A biomarker signature to predict complete response to itacitinib and corticosteroids in acute graft-versus-host disease.

A broad proteomic analysis was conducted to identify and evaluate candidate biomarkers potentially predictive of response to treatment with an oral selective Janus kinase 1 (JAK1) inhibitor, itacitinib, in acute graft-versus-host disease (GVHD). Plasma samples from 25 participants (identification cohort; NCT02614612) were used to identify novel biomarkers that were tested in a validation cohort from a placebo-controlled, randomised trial (n = 210; NCT03139604). The identification cohort received corticosteroids plus 200 or 300 mg itacitinib once daily. The validation cohort received corticosteroids plus 200 mg itacitinib once daily or placebo. A broad proteomic analysis was conducted using a proximity extension assay. Baseline and longitudinal comparisons were performed with unpaired t-test and one-way analysis of variance used to evaluate biomarker level changes. Seven candidate biomarkers were identified. Monocyte-chemotactic protein (MCP)3, pro-calcitonin/calcitonin (ProCALCA/CALCA), together with a previously identified prognostic acute GVHD biomarker, regenerating islet-derived protein (REG)3A, stratified complete responders from non-responders (participants with progressive disease) to itacitinib, but not placebo, potentially representing predictive biomarkers of itacitinib in acute GVHD. ProCALCA/CALCA, suppressor of tumorigenicity (ST)2, and tumour necrosis factor receptor (TNFR)1 were significantly reduced over time by itacitinib in responders, potentially representing response-to-treatment biomarkers. Novel biomarkers have the potential to identify patients with acute GVHD that may respond to itacitinib plus corticosteroid treatment (NCT02614612; NCT03139604).

Modeling Skin Inflammation Using Human In Vitro Models.

Skin is made up of an epidermis and, dermis which serve as a barrier against physical and environmental threats. Keratinocytes make up greater than 95% of the epidermis and form different layers based on their level of differentiation. Millions of individuals suffer from skin diseases, which are characterized by significant barrier disruption and inflammation. Investigators previously relied on animal models to investigate inflammatory skin diseases; however, technological advances have enabled the use of physiologically human skin models to investigate the effects of inflammatory mediators on the structure and function of skin cells. In this article, we describe two protocols using keratinocytes to investigate tumor necrosis factor alpha (TNF-α) and interferon gamma (IFN-γ) driven skin inflammation as a surrogate for psoriasis, vitiligo, and other autoimmune skin diseases driven by these cytokines. © 2021 Wiley Periodicals LLC. Basic Protocol 1: Preparing a HaCaT keratinocyte culture Basic Protocol 2: 3-Dimensional organotypic skin cultures to assess TNF-α and IFN-γ driven skin inflammation.

Ruxolitinib for the treatment of steroid-refractory acute GVHD (REACH1): a multicenter, open-label phase 2 trial.

Patients who develop steroid-refractory acute graft-versus-host disease (aGVHD) after allogeneic hematopoietic cell transplantation have poor prognosis, highlighting an unmet therapeutic need. In this open-label phase 2 study (ClinicalTrials.gov identifier: NCT02953678), patients aged at least 12 years with grades II to IV steroid-refractory aGVHD were eligible to receive ruxolitinib orally, starting at 5 mg twice daily plus corticosteroids, until treatment failure, unacceptable toxicity, or death. The primary end point was overall response rate (ORR) at day 28; the key secondary end point was duration of response (DOR) at 6 months. As of 2 July 2018, 71 patients received at least 1 dose of ruxolitinib. Forty-eight of those patients (67.6%) had grade III/IV aGVHD at enrollment. At day 28, 39 patients (54.9%; 95% confidence interval, 42.7%-66.8%) had an overall response, including 19 (26.8%) with complete responses. Best ORR at any time was 73.2% (complete response, 56.3%). Responses were observed across skin (61.1%), upper (45.5%) and lower (46.0%) gastrointestinal tract, and liver (26.7%). Median DOR was 345 days. Overall survival estimate at 6 months was 51.0%. At day 28, 24 (55.8%) of 43 patients receiving ruxolitinib and corticosteroids had a 50% or greater corticosteroid dose reduction from baseline. The most common treatment-emergent adverse events were anemia (64.8%), thrombocytopenia (62.0%), hypokalemia (49.3%), neutropenia (47.9%), and peripheral edema (45.1%). Ruxolitinib produced durable responses and encouraging survival compared with historical data in patients with steroid-refractory aGVHD who otherwise have dismal outcomes. The safety profile was consistent with expectations for ruxolitinib and this patient population.

