile from the gut lumen and diminished inflammation. Mutation of tyrosine 1138 in the intracellular domain of LepRb that mediates signaling through the STAT3/SOCS3 pathway also resulted in decreased mucosal chemokine and cell recruitment. Collectively, these data support a protective mucosal immune function for leptin in C. difficile colitis partially mediated by a leptin-STAT3 inflammatory pathway that is defective in the LEPR Q223R mutation. Identification of the role of leptin in protection from C. difficile offers the potential for host-directed therapy and demonstrates a connection between metabolism and immunity.

Mycobacterial infections in a large Virginia hospital, 2001-2009.

BACKGROUND: In areas where both tuberculosis (TB) and nontuberculous mycobacteria (NTM) are prevalent, descriptive studies of the clinical features of individual mycobacteria are needed to inform clinical triage. METHODS: We queried the University of Virginia Clinical Data Repository for all mycobacterial infections from 2001-2009. RESULTS: Of 494 mycobacterial infections in 467 patients there were 22 species. Patients with pulmonary Tb were more likely to be reported as immigrants (p < 0.001) and less likely to have a predisposing risk factor for NTM (pre-existing lung disease or host predisposition; p = 0.002). Review of chest CT scans revealed that TB infection was more likely to exhibit cavities and pleural effusion than NTM infection (p < 0.05). Among NTM infections M. kansasii, M. xenopi, and M. fortuitum were more likely than MAC to have cavities. There were at least 83 patients that met criteria for NTM lung disease and these were caused by 9 species. M. abscessus infection was associated with cystic fibrosis and M. xenopi infection was associated with male gender. CONCLUSIONS: In our center mycobacterial infections were common and of diverse species. Immigrant status, cavities, and effusion were associated with TB vs. NTM.

Improving quality measurement using multiple data sources.

We calculated a sample of AHRQ Quality and Patient Safety Indicators for UVa hospitalized patients over a 3 year period using diagnoses and procedure codes from two different billing systems. Significant differences in results were observed suggesting that quality indicators calculated from hospital billing sources alone may be understated.