Bridging the Gap: Interdepartmental Quality Improvement and Patient Safety Curriculum Created by Hospital Leaders, Faculty, and Trainees.

BACKGROUND: The Accreditation Council for Graduate Medical Education Clinical Learning Environment Review recommends that quality improvement/patient safety (QI/PS) experts, program faculty, and trainees collectively develop QI/PS education. OBJECTIVE: Faculty, hospital leaders, and resident and fellow champions at the University of Chicago designed an interdepartmental curriculum to train postgraduate year 1 (PGY-1) residents on core QI/PS principles, measuring outcomes of knowledge, attitudes, and event reporting. METHODS: The curriculum consisted of 3 sessions: PS, quality assessment, and QI. Faculty and resident and fellow leaders taught foundational knowledge, and hospital leaders discussed institutional priorities. PGY-1 residents attended during protected conference times, and they completed in-class activities. Knowledge and attitudes were assessed using pretests and posttests; graduating residents (PGY-3-PGY-8) were controls. Event reporting was compared to a concurrent control group of nonparticipating PGY-1 residents. RESULTS: From 2015 to 2017, 140 interns in internal medicine (49%), pediatrics (33%), and surgery (13%) enrolled, with 112 (80%) participating and completing pretests and posttests. Overall, knowledge scores improved (44% versus 57%, P < .001), and 72% of residents demonstrated increased knowledge. Confidence comprehending quality dashboards increased (13% versus 49%, P < .001). PGY-1 posttest responses were similar to those of 252 graduate controls for accessibility of hospital leaders, filing event reports, and quality dashboards. PGY-1 residents in the QI/PS curriculum reported more patient safety events than PGY-1 residents not exposed to the curriculum (0.39 events per trainee versus 0.10, P < .001). CONCLUSIONS: An interdepartmental curriculum was acceptable to residents and feasible across 3 specialties, and it was associated with increased event reporting by participating PGY-1 residents.

No Exit: Identifying Avoidable Terminal Oncology Intensive Care Unit Hospitalizations.

PURPOSE: Terminal oncology intensive care unit (ICU) hospitalizations are associated with high costs and inferior quality of care. This study identifies and characterizes potentially avoidable terminal admissions of oncology patients to ICUs. METHODS: This was a retrospective case series of patients cared for in an academic medical center's ambulatory oncology practice who died in an ICU during July 1, 2012 to June 30, 2013. An oncologist, intensivist, and hospitalist reviewed each patient's electronic health record from 3 months preceding terminal hospitalization until death. The primary outcome was the proportion of terminal ICU hospitalizations identified as potentially avoidable by two or more reviewers. Univariate and multivariate analysis were performed to identify characteristics associated with avoidable terminal ICU hospitalizations. RESULTS: Seventy-two patients met inclusion criteria. The majority had solid tumor malignancies (71%), poor performance status (51%), and multiple encounters with the health care system. Despite high-intensity health care utilization, only 25% had documented advance directives. During a 4-day median ICU length of stay, 81% were intubated and 39% had cardiopulmonary resuscitation. Forty-seven percent of these hospitalizations were identified as potentially avoidable. Avoidable hospitalizations were associated with factors including: worse performance status before admission (median 2 v 1; P = .01), worse Charlson comorbidity score (median 8.5 v 7.0, P = .04), reason for hospitalization (P = .006), and number of prior hospitalizations (median 2 v 1; P = .05). CONCLUSION: Given the high frequency of avoidable terminal ICU hospitalizations, health care leaders should develop strategies to prospectively identify patients at high risk and formulate interventions to improve end-of-life care.

Prevalence and Predictive Value of Dyspnea Ratings in Hospitalized Patients: Pilot Studies.

BACKGROUND: Dyspnea (breathing discomfort) can be as powerfully aversive as pain, yet is not routinely assessed and documented in the clinical environment. Routine identification and documentation of dyspnea is the first step to improved symptom management and it may also identify patients at risk of negative clinical outcomes. OBJECTIVE: To estimate the prevalence of dyspnea and of dyspnea-associated risk among hospitalized patients. DESIGN: Two pilot prospective cohort studies. SETTING: Single academic medical center. PATIENTS: Consecutive patients admitted to four inpatient units: cardiology, hematology/oncology, medicine, and bariatric surgery. MEASUREMENTS: In Study 1, nurses documented current and recent patient-reported dyspnea at the time of the Initial Patient Assessment in 581 inpatients. In Study 2, nurses documented current dyspnea at least once every nursing shift in 367 patients. We describe the prevalence of burdensome dyspnea, and compare it to pain. We also compared dyspnea ratings with a composite of adverse outcomes: 1) receipt of care from the hospital's rapid response system, 2) transfer to the intensive care unit, or 3) death in hospital. We defined burdensome dyspnea as a rating of 4 or more on a 10-point scale. RESULTS: Prevalence of burdensome current dyspnea upon admission (Study 1) was 13% (77 of 581, 95% CI 11%-16%). Prevalence of burdensome dyspnea at some time during the hospitalization (Study 2) was 16% (57 of 367, 95% CI 12%-20%). Dyspnea was associated with higher odds of a negative outcome. CONCLUSIONS: In two pilot studies, we identified a significant symptom burden of dyspnea in hospitalized patients. Patients reporting dyspnea may benefit from a more careful focus on symptom management and may represent a population at greater risk for negative outcomes.

Estimating duration of central venous catheter at time of insertion: Clinician judgment and clinical predictors.

PURPOSE: The aim of this study was to investigate whether clinicians can estimate the length of time a central venous catheter (CVC) will remain in place and to identify variables that may predict CVC duration. MATERIALS AND METHODS: We conducted a prospective study of patients admitted to the intensive care unit over a 1-year period. Clinicians estimated the anticipated CVC duration at time of insertion. We collected demographics, medical history, type of intensive care unit, anatomical site of CVC placement, vital signs, laboratory values, Sequential Organ Failure Assessment score, mechanical ventilation, and use of vasopressors. Pearson correlation coefficient was used to assess the correlation between estimated and actual CVC time. We performed multivariable logistic regression to identify predictors of long duration (>5 days). RESULTS: We enrolled 200 patients; median age was 65 years (quartiles 52, 75); 91 (46%) were female; and mortality was 24%. Correlation between estimated and actual CVC time was low (r=0.26; r2=0.07; P<.001). Mechanical ventilation (odds ratio, 2.20; 95% confidence interval, 1.22-3.97; P=.009) at time of insertion and a medical history of cancer (odds ratio, 0.35; 95% confidence interval, 0.16-0.75; P=.007) were significantly associated with long duration. CONCLUSION: Our results suggest a low correlation between clinician prediction and actual CVC duration. We did not find any strong predictors of long CVC duration identifiable at the time of insertion.

Incidence and Prognostic Value of the Systemic Inflammatory Response Syndrome and Organ Dysfunctions in Ward Patients.

RATIONALE: Tools that screen inpatients for sepsis use the systemic inflammatory response syndrome (SIRS) criteria and organ dysfunctions, but most studies of these criteria were performed in intensive care unit or emergency room populations. OBJECTIVES: To determine the incidence and prognostic value of SIRS and organ dysfunctions in a multicenter dataset of hospitalized ward patients. METHODS: Hospitalized ward patients at five hospitals from November 2008 to January 2013 were included. SIRS and organ system dysfunctions were defined using 2001 International Consensus criteria. Patient characteristics and in-hospital mortality were compared among patients meeting two or more SIRS criteria and by the presence or absence of organ system dysfunction. MEASUREMENTS AND MAIN RESULTS: A total of 269,951 patients were included in the study, after excluding 48 patients with missing discharge status. Forty-seven percent (n = 125,841) of the included patients met two or more SIRS criteria at least once during their ward stay. On ward admission, 39,105 (14.5%) patients met two or more SIRS criteria, and patients presenting with SIRS had higher in-hospital mortality than those without SIRS (4.3% vs. 1.2%; P < 0.001). Fourteen percent of patients (n = 36,767) had at least one organ dysfunction at ward admission, and those presenting with organ dysfunction had increased mortality compared with those without organ dysfunction (5.3% vs. 1.1%; P < 0.001). CONCLUSIONS: Almost half of patients hospitalized on the wards developed SIRS at least once during their ward stay. Our findings suggest that screening ward patients using SIRS criteria for identifying those with sepsis would be impractical.

Reappraisal of routine oral care with chlorhexidine gluconate for patients receiving mechanical ventilation: systematic review and meta-analysis.

IMPORTANCE: Regular oral care with chlorhexidine gluconate is standard of care for patients receiving mechanical ventilation in most hospitals. This policy is predicated on meta-analyses suggesting decreased risk of ventilator-associated pneumonia, but these meta-analyses may be misleading because of lack of distinction between cardiac surgery and non-cardiac surgery studies, conflation of open-label vs double-blind investigations, and insufficient emphasis on patient-centered outcomes such as duration of mechanical ventilation, length of stay, and mortality. OBJECTIVE: To evaluate the impact of routine oral care with chlorhexidine on patient-centered outcomes in patients receiving mechanical ventilation. DATA SOURCES: PubMed, Embase, CINAHL, and Web of Science from inception until July 2013 without limits on date or language. STUDY SELECTION: Randomized clinical trials comparing chlorhexidine vs placebo in adults receiving mechanical ventilation. Of 171 unique citations, 16 studies including 3630 patients met inclusion criteria. DATA EXTRACTION AND SYNTHESIS: Eligible trials were independently identified, evaluated for risk of bias, and extracted by 2 investigators. Differences were resolved by consensus. We stratified studies into cardiac surgery vs non-cardiac surgery and open-label vs double-blind investigations. Eligible studies were pooled using random-effects meta-analysis. MAIN OUTCOMES AND MEASURES: Ventilator-associated pneumonia, mortality, duration of mechanical ventilation, intensive care unit and hospital length of stay, antibiotic prescribing. RESULTS: There were fewer lower respiratory tract infections in cardiac surgery patients randomized to chlorhexidine (relative risk [RR], 0.56 [95% CI, 0.41-0.77]) but no significant difference in ventilator-associated pneumonia risk in double-blind studies of non-cardiac surgery patients (RR, 0.88 [95% CI, 0.66-1.16]). There was no significant mortality difference between chlorhexidine and placebo in cardiac surgery studies (RR, 0.88 [95% CI, 0.25-2.14]) and nonsignificantly increased mortality in non-cardiac surgery studies (RR, 1.13 [95% CI, 0.99-1.29]). There were no significant differences in mean duration of mechanical ventilation or intensive care length of stay. Data on hospital length of stay and antibiotic prescribing were limited. CONCLUSIONS AND RELEVANCE: Routine oral care with chlorhexidine prevents nosocomial pneumonia in cardiac surgery patients but may not decrease ventilator-associated pneumonia risk in non-cardiac surgery patients. Chlorhexidine use does not affect patient-centered outcomes in either population. Policies encouraging routine oral care with chlorhexidine for non-cardiac surgery patients merit reevaluation.

Miscount incidents: a novel approach to exploring risk factors for unintentionally retained surgical items.

BACKGROUND: An estimated 1,500 operations result in retained surgical items (RSIs) each year in the United States, resulting in substantial morbidity. The rarity of these events makes studying them difficult, but miscount incidents may provide a window into understanding risk factors for RSIs. METHODS: A cohort study of all consecutive operative cases during a 12-month period was conducted at a large academic medical center to identify risk factors for surgical miscounts. A multidisciplinary electronic miscount reconciliation checklist (necessitating both surgeon and nurse input) was introduced into the internally developed electronic Perioperative Information Management System to build a predictive model for RSI cases. RESULTS: Among 23,955 operations, 84 resulted in miscount incidents (0.35% [95% confidence interval: 0.28% to 0.43%]). Increased case duration was strongly associated with increased risk of a miscount in unadjusted analyses (p < .0001). In the nested case-control analysis, both the case duration and the number of providers present were independently associated with a more than doubling of the odds of a miscount, even after adjustment for one another, the elective/urgent/emergent status of a case, and personnel changes occurring during the case. CONCLUSIONS: The finding that both the length of the case and the number of providers involved in the case were independent risk factors for miscount incidents may offer insight into risk-targeted strategies to prevent RSIs, such as postoperative imaging, bar-coded surgical items, and radiofrequency technology. Miscounts trigger use of the Incorrect Count Safety Checklist, which can be used to determine whether a count completed at the procedure's conclusion is consistent across disciplines (circulating nurses, scrub persons, surgeons).

Lactate clearance as a predictor of mortality in trauma patients.

BACKGROUND: Initial serum lactate has been associated with mortality in trauma patients. It is not known if lactate clearance is predictive of death in a broad cohort of trauma patients. METHODS: We enrolled 4,742 trauma patients who had an initial lactate measured during a 10-year period. Patients were identified via the trauma registry. Lactate clearance was calculated at 6 hours. Multivariable logistic regression was used to identify the independent contribution of both initial lactate and lactate clearance with mortality, after adjustment for severity of injury. RESULTS: Initial lactate level was strongly correlated with mortality: when lactate was less than 2.5 mg/dL, 5.4% (95% confidence interval [CI], 4.5-6.2%) of patients died; with lactate 2.5 mg/dL to 4.0 mg/dL, mortality was 6.4% (95% CI, 5.1-7.8%); with lactate 4.0 mg/dL or greater, mortality was 18.8% (95% CI, 15.7-21.9%). After adjustment for age, Injury Severity Score (ISS), Glasgow Coma Scale (GCS) score, heart rate, and blood pressure, initial lactate remained independently associated with increased mortality, with adjusted odds ratios of 1.0, 1.5 (95% CI, 1.1-2.0) and 3.8 (95% CI, 2.8-5.3), for lactate less than 2.5 mg/dL, 2.5 mg/dL to 4.0 mg/dL, and 4.0 mg/dL or greater, respectively. Among patients with an initially elevated lactate (≥4.0 mg/dL), lower lactate clearance at 6 hours strongly and independently predicted an increased risk of death. For lactate clearances of 60% or greater, 30% to 59%, and less than 30%, the adjusted odds ratio for death were 1.0, 3.5 (95% CI 1.2-10.4), and 4.3 (95% CI, 1.5-12.6), respectively. CONCLUSION: Both initial lactate and lactate clearance at 6 hours independently predict death in trauma patients. LEVEL OF EVIDENCE: Prognostic study, level III.

Proton-pump inhibitor use is associated with low serum magnesium concentrations.

Although case reports link proton-pump inhibitor (PPI) use and hypomagnesemia, no large-scale studies have been conducted. Here we examined the serum magnesium concentration and the likelihood of hypomagnesemia (<1.6 mg/dl) with a history of PPI or histamine-2 receptor antagonist used to reduce gastric acid, or use of neither among 11,490 consecutive adult admissions to an intensive care unit of a tertiary medical center. Of these, 2632 patients reported PPI use prior to admission, while 657 patients were using a histamine-2 receptor antagonist. PPI use was associated with 0.012 mg/dl lower adjusted serum magnesium concentration compared to users of no acid-suppressive medications, but this effect was restricted to those patients taking diuretics. Among the 3286 patients concurrently on diuretics, PPI use was associated with a significant increase of hypomagnesemia (odds ratio 1.54) and 0.028 mg/dl lower serum magnesium concentration. Among those not using diuretics, PPI use was not associated with serum magnesium levels. Histamine-2 receptor antagonist use was not significantly associated with magnesium concentration without or with diuretic use. The use of PPI was not associated with serum phosphate concentration regardless of diuretic use. Thus, we verify case reports of the association between PPI use and hypomagnesemia in those concurrently taking diuretics. Hence, serum magnesium concentrations should be followed in susceptible individuals on chronic PPI therapy.

The signal transducer and activator of transcription 6 gene (STAT6) increases the propensity of patients with atopic dermatitis toward disseminated viral skin infections.

BACKGROUND: Atopic dermatitis (AD) is a chronic inflammatory skin disease associated with increased susceptibility to recurrent skin infections. OBJECTIVE: We sought to determine why a subset of patients with AD have an increased risk of disseminated viral skin infections. METHODS: Human subjects with AD with a history of eczema herpeticum (EH) and various control groups were enrolled. Vaccinia virus (VV) expression was measured by means of PCR and immunofluorescent staining in skin biopsy specimens from each study group after incubation with VV. Transgenic mice with a constitutively active signal transducer and activator of transcription 6 gene (STAT6) were characterized for response to VV skin inoculation. Genotyping for 10 STAT6 single nucleotide polymorphisms (SNPs) was performed in a white patient sample (n = 444). RESULTS: VV gene and protein expression were significantly increased in the skin of patients with EH compared with other subject groups after incubation with VV in vitro. Antibody neutralization of IL-4 and IL-13 resulted in lower VV replication in patients with a history of EH. Mice that expressed a constitutively active STAT6 gene compared with wild-type mice had increased mortality and satellite lesion formation after VV skin inoculation. Significant associations were observed between STAT6 SNPs and EH (rs3024975, rs841718, rs167769, and rs703817) and IFN-γ production. The strongest association was observed for a 2-SNP haplotype (patients with AD with a history of EH vs patients with AD without a history of EH, 24.9% vs 9.2%; P = 5.17 × 10(-6)). CONCLUSION: The STAT6 gene increases viral replication in the skin of patients with AD with a history of EH. Further genetic association studies and functional investigations are warranted.

Diabetes is not associated with increased mortality in emergency department patients with sepsis.

STUDY OBJECTIVE: Despite its high prevalence, the influence of diabetes on outcomes of emergency department (ED) patients with sepsis remains undefined. Our aim is to investigate the association of diabetes and initial glucose level with mortality in patients with suspected infection from the ED. METHODS: Three independent, observational, prospective cohorts from 2 large US tertiary care centers were studied. We included patients admitted to the hospital from the ED with suspected infection. We investigated the association of diabetes and inhospital mortality within each cohort separately and then overall with logistic regression and generalized estimating equations adjusted for age, sex, disease severity, and sepsis syndrome. We also tested for an interaction between diabetes and hyperglycemia/hypoglycemia. RESULTS: A total of 7,754 patients were included. The mortality rate was 4.3% (95% confidence interval [CI] 3.9% to 4.8%) and similar in diabetic and nondiabetic patients (4.1% versus 4.4%; absolute risk difference 0.4%; 95% CI -0.7% to 1.4%). There was no significant association between diabetes and mortality in adjusted analysis (odds ratio [OR] overall 0.85; 95% CI 0.71 to 1.01). Diabetes significantly modified the effect of hyperglycemia and hypoglycemia with mortality; initial glucose levels greater than 200 mg/dL were associated with higher mortality in nondiabetic patients (OR 2.1; 95% CI 1.4 to 3.0) but not in diabetic patients (OR 1.0; 95% CI 0.2 to 4.7), whereas glucose levels less than 100 mg/dL were associated with higher mortality mainly in the diabetic population (OR 2.3; 95% CI 1.6 to 3.3) and to a lesser extent in nondiabetic patients (OR 1.1; 95% CI 1.03 to 1.14). CONCLUSION: We found no evidence for a harmful association of diabetes and mortality in patients across different sepsis severities. High initial glucose levels were associated with adverse outcomes in the nondiabetic population only. Further investigation is warranted to determine the mechanism for these effects.

TNF-α downregulates filaggrin and loricrin through c-Jun N-terminal kinase: role for TNF-α antagonists to improve skin barrier.

Filaggrin (FLG), loricrin (LOR), and involucrin are important epidermal barrier proteins. As psoriasis is characterized by overexpression of tumor necrosis factor-α (TNF-α) and impaired skin barrier, we investigated the expression of skin barrier proteins in psoriasis patients and whether their expression was modulated by TNF-α. The expression of FLG and LOR was found to be decreased in lesional and non-lesional skin of psoriasis patients. A correlation was found between the expression of TNF-α and epidermal barrier proteins in psoriasis. TNF-α was found to modulate the expression of FLG and LOR via a c-Jun N-terminal kinase-dependent pathway. Importantly, we report that clinical treatment of psoriasis patients with a TNF-α antagonist results in significant enhancement of epidermal barrier protein expression. Our current study suggests that TNF inhibits barrier protein expression, and TNF-α antagonists may contribute to clinical improvement in patients with psoriasis by improving barrier protein expression.

Proof of principle: the predisposition, infection, response, organ failure sepsis staging system.

OBJECTIVE: In an effort to improve upon the traditional sepsis syndrome definitions, the predisposition, infection, response, organ dysfunction (PIRO) model was proposed to better characterize sepsis. The objective of this investigation was to derive and validate a sepsis staging system based on the PIRO concept that risk stratifies patients with suspected infection. DESIGN: Three independent, observational, prospective cohorts were studied. A derivation cohort (n = 2,132) was used to create the PIRO score, identifying independent predictors of mortality. Individual values were assigned to create the weighted integer score for each parameter, yielding the final PIRO score. The prognostic performance was then investigated in independent internal (n = 4,618) and external (n = 1,004) validation cohorts. SETTING: Two large U.S. tertiary care centers. PATIENTS: Patients admitted to the hospital from the emergency department with suspected infection. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The PIRO staging system was created by combining components of predisposition (age, chronic obstructive pulmonary disease, liver disease, nursing home residency, and malignancy with and without metastasis), infection (pneumonia and cellulitis), response (tachypnea, bandemia, and tachycardia), and organ dysfunction (renal, respiratory, cardiac, metabolic, and hematologic). The derived PIRO score showed stepwise increase in mortality with increasing points and high discriminatory ability with an area under the curve of 0.90 in the derivation cohort, 0.86 in internal validation, and 0.83 in external validation. CONCLUSIONS: This study provides evidence-based support for the PIRO approach to sepsis staging. Future efforts may utilize this approach with additional parameters (e.g., genetics and novel biochemical markers) to develop further the PIRO stratification system